Treatment of multiple sclerosis: beyond the NICE guidelines

Abstract

Multiple sclerosis (MS) is a common, disabling neurological condition whose pathogenesis is not clearly understood. Although current treatment recommendations assume an immunopathogenic disease mechanism, MS may not be an autoimmune disorder. Long-term immunological therapy for MS is in our view an untested approach, guided by uncritical acceptance of data from drug trials. We do not believe that there is convincing evidence that any of these immune-based treatments prevents long-term disease progression, or has much effect on common disabilities such as fatigue, pain, depression and cognitive impairment. The recent recommendations of the National Institute of Clinical Excellence did not address important issues regarding disease modification, management of paroxysmal symptoms and the likely therapeutic candidates for future treatment trials. We discuss treatment options for MS beyond the NICE guidelines.

Introduction

Multiple sclerosis (MS) is a chronic neurological disorder that is a common cause of disability in young adults. Pathologically, the disease is characterized by multi-focal demyelination, neurodegeneration and astroglial proliferation,¹ although the cause and exact pathogenesis remain unknown. The idea that it is an inflammatory, autoimmune disease mediated by specific T-cell sensitization against putative myelin antigens of the central nervous system is unproven;^1,2 despite extensive research, no specific immunological marker has been identified. Acute demyelinating lesions evolve in the virtual absence of lymphocytes,³ and inflammatory infiltrates are absent in at least a third of all demyelinating plaques.¹

We have recently proposed that MS is not an autoimmune disease, but a metabolically determined neurodegenerative disorder with a genetic influence.² Neurodegeneration in the pathological process of MS is an early, constant feature, and runs a progressive course independent of demyelination. Histopathological and neuroradiological studies show that grey matter involvement is present early in the disease, and is extensive throughout the brain. Indeed, the number of deep grey-matter lesions per gram wet weight is higher than that of any other brain structure in MS.⁴ While axonal transection may be degenerative, inflammatory or both, brain and spinal cord atrophy is the direct result of neurodegeneration. Progressive loss of brain volume can be identified in clinically isolated demyelinating syndromes before further evolution into definite MS.⁵ Neurodegeneration and progressive loss of brain volume in MS correlate poorly with demyelination, traditionally considered to be the hallmark of inflammatory process. Long-term disability in patients with MS, therefore, is a direct result of progressive neurodegeneration.

Currently advocated disease-modifying treatments in MS are based on the assumption that the primary pathology of the disease is autoimmune and inflammatory, with an animal model of experimental allergic encephalomyelitis (EAE) being used to develop and test treatments. However, EAE is clinically and pathologically sufficiently distinct from MS. It mirrors acute disseminated encephalomyelitis in humans, rather than MS, and does not reflect the progressive neurodegenerative process that is integral to the disease pathology. It is therefore unsurprising that immune-based approaches effective in EAE have failed to modify the chronic progressive disability that is typical of MS. There are also important concerns regarding cost-effectiveness, long- and short-term serious adverse events, and uncertainty about the optimal duration of therapy with such immune-based disease-modifying treatments. More fundamentally, these treatments have not been adequately evaluated against neuroprotection and prevention of progressive brain and spinal cord atrophy, and yet continue to be widely advocated for long-term use. This, in our opinion, represents an example of collective failure in evaluating treatments whose use in clinical practice is driven by the pharmaceutical industry.

An important lesson from the natural history of MS is that relapse rates are not related to long-term disability. A biological dissociation between these two events appears early in the clinical course,⁶ and consequently, prevention of relapses is not translated into prevention of life-long disability. Current enthusiasm driving the use of beta-interferon, glatiramer and mitoxantrone in MS is guided by uncritical assumptions of treatment efficacy. However, MS patients need to be treated for an average of 3 years to prevent only one relapse, while receiving beta-interferon and glatiramer, drugs of unconvincing efficacy.^7,8 There is not enough evidence that mitoxantrone, a potent cytotoxic anti-cancer therapy, is either safe or effective.⁹ Few physicians are prepared to look beyond autoimmunity. We believe that the practice of medicine is meant to offer greatest benefit to most sufferers, and thus it is important to know how patients with MS may be helped, beyond the treatment currently offered.

Disease modification in MS and the NICE guidelines

Recently, the National Institute of Clinical Excellence (NICE) published the much-awaited clinical guidelines for the management of MS.¹⁰ Due emphasis was placed on specialized, seamless and responsive service, rapid diagnosis, and sensitive assessment regarding ‘hidden’ problems such as fatigue, depression, cognitive dysfunction, impaired sexual function or reduced bladder control. Surprisingly, the guidelines chose not to review the existing mandate for the current disease-modifying drugs, despite evidence questioning the efficacy of beta-interferon,⁷ the most widely prescribed disease-modifying treatment. The guidelines also did not attempt to provide answers for those patients who do not qualify for, or who choose not to accept, such treatments. For example, a 16-year-old patient with newly diagnosed MS is likely to be disappointed at the lack of advice for younger sufferers. If a MS parent is concerned about the risk of the disease affecting his or her children later in life,¹¹ the guidelines provide little information and no hope for disease modification.

From the point of view of ‘evidence-based medicine’, the NICE guidelines for specific MS treatments recommend treatments under ‘specific circumstances’ for which evidence is extremely weak (Table 1). The advice is based on the assumption that ‘demyelination has an inflammatory component and therefore most treatments target the immune system’. The guidelines propose that such treatments may be used ‘after full discussion and consideration of all the risks, with formal evaluation, preferably in a randomised or other prospective study; and by an expert in the use of these medicines in MS with close monitoring of adverse events’.¹⁰

In our view, this is poor advice, since data from the randomized controlled trials of such treatments clearly suggest that the benefit is, at best, very modest or equivocal. It is also difficult to understand why treatments that lack robust or long-term evidence of benefit would be suitable for clinical use, and worse, recommended for open prospective study at a national level. We are also surprised that the guidelines overlooked the more obvious evidence that treatments that target the immune system have not been effective in MS—and there is a long list of such therapies.² Disabilities in MS are due to neurodegeneration, so it makes little sense to target the immune system unless there is evidence that it works. In making these recommendations, the guidelines do not provide criteria for choosing individual treatment options (corticosteroids, immunoglobulin or plasma exchange?) and the optimal duration of therapy (3 months, 1 year or life long?), indicating uncertainty and inconsistency of approach. Why should a patient with MS receive intravenous immunoglobulin, an expensive treatment with limited availability, when this treatment has no effect on progressive disability?¹² In our previous example, when the 16-year-old patient with progressive MS turns 18, how comfortable would a neurologist feel in recommending mitoxantrone, an anti-cancer drug with restricted use, and advising the sufferer to accept the risks of cardiotoxicity or leukaemia, not to mention infertility and mutagenesis in females, when there is no evidence that it can protect against neurodegeneration? The classification of tuberculin in with acyclovir as ‘antiviral’ in the NICE guidelines,¹⁰ is also confusing.

Treatment strategies in multiple sclerosis

The primary target in MS therapy is prevention of disability due to progressive neurodegeneration. The secondary aim is to improve quality of life, which is significantly influenced by symptoms of chronic fatigue, pain, depression and emotional distress, and the often unpredictable fluctuations in the severity of some of these symptoms.

Prevention of progressive disability

The concordance rate of MS in identical twins is only about 30%,¹³ but there appears to be a familial and a specific, maternal contribution to the disease risk.¹⁴ Epidemiological studies show an increased prevalence of the disease in the northern latitudes, and this environmental risk is dependent on the age of migration. MS is rare in the tropics, and a direct relationship between sunlight exposure and MS has been confirmed in a number of epidemiological studies since 1960.¹⁵ Recently, a case-control study found higher sun exposure during childhood and early adolescence to be associated with a reduced risk of MS.¹⁶ These and other epidemiological studies support the view that sufficient endogenous vitamin D may favourably modify the life-time risk of MS.¹⁷ The increased physiological needs during pregnancy and more indoor activity (less outdoor exposure to sunlight) are additional risk factors for vitamin D deficiency in women living in high northern latitudes where winter solar radiation is insufficient for vitamin D synthesis. Given that the maternal contribution to the risk of her offspring developing MS may be uterine or perinatal,¹⁸ there is a strong case for routine vitamin D supplementation in pregnancy, particularly in affected women in areas of high disease prevalence.¹⁷ In a prospective, longitudinal follow-up study in over 90 000 women, vitamin D supplement (400 U/day) reduced the incidence of MS by 40%.¹⁹ Vitamin D supplementation in susceptible patients with monosymptomatic demyelination or in those with an early relapsing-remitting MS is an option that deserves consideration.²⁰ In high prevalence areas of MS, vitamin D levels should be measured in patients presenting with demyelinating symptoms and vitamin D supplement (400 U/day) should be recommended in all cases where the levels are borderline or low.

Smoking is considered to be a risk factor for MS,^21,22 and patients who smoke must be actively persuaded to quit smoking and offered smoking cessation therapy at the time of their diagnosis, not least because of its other health risks. Vascular risk factors in MS patients should be identified early and treated effectively. Statins may have a role in MS, and high-dose simvastatin had short-term benefits in an open study of relapsing-remitting MS.²³ Preventive use of statins in patients with MS might also protect against vascular risks that are increased due to reduced physical activity and sedentary lifestyle.

The NICE guidelines recommend that MS patients should be advised to take high doses (17–23 g/day) of linoleic acid (an essential fatty acid) for possible reduction in progressive disability.¹⁰ However, in functional terms, arachidonic acid (AA) and docosahexanoic acid (DHA) are the most important fatty acids required for brain phospholipid metabolism. The formation of AA and DHA in the liver is blocked by stress and viral infection,²⁴ both of which trigger MS relapses. Highly unsaturated fatty acids also have anti-oxidant property, and oxidative stress is considered to be the final common pathway in excitotoxic neurodegeneration. Anti-oxidants such as Co-enzyme Q₁₀ may have a role, and this is one of the uncharted areas in MS therapy.

Symptomatic treatment

One of the main reasons as to why beta-interferon, glatiramer and mitoxantrone have been accepted to be disease-modifying in MS is that the treatment with these agents was generally shown to improve MRI scan appearances in terms of the number of the T₂-weighted and gadolinium-enhanced T₁-weighted lesions. The problem is that the correlation between lesion load and the quality of life in MS is poor. Chronic fatigue and pain are usually the two self-rated worst symptoms in MS,²⁵ and bear little relationship to the MRI changes. Clinically, it is necessary to distinguish fatigue from depression and anxiety. The NICE guideline emphasises under-diagnosed depression, but depression may be mistaken for neurogenic fatigue.²⁶ Because fatigue is so common (present in nearly 90% of MS patients) and is often disabling, every MS patient should be offered a comprehensive management plan that encompasses life style, diet, social issues, level of physical activity and emotional support.²⁶ Besides a number of pharmacological options (amantadine, pemoline, modafinil and possibly acetyl L-carnitine), restriction of caffeine and alcohol, regular physical activity and yoga may be helpful in fatigue management.

A greater disappointment in the NICE guidelines, however was that they placed no emphasis on paroxysmal events in MS. Patients with MS frequently report a variety of paroxysmal motor, sensory and emotional symptoms. These symptoms must be distinguished from both true relapses and conversion disorder or somatization (hysteria). Paroxysmal dystonia, hemifacial spasms (facial myokymia), dysarthria with ataxia, tonic seizures and diplopia are well-recognized motor symptoms,²⁷ and usually respond to anti-epileptic drugs. Paroxysmal itching, cough and hiccups are some of the more unusual and rare symptoms. The range of paroxysmal sensory symptoms in MS may include facial pain, trigeminal neuralgia, hemisensory pain or paresthesia, paraesthetic or pseudoradicular painful symptoms affecting limbs, girdle pain and unusually, pelvic pain. Lamotrigine is usually effective in trigeminal neuralgia and other sensory symptoms in MS, and probably works by blocking sodium channels in the demyelinated sensory axons; low-dose gabapentin combined with lamotrigine can also be useful for trigeminal neuralgia in MS.²⁸ Acetazolamide, an inhibitor of carbonic anhydrase and an effective treatment in other paroxysmal neurological disorders (periodic paralysis and episodic ataxia) may also be useful in patients with paroxysmal MS symptoms of brain-stem origin.²⁹

Paroxysmal laughing or crying occurs in 10% of patients with MS with disease duration of over 10 years.³⁰ Unlike emotional lability (incontinence), the episodes of pathological laughing or crying are unrelated to internal or external emotional stimuli. Pathological crying is more common than laughing and is often mistaken for depression. In a double-blind, crossover trial, two-thirds of the treated patients responded to low-dose amitriptyline (none requiring >75 mg/day); improvement is usually rapid and seen within 48 h of starting treatment.³¹ Dopaminergic drugs (levodopa or amantadine) are possible alternatives. Emotional lability, however, is a very distressing experience for patients with MS. It is characterized by an uncontrollable, exaggerated emotional response to an external stimulus (e.g. while watching a movie or a television show). Often called the April shower phenomenon, both carbamazepine and selective serotonin reuptake inhibitors are helpful for symptomatic treatment of emotional lability.

Like fatigue, there is no correlation between changes in the conventional MRI brain scans and depression in MS. The lifetime prevalence of depression in MS is high (30–50%), and patients have a significantly increased rate of suicide compared to the general population and patients with other neurological disorders.^30,32 One has to be cautious regarding iatrogenesis, since depression is a common side-effect of beta-interferon therapy,^33,34 especially among those with a previous history of mood disorder.³⁵ Equally, electroconvulsive therapy for refractory depression in MS carries a significant risk of triggering a relapse.^36,37

Testing available drugs in new treatment trials

The NICE guidelines¹⁰ provide no direction for new clinical trials in MS independent of the pharmaceutical industry. We believe any rational therapeutic trial in MS should be targeted to neuroprotection. Available pharmacological agents that deserve attention as neuroprotective therapy are anti-oxidants, minocycline (an antibiotic that reduces apoptosis in experimental studies),³⁸ low-dose levodopa and NMDA-antagonists. The multi-centre, randomized placebo-controlled trial of cannabinoids in MS (the CAMS study) did not show any significant treatment effect on spasticity, but there was a surprising improvement in a secondary objective measure, the 10 m timed walk.³⁹ Cannabinoids may be neuroprotective in MS, and trials are needed to evaluate the effect on chronic pain. A neglected area in MS is cognitive dysfunction, which is present in up to two-thirds of chronic cases.⁴⁰ An operational advantage of a therapeutic trial for cognitive impairment in MS is that there is a reasonable correlation between the level of cognitive dysfunction, results of psychometric tests and brain MRI changes. There is very little evidence that any of the disease-modifying drugs improve cognitive dysfunction in MS. Because the primary outcome measure for any effective MS therapy needs to be clinical (changes in disability scores), it is possible to test a number of suitable and existing drugs in pilot clinical trials in MS within the next decade, if we are willing to accept the challenge. Future therapeutic trial designs in MS are also likely to be influenced by work at the Sylvia Lawry Centre currently in progress.⁴¹

Conclusions

Rather being primarily autoimmune, MS may be a metabolically determined neurodegenerative disease. We do not claim that the treatment strategies summarized in Table 2 provide the final answer, but they may offer a useful starting point. A successful interventional trial has the prospect of saving large amounts of money, thus freeing resources for improved social service and multi-disciplinary care for all MS patients. Clinicians involved in future research and treatment trials of MS should remember that their commitment is to the patients and not to the pharmaceutical sponsors. We must take the lessons from failed immunotherapy back to the bench, and develop new experimental models for MS based on axonal degeneration and non-immune demyelination. There are a number of possible models, such as osmotic demyelination, toxic demyelination after exposure to organic solvents, viral demyelination and leukodystrophy. Lewis Thomas once said: ‘My unsolicited and perhaps unwelcome advice … would be to plunge, to splurge, to cut back nowhere, to encourage the doing of basic research wherever the questions seem engrossing and fascinating, and not to think of excluding any field … It is the best investment, short-term or long-term, that the country can make’.⁴² We could not agree more.

The article is partly based on an invited talk given by AC in the symposium on multiple sclerosis at the 4th international conference of neurology (Santiago de Cuba, March 2004). AC is supported by the David & Frederick Barclay Foundation.

References