The History of Diagnosis and Treatment of MS: a Brief Overview.

PURPOSE OF REVIEW: This overview of the history of diagnosis and treatment of multiple sclerosis serves as an introduction to the rich history of multiple sclerosis, and shows we are on a continuum of incremental advances that date back centuries. RECENT FINDINGS: The current understanding of MS demonstrates a dramatic series of advances and this brief historical overview will provide some context for these discoveries. Although cases we would now recognize as multiple sclerosis can be found in older literature and diaries, the contribution of Jean-Martin Charcot at the Salpêtrière in Paris in 1868 was to frame the clinical and pathological features of a disorder he called la sclérose en plaque disséminées. Soon after, reports came from many countries. Over the next half-century, the diagnosis was a clinical conclusion with no confirmatory tests. Some CSF and evoked potential tests later helped but it remained for the MRI imaging and oligoclonal banding to substantially aid the clinical diagnosis. It is tempting to think that therapy is new in MS, but in previous centuries, hundreds of drugs, procedures, and surgeries were applied to patients with MS, many more than we use today. It remained for the development of the randomized clinical trial to show which therapies were beneficial and safe. Everything changed in 1993 when the first of a long list of new therapies was approved, therapies that were shown to alter the activity and outcome of the disease.

The 1917 Halifax Explosion: the first coordinated local civilian medical response to disaster in Canada.

SUMMARY: The 1917 Halifax Explosion was an unfortunate but predictable tragedy, given the sea traffic and munitions cargo, resulting in sudden large-scale damage and catastrophic injuries, with 1950 dead and 8000 injured. Although generous support was received from the United States, the bulk of the medical work was undertaken using local resources through an immediate, massive, centrally coordinated medical response. The incredible care provided 100 years ago by these Canadian physicians, nurses and students is often forgotten, but deserves attention. The local medical response to the 1917 disaster is an early example of coordinated mass casualty relief, the first in Canada, and remains relevant to modern disaster preparedness planning. This commentary has an appendix, available at canjsurg.ca/016317-a1.

The history of multiple sclerosis: the changing frame of the disease over the centuries.

For centuries, it was recognised that there was a condition characterised by episodic and progressive neurological deterioration, classified as 'paraplegia'. Some early cases of 'paraplegia' have been described in sufficient detail to recognise a condition resembling what we now call multiple sclerosis and these cast an interesting light on the approach to therapy before the disease had a name. Multiple sclerosis was differentiated and 'framed' as a separate identifiable entity by von Frerichs, Vulpian, Charcot and others in the mid-nineteenth century. Once framed by its pathology, clinical picture, course and prognosis, cases were diagnosed by others around the world. As knowledge of the disease increased, theories of cause and approaches to treatment increased so that a review in 1935 covered 158 treatments used in MS. There were subsequent waves of therapies including anticoagulants, antibiotics, histamine desensitisation, various diets, vaccines and anti-cancer agents, as well as numerous claims of 'cures'. After the 1960s the methodology for carrying out randomised clinical trials became better defined, aided by improved disease classification and disability scales. As data accumulated, theories were tested to account for observations of genetic influences, environmental factors, geographical variations, infections and immunological changes. The development of multiple sclerosis societies advanced research and public education and changed attitudes towards the disease. At the same time, attitudes of physicians towards management of people with multiple sclerosis changed. In the last fifty years, the major advances have been in basic research to elucidate the mechanisms and processes underlying the disease, the development of imaging techniques (MRI) and the development of immunomodulatory drugs which, for the first time, are altering the outcome of the disease. We have now entered the therapeutic era of multiple sclerosis, with continual major advances bringing hope and benefit to people with multiple sclerosis.

The Halifax Explosion of 1917: the oculist experience.

BACKGROUND: Despite its prominence in Canadian history, there are few publications about the Halifax Explosion of 1917 that deal with the care of victims with eye injuries. METHODS: Archived documents relating to the nature and treatment of eye injuries sustained during the Halifax Explosion were reviewed at the Public Archives of Nova Scotia and the Maritime Museum of the Atlantic. A review of current literature was performed. RESULTS: Detailed accounts regarding the personal and surgical experience of 2 ophthalmologists, G.H. Cox and F.T. Tooke, were found. Several unpublished government and personal documents on eye injuries sustained during the Halifax Explosion are filed at the Public Archives of Nova Scotia. Twelve ophthalmologists treated 592 people with eye injuries and performed 249 enucleations. Sixteen people had double enucleations. Most of the eye injuries were caused by shards of shattered glass. Sympathetic ophthalmia was the feared complication for penetrating eye injuries and a common indication for enucleation in 1917. A Blind Relief Fund was established to help treat, rehabilitate, and compensate the visually impaired. INTERPRETATION: Many of the eye injuries sustained during the Halifax Explosion were due to flying shards of glass. Details of their treatment provide insight into a unique and devastating event in Canadian medical history and demonstrate how eye injuries were managed in 1917.

The Halifax disaster (1917): eye injuries and their care.

Explosions, man-made and accidental, continue to require improved emergency medical responses. In the 1917 Halifax Explosion, an inordinate number of penetrating eye injuries occurred. A review of their treatment provides insight into a traumatic event with unique ophthalmological importance. Archived personal and government documents relating to the Halifax Explosion were reviewed at the Public Archives of Nova Scotia, Canada, along with a review of current literature. Twelve ophthalmologists treated 592 people with eye injuries and performed 249 enucleations. Sixteen people had both eyes enucleated. Most of the eye injuries were caused by shards of shattered glass. A Blind Relief Fund was established to help treat and rehabilitate the visually impaired. The injured were given pensions through the Canadian National Institute for the Blind, Toronto, Ontario, Canada, which continue to this day. Sympathetic ophthalmia was the feared complication for penetrating eye injuries and a common indication for enucleation in 1917. Even so, the severity and the overwhelming number of eye injuries sustained during the Halifax Explosion made it impossible for lengthy eye-saving procedures to be performed. Enucleation was often the only option.

A multicenter, open-label, phase II study of the immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis.

BACKGROUND: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta. OBJECTIVE: This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS. METHODS: This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay. RESULTS: A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA. CONCLUSIONS: The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).

Rationale and design of the prospective and retrospective observational study of Avonex and Rebif (PROOF) for the treatment of relapsing-remitting multiple sclerosis.

Previous studies comparing the two available interferon beta (IFNbeta)-1a products, Avonex and Rebif, for the treatment of relapsing-remitting multiple sclerosis (RRMS) have been limited and of short duration. Therefore, the Prospective and Retrospective Observational Study of Avonex and Rebif (PROOF) was designed to provide long-term (up to 5 years) comparative data on the efficacy, safety, and tolerability of these two agents. Patients with RRMS receiving treatment with either Avonex 30 microg intramuscularly once weekly or Rebif 44 microg subcutaneously three times weekly from 12 to 24 months are being enrolled and will continue their respective treatments for the 36-month duration of the study. The primary efficacy endpoint will be change in brain parenchymal fraction, which will be evaluated through magnetic resonance imaging scans by blinded radiologists. Secondary endpoints will include the following: relapse rates; intravenous steroid use; the proportion of patients with an increase of > or = 1 point on the Expanded Disability Status Scale (EDSS) and with an increase in EDSS score sustained for 6 months; mean change in EDSS score; cumulative number of new or enlarging T2 lesions; T2 and T1 lesion volumes; gadolinium-enhanced lesion number and volume; and safety and tolerability. The study design of PROOF will permit more meaningful conclusions regarding the optimal IFNbeta-1a product for the long-term treatment of patients with multiple sclerosis.

Samuel Johnson: his ills, his pills and his physician friends.

Samuel Johnson (1709-1784) was one of the greatest men of his age. Although famed for his writings, especially his Dictionary and his folio on Shakespeare, he is remembered for his tavern conversations, his literary clubs and the great biography of his life by Boswell. He always enjoyed having physicians as his friends, and took a great interest in all branches of medicine. He would advise and prescribe for friends who regularly consulted him, and he was not unhappy when mistaken for a physician. Particularly in his last years he had need of physicians for his own care, but held his own distinct views on whether to take their medicines and in what dose--usually much higher than prescribed. His many illnesses and his knowledge and views on medicine make him of continuing interest to physicians and give us insight into medical practice and beliefs in the Age of Enlightenment.

Hand dexterity and direct disease related cost in multiple sclerosis.

METHODS: The nine hole peg test (9HPT) is an emerging outcome measure in clinical trials in multiple sclerosis (MS). In this study we investigated how performance on the 9HPT at baseline is related to annualized direct MS related cost. METHODS: We enrolled patients with a definite diagnosis of MS from two Canadian MS centers. 9HPT and demographic information were recorded at baseline, and patients prospectively recorded all MS related costs for 6months. Costs were compared among five groups according to the baseline 9HPT, and we built a multiple linear regression model including cost (dependent variable) and 9HPT at baseline, age, disease duration, sex and disease course (independent predictor variables). RESULTS: We analyzed data from 298 patients. Cost significantly increased with increasing 9HPT scores (p<0.0001), with the costs for health care providers, changes to the home or car and long-term care dominating in the most disabled patient groups. The 9HPT score was a significant predictor of cost in the regression model (p=0.006). CONCLUSION: Performance on the 9HPT is closely related to cost. Our data add another aspect of patient relevance to using the 9HPT as an outcome measure in clinical trials.

Efficacy and tolerability of intramuscular interferon beta-1a compared with subcutaneous interferon beta-1a in relapsing MS: results from PROOF.

OBJECTIVE: Benefits from interferon beta (IFNbeta treatment in patients with multiple sclerosis are affected by many factors, including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of neutralizing antibodies (NAbs). The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFNbeta-1a products for up to 5 years. METHODS: PROOF compared the relative efficacy and tolerability of intramuscular (IM) IFNbeta-1a (Avonex) 30 microg once weekly (n = 69) and subcutaneous (SC) IFNbeta-1a (Rebif) 44 microg three times per week (n = 67). The duration of the retrospective portion of the study was 12-24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months. Therefore, between 18 and 30 months of efficacy and tolerability data were available for analysis. RESULTS: After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups during the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFNbeta-1a 30 mug once weekly vs. 26.7% SC IFNbeta-1a 44 mug three times per week). Relapse rates were similar in the groups, as were MRI endpoints of brain parenchymal fraction, T1 lesion volume, T2 lesion volume, number of new/enlarging T2 lesions, and gadolinium-enhancing (Gd+) lesion volume and count. Treatment groups differed in frequency of NAbs, with 19% of patients treated with SC IFNbeta-1a 44 microg three times per week NAb+ compared with none treated with IM IFNbeta-1a 30 microg once weekly. More NAb+ patients compared with NAb- patients had disability progression (40.0% vs. 27.8%, p = NS), new or enlarging T2 lesions at the end of treatment (63.6% vs. 40.7%, p = 0.003), and Gd+ lesions after 12-24 months of treatment (36.4% vs. 15%, p = 0.001). The IFNbeta-1a products had comparable tolerability. However, fewer patients treated with IM IFNbeta-1a 30 microg once weekly had injection-site reactions (2.9% vs. 6.0%). Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFNbeta-1a treatments. CONCLUSIONS: The results of the present study show that the two IFNbeta-1a products have comparable efficacy and differing immunogenicity.

The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks?

Mitoxantrone, an immunosuppressant agent with potent anti-inflammatory activity, has been used to treat patients with multiple sclerosis (MS) who have worsening relapsing-remitting (RRMS) or secondary progressive multiple sclerosis (SPMS) despite prior therapy with interferons or glatiramer acetate. From previous experience of treating cancer with mitoxantrone, it was expected that cardiotoxic effects and occasional malignancy would develop in some patients treated with this agent. From the earliest trials, reduction of left ventricular ejection fraction (LVEF) was seen in 2-3% of cases, and in some this effect may persist and less commonly there can be congestive heart failure and even death. There are also occasional reports of leukaemia developing in MS patients treated with this agent. Mitoxantrone has been shown to reduce relapses, the number of new lesions visualised on magnetic resonance imaging and stop or reduce the progression of the disease in many patients treated. The drug has found a place in MS therapy because in this progressing group of MS patients who are failing on the disease-modifying therapies with interferons or glatiramer acetate, trials have shown that mitoxantrone may arrest or even improve many patients. Recognising the risks, mitoxantrone therapy is a reasonable option for MS patients with RRMS and SPMS who are progressing despite current disease-modifying therapy.

Complementary and alternative medicine for MS.

Neurologists are often uncertain how to view the many complementary and alternative medicine (CAM) approaches, used by their patients. This is an important issue, as studies show that 50-75% of MS patients use one or more CAM therapies, and see CAM therapists more than conventional physicians. Moreover, many MS patients do not tell their physicians what they are doing, especially if they feel the physician will be judgmental.

Timing of birth and risk of multiple sclerosis: population based study.

OBJECTIVES: To determine if risk of multiple sclerosis (MS) is associated with month of birth in countries in the northern hemisphere and if factors related to month of birth interact with genetic risk. DESIGN: Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark. SETTING: 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General. POPULATIONS: 17,874 Canadian patients and 11,502 British patients with multiple sclerosis. MAIN OUTCOME MEASURE: Diagnosis of multiple sclerosis. RESULTS: In Canada (n = 17,874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11, 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42,045) showed that significantly fewer (8.5%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest. CONCLUSIONS: Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied.

Strategies for managing the side effects of treatments for multiple sclerosis.

Disease-modifying therapies for multiple sclerosis (MS) are a mainstay of treatment. All of these agents are associated with side effects, most of which are easily managed with only minimal additional pharmacotherapy. Appropriate patient education and physician support are critical to achieve the best medical outcome and to maximize patient compliance with long-term therapies for this debilitating condition. Although many side effects subside shortly after initiation of treatment, such as flu-like symptoms with interferon treatment, some side effects are cumulative and can become life-threatening if they are unrecognized (e.g., cardiotoxicity with mitoxantrone). Therefore, physicians must be aware of appropriate laboratory monitoring schedules to prevent serious toxicities and to become familiar with less serious but more common side effects that often threaten patient compliance. Patients should be encouraged to communicate with their physicians so that side effects can be managed promptly. This article describes and provides management strategies for side effects associated with MS treatments.