- Email: [email protected]
Highly active multiple sclerosis: An update
Accepted Manuscript
Highly Active Multiple Sclerosis: An update Cindy D´ıaz , Luis Zarco , Diego M. Rivera PII: DOI: Reference:
S2211-0348(19)30038-0 https://doi.org/10.1016/j.msard.2019.01.039 MSARD 1145
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
9 November 2018 21 January 2019 23 January 2019
Please cite this article as: Cindy D´ıaz , Luis Zarco , Multiple Sclerosis: An update, Multiple Sclerosis and https://doi.org/10.1016/j.msard.2019.01.039
Diego M. Rivera , Highly Active Related Disorders (2019), doi:
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Highlights •
Multiple sclerosis is the most prevalent chronic inflammatory disease of the central
nervous system There are the relapsing remitting MS (RRMS), primary progressive MS (PPMS),
and secondary progressive MS (SPMS) phenotypes. •
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•
There is a subgroup of RRMS patients who have a more aggressive disease course
marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more disease modifying drugs (DMTs).
In the past, this disease phenotype was called “aggressive” MS (AMS); it is now
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•
called highly active MS (HAMS). •
It is generally agreed that the severe nature of this phenotype requires different
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treatment decisions. Unfortunately, there is no consensus on the definition of AMS or the
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treatment algorithm.
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Highly Active Multiple Sclerosis: An update
Authors: Cindy Díaz1 Luis Zarco2
Neurological Resident. Department of Neurology, Hospital Universitario San Ignacio,
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1.
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Diego M. Rivera3
Universidad Javeriana, Bogotá, Colombia.
Neuroimmunologist, Director of the Neurology Service, Hospital Universitario San
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2.
Ignacio, Universidad Javeriana, Bogotá, Colombia. Neuroradiológo; Hospital Universitario San Ignacio; Universidad Pontifica Javeriana,
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3.
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Bogotá, Colombia.
Corresponding author: Cindy Díaz
Email: [email protected]
Highly Active Multiple Sclerosis: An update
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Cindy Díaz1, Luis Zarco2, Diego M. Rivera3
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Abstract: Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system (CNS), affecting more than 2 million people worldwide. It is characterized by brain and spinal cord involvement. There are the relapsing remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) phenotypes. There is a subgroup of RRMS patients who have a more aggressive disease course marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more disease modifying drugs (DMTs). In the past, this disease phenotype was called "aggressive" MS (AMS); it is now called highly active MS (HAMS). It is generally agreed that the severe nature of this phenotype requires different treatment decisions. Unfortunately, there is no consensus on the definition of AMS or the treatment algorithm. In this article we review HAMS in relation to its definition and the treatments available.
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Keywords: Review, Multiple Sclerosis, Highly Active Multiple Sclerosis
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Introduction
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Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central
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nervous system (CNS), affecting more than 2 million people worldwide. (1)
It is characterized by brain and spinal cord involvement.(2)(3) There are the relapsingremitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) phenotypes.(4)
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After 10 to 20 years, a progressive clinical course develops in many of the persons affected, leading to impaired mobility, loss of sphincter control and slowed cognitive processing.(5) Approximately 4-15% of patients have a highly active course from the onset.
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Tissue damage in MS results from a complex and dynamic interaction between the immune system, glia (oligodendrocytes and their precursors, microglia and astrocytes) and neurons. There is an associated immune process, with the participation of helper lymphocytes (CD4+ T) that are more concentrated in the peri-vascular cuffs, cytotoxic (CD8+ T) widely
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distributed within the brain parenchyma, B lymphocytes, antibodies and innate immune system cells.(6)(7)
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The inflammatory response leads to demyelination and early neuronal transection.(8) Late in the natural course of the disease, there is a neurodegenerative process with more diffuse
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inflammation.(9)(10) The inflammatory and neurodegenerative processes can occur in parallel. MS lesions may appear in gray or white matter (WM);(11)(12) however, they are
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more easily recognized in WM as focal areas of demyelination, inflammation and glial
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reaction. In early stages, WM demyelination (known as early active WM lesions) is heterogeneous(13) and evolves over the course of months. Regardless of the particular
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immunological pattern of early demyelination, analysis of active lesions, over both time and space, suggests that there is a single dominant immune-effector mechanism in each person.(14) Consistent with this notion, the plasmapheresis (PPH) that removes pathogenic antibodies from the circulation, ameliorates relapses that are refractory to initial treatment with glucocorticoids in patients whose active lesions contain immunoglobulin and complement.(15) It is not known what determines the long-term evolution of the lesion,
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whether the resolution, chronification or remyelination of the lesion. Recent data from longitudinal studies suggest that lesions in young people may repair more effectively; (16) findings from pre-clinical studies indicate that age strongly modulates immune-mediated
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regenerative processes.(17)(18)
Treatment of MS is based on disease modifying drugs (DMTs) for the classic RRMS phenotype; several treatment algorithms have been proposed. Often, a first line treatment (platform) is started that has moderate effectiveness but is relatively safe, and according to
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the response and/or tolerance it is modified to a second or third line. There is a subgroup of RRMS patients who have a more aggressive disease course marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more DMTs. In
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the past, this disease phenotype was called “aggressive” MS (AMS); it is now called highly active MS (HAMS). It is generally agreed that the severe nature of this phenotype requires
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different treatment decisions. Unfortunately, there is no consensus on the definition of
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AMS or the treatment algorithm.
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In this article we review HAMS in relation to its definition and the treatments available.
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Definition of Highly Active Multiple Sclerosis
HAMS is defined as an RRMS phenotype with one or more of the following characteristics:
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1. EDSS scale of 4 points at 5 years of onset of the disease 2. Multiple relapses (two or more) with incomplete recovery in the ongoing year 3. More than 2 brain magnetic resonance imaging (MRI) studies demonstrating new
gadolinium despite treatment (Clinical case 1 and 2).
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lesions or increase in the size of the lesions in T2, or lesions that enhance with
4. No response to treatment with one or more DMTs for at least one year.
There are risk factors that help identify patients at risk of EMA; they must be identified at
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the onset of the disease and during follow-up, in the RRMS (19)(20) phenotypes (Figure 1). These factors include demographic, clinical (type of relapse, severity of attacks, frequency of relapses) and imaging characteristics that also provide important prognostic markers both
at
the
onset
and
during
the
follow-up
of
the
disease.
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(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)
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Importance of early identification of HAMS
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RRMS relapses that occur in the first 2 years lead to an early progression of the disease, with a lower contribution of subsequent relapses (after year 3 (third)). The predictors of
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rapid conversion to SPMS are: (36) Short time to accumulate 3 points in EDSS (independent time predictor to achieve an EDSS of 6, 8 and 10 points 1. High rates of early relapses in the course of the disease 2. Short intervals between attacks
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By identifying risk factors and predictors of aggressive behavior within the RRMS phenotype, it is possible to predict, by identifying them in the early phases of the disease, which patients are at higher risk of developing a HAMS phenotype. In long-term follow-up studies of patients presenting with optic neuritis, a high lesion load in the brain MRI leads
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to greater disability in the next 20 years, and in those who convert from RRMS to SPMS, the rate of changes in the volume of lesions was 3 times higher than in those that did not experienced conversion.(37)
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In the natural course of the disease, there is a “window of opportunity” for an effective treatment of RRMS patients, which covers the period of greatest CNS inflammation. (38) This window starts after the first demyelinating attack, and probably closes early after the development of SPMS. It is quite challenging to identify in which part of the window a
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particular patient is, especially in patients with the HAMS phenotype, who have a short
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window of opportunity that can close quickly. Currently, the DMTs target the early attack of the CNS inflammatory process, which
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contributes substantially to demyelination and axonal damage. These therapies are more effective when the inflammatory process is greater, as in the early stages of the disease. The
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severity of inflammation in the first few years after the onset of the disease is what causes
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early disability, which eventually evolves into a chronic neurodegenerative process, and the disease-modifying therapies have no major effect on that process. The goal of treatment is to minimize the accumulation of irreversible disability and, ultimately, decrease or stop the progression of the disease, minimizing long-term disability, which allows having a good quality of life. The treatment algorithms are different in the HAMS patient scenario. Conventional treatments should be reconsidered in this group of patients, in order to avoid
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missing the window of opportunity, with greater irreversible disability.(39)
Highly Active Multiple Sclerosis: Induction vs. Escalating Therapy
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Patients who meet the HAMS diagnostic criteria have a high risk of imminent disease progression, and their window of therapeutic opportunity closes rapidly. Therefore, a definitive and not temporary treatment is justified, that is, they require a powerful induction therapy instead of the standard immunomodulated escalating therapy. The concept of “early
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treatment is best” changes to “maximum effectiveness in early treatment”.
Induction therapy(39) represents a more aggressive therapy with potent immunosuppressive drugs that are used from the beginning of therapeutic management to stop the inflammatory
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process. Figure 2. The goal is to “reset” the immune system to prevent the spread of epitopes and prevent early structural damage. Potent immunosuppressants are used for a
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short period of time and, once disease control is achieved, the change is made to maintenance therapy with immunomodulatory drugs that are better tolerated. The success
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of this approach is to use immunosuppressants for the shortest time possible to achieve and
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maintain control of disease activity (rapid remission). The advantage of the induction therapy is that it makes it easier to achieve NEDA (no evidence of disease activity) earlier
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or “the closest thing to NEDA”, which is the “gold standard” of MS treatment for some schools of thought. Induction therapy (IT) protocols include: 1. Limited-dose agents: mitoxantrone, cladribine and cyclophosphamide
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2. Continuous use agents: natalizumab 3. Agents used during a limited time: alemtuzumab, rituximab(40)(41)(42)(43), ocrelizumab 4. Definitive ablative agents: autologous hematopoietic stem cell transplantation
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(AHSCT)(44)
First-line agents (platform treatment) are not effective in controlling the high inflammatory
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power in the HAMS phenotype; second-line agents, such as fingolimod, have a low efficacy, as observed in clinical trials. (45)(46)(47) Third-line agents such as natalizumab, allow controlling the inflammatory process, as long as its use is maintained; if they are interrupted, the disease becomes active again. (48)
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The classic paradigm of maintenance versus escalating therapy, which prioritizes safety
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over efficacy, is appropriate for most RRMS patients, always with close monitoring to detect sub-optimal response. The approach of starting with first-line agents and then
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escalating to second or third line agents, in cases of inadequate response, is not suitable for HAMS patients. Since these patients have a short window of opportunity to receive
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treatment, the opportunity to control the disease would be missed. In this context it is
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important to take into account the new treatment algorithms for the HAMS phenotype, which ensure greater efficacy and aggressive control of the inflammatory process. This is why when treating HAMS, the “escalation” paradigm is changed to an “induction” treatment approach, with the premise of “hitting hard and early”; this involves highly potent agents that allow an early control of the severe inflammatory process in patients with the
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HAMS phenotype; however, the potential for serious and irreversible toxicity makes it critical to use the appropriate patient selection criteria for this type of disease modifying agents. Hence the importance of suspecting and identifying patients with HAMS early.
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The duration of IT is often limited due to specific toxicity, cumulative dose and the selection of an “exit strategy”. The response to treatment should be closely monitored for
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an early and timely identification of patients with therapeutic failure.(39)
Specific treatments for HAMS
Agents available for HAMS (Table 1) share the characteristic of substantially depleting the autoimmune cells that cause the disease. In many cases, they do not remove all cells, and
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different medications are distinguished by the time required before immune cells return and
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disease activity returns. In some cases, a second treatment cycle may be possible, but in other cases combined treatments may lead to a new toxicity. Given the risk of MS rebound
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activity, it may be appropriate to use a first-line DMT after treatment, in order to extend the
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benefit obtained with aggressive treatment. Treatment algorithm for HAMS
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Currently there are no treatment algorithms for HAMS patients. (39) Rush et al proposed a specific practical treatment model for these patients (Figure 3). With the limitations given by: 1. There is no optimal strategy for the sequence of these therapies
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2. The availability of the various therapies varies from one center to another, depending on familiarity, experience and hematological support.
The choice of treatment often depends on risk tolerance, which varies widely between
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patients and their neurologists. Different studies have shown that MS patients are willing to take more risks than their treating neurologists, possibly due to the impact of the disease on their quality of life. (49)(50)(51)(52) Alemtuzumab has demonstrated efficacy and manageable adverse effects in HAMS patients. However, in the CARE-MS II trial, the
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annualized relapse rate after treatment with alemtuzumab was 0.26, and 13% of patients continued to progress. Although this treatment was significantly better than the comparator, high dose IFN-β, this level of efficacy might not be acceptable in certain cases of HAMS.
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(53)(54) AHSCT has been used to treat HAMS, but its availability varies around the world. It should only be considered in centers with hematological and neurological experience.
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(55)
In the treatment algorithm, if alemtuzumab maintains a good disease control during the first
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2 years of treatment, we recommend to use it intermittently afterwards. However, if the
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drug fails to control the disease during the first year, we suggest moving quickly to AHSCT. (56)(57)(58)(59)(60)(61) If AHSCT is not available, we recommend switching to
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another
form
of
potent
immunosuppression,
cyclophosphamide,(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)
such
as
mitoxantrona
(73)(74)(75)(76)(77)(78)(79) or even cladribine(80)(81)(82)(82), to induce remission. It remains uncertain whether the use of these immunosuppressants after alemtuzumab failure provides an additional benefit. In theory, these options could be used as a last resort. Cyclophosphamide and mitoxantrone have limited utility due to their cumulative toxicity,
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but if it is possible to control the disease activity, the benefit can be maintained later with a safer first-line agent. In regions where AHSCT and alemtuzumab are not available, the immunosuppressive agents cladribine, cyclophosphamide and mitoxantrone would be the first logical consideration in the therapeutic algorithm, always bearing in mind the risk-
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benefit equation, and evaluating toxicity and cumulative doses. Patients can stabilize or continue to show a sub-optimal response. If it is clear that the disease is refractory, a second immunosuppression cycle could be attempted.
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If after a period of clinical stability after treatment with alemtuzumab or cladribine, patients experience a resurgence of disease activity, either of these agents could be used again (a 3day treatment with alemtuzumab or two treatments every 6 months with cladribine), to induce remission. If relapse occurs after treatment with cyclophosphamide or mitoxantrone,
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alemtuzumab, cladribine or AHSCT may be used.
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To evaluate the response to treatment in patients with aggressive MS, we recommend low
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thresholds of acceptable disease activity. Strict monitoring is essential to achieve a timely sub-optimal response. However, there is no consensus regarding the frequency with which
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patients should be monitored. The literature suggests a clinical evaluation every 3 months and a radiological evaluation every 6 months. We should accept only minimal evidence of
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disease activity (such as relapse, MRI activity or EDSS progression) as a reason to further intensify treatment: in other words, we must strive to achieve NEDA.
Conclusion
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Early detection of HAMS is essential, since these patients have a much higher risk of early progression than other MS patients. In addition, HAMS tends to be refractory to conventional DMTs. A timely and adapted implementation of specific treatment strategies
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for this group of patients can have a positive impact on the severity of the disease and the disability. The use of more aggressive treatment agents will require closer continuous
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Edan G, Comi G, Le Page E, Leray E, Rocca MA, Filippi M. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: A 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344–50.
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Ramtahal J, Jacob A, Das K, Boggild M. Sequential maintenance treatment with
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Rice GPA, Filippi M, Comi G. Cladribine and progressive MS: Clinical and MRI
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Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. Supplementary Appendix. N Engl J Med [Internet]. 2010;362(5):416–26. Available
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from: http://www.ncbi.nlm.nih.gov/pubmed/20089960
Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, et al. Cladribine tablets added to IFN-β in active relapsing MS. Neurol - Neuroimmunol [Internet].
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Neuroinflammation
2018;5(5):e477.
Available
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http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000000477
Tables
Table 1. Specific treatments for HAMS
from:
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Drug
Protocol
Mechanism of Action
Alemtuzumab
DI: IV infusion 12 Humanized monoclonal directed
(93%)
Monitoring
Related
against infusion:
mild
to No
specific
to recommendation
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mg per day for 5 ab
Side Effects
days followed by 2 CD52, high levels of moderate
(>90%),
cycles of 12 mg for surface antigen present in serious reactions (3%). 3 days after 12 T and B lymphocytes
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months
(71%)
infections:
Serious
cerebral No milk, seafood listeria consumption.
nocardiosis, meningitis,
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tuberculosis, pancolitis due to E. coli (2.7%). PML Nasopharyngitis. ARI. UTI. (36%)
TSH
every
3
months. Monthly Thyroid monitoring
of
hypo- symptoms
disorders: hyperthyroidism,
Serious Dis., thyroid
No
specific
recommendation
ophthalmopathy. Thyroid cancer. (12%)
Superficial
Annual screening
for
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fungal infections: oral- HPV vaginal candidiasis. (3%)
Herpes
Monthly
virus monitoring with
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infections: HPV (2%), blood count and oral herpes simplex, blood VZV (0.3%).
differential.
(1%) Haematological
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disorders: ITP, other cytopenias
(neutropenia, hemolytic
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pancytopenia)
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(0.3%)
for 4 days every 6 nucleoside months
urinalysis
and
creatinine,
and
48 months posttreatment
Nephropathy:
Membranous
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0.875 mg/kg daily Synthetic
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Cladribine
anemia,
Monthly
GN,
anti-glomerular membrane purine Risk
of
long-term Screening
and malignancy
antimetabolite that acts as an antineoplastic agent with immunosuppressive
Infectious: zoster
cancer herpes
for
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effect. It reduces the number of CD4+ and CD8+ T lymphocytes Induction protocol: Nonspecific
cytotoxic (33-47%) infertility
de
600mg/m2 daily for agent of the cell cycle 5 days + MTP, that exerts its effect on T
(800-1000mg/m )
suppresses humoral and cystitis
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2
monthly for every cellular immunity, broad 12-24 months; with spectrum. or without MTP.
(120-200
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High dose protocol mg/kg
specific
recommendation
protocol and B lymphocytes, it (7-15%) Hemorrhagic
pulse
No
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Cyclophosphami
(5-7%) Bladder cancer
Urinalysis
and
cytology every 6 months.
If
cytology
is
abnormal, annual
Brain atrophy
cystoscopy
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daily for 5 days).
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Maximum lifetime cumulative
dose:
12mg/m2 every 3 It is an anthracenedione (22-26%)
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Mitoxantrone
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80-100 g.
months
for
24 similar to doxorubicin.
months. Maximum lifetime cumulative dose: 140mg/m
amenorrhea
It inhibits proliferation of (12%)
Permanent No
specific
recommendation Systolic Annual
T and B lymphocytes. It dysfunction
echocardiogram
suppresses
or CAT scan for
2
cytokines
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secreted
by
Th1 (10%) Cardiotoxicity
lymphocytes (TNF, IL-
(0.4%) Heart failure
12)
5
years
post-
treatment. Complete blood
(1%) Leukemia
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count every 6 months for 10 years
Initial dose: 1 g and Partially again after 15 days. Maintenance dose: 1 g every 6 months
monoclonal
humanized Infusion
reactions
antibody 7.8%:
headache,
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Rituximab
against CD20 antigen in malaise, chills, nausea. B lymphocytes, leading
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to B cell depletion.
Bacterial
systemic
infections
(1.7%):
pneumonia
(2.3%),
otitis
(1.5%)
pyelonephritis, sepsis, sinusitis
(1.2%),
appendicitis, enteritis, bronchitis
(0.5%),
erysipelas , intestinal abscess, tubulointerstitial nephritis)
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Cardiac
alterations
0.1% (acute coronary syndrome)
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Respiratory alterations 0.1%:
interstitial
pneumonitis
CNS alterations 0.1%:
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bilateral
facial
paralysis
Alterations
of
the
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immune system 0.1%: rheumatoid arthritis. Alterations 0.1%: syndrome,
in
skin
Sweet’s herpes
0.7% Neoplasms: basal cell carcinoma 0.2% and pyoderma gangrenosum 0.1%
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Progressive multifocal leukoencephalopathy Methodology:
Transplantation
-Mobilization
of hematopoietic
-Immunoablation
cells -Autograft
lymphoid
viremia of EB
system spectrum
vivo
B
cell
depletion comprises
cells
post-transplant
is
eliminated, adaptive
system cells [B and T
Transient alopecia
preventive
cells
[cells:
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Permanent infertility
and Secondary with
a autoimmune diseases
cytotoxic new one derived from (3.6-6.4%): thyroiditis
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chemotherapy with HSCs. cyclophosphamide
HSCs
are Cancer
obtained by allogeneic or
2-4g/m2SC autologous
combined
with transplantation. and
hyperhydration for bladder protection)
increase
system
monocytes
HSC:
mesna
and in case of
viremia,
A. Mobilization of granulocytes])
dose
Viral infections
lymphocytes] and innate Amenorrhea
4 natural killer, dendritic,
steps:
and CMV in the first 3 months
M
It
of
Sepsis
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-Serotherapy for in
(a
of
lymphoid and myeloid Urinary infection
including
CE
(HSCs)
Monitoring
broad
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stem
It replaces the blood and Febrile neutropenia
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AHSC
It eliminates the aberrant adaptive immune system, reconstituting
the
treatment required.
in
is
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associated
with immune
granulocyte colony achieve stimulating
system
to
immunological
factor tolerance.
5-10ug/kg/day until the
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completing
collection of HSC. B. HSC extraction
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(leukapheresis). C. Ablation. D. Reinfusion
or
Duration:
extraction:
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1.Mobilization and 5-15
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days 2. Ablation: begins 2-4 weeks
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after A-B step.
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transplant.
Abbreviation: ID, initial dose.
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Figures
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Figure 1: Risk factors for HAMS
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Figure 2. Induction therapy in HAMS
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Figure 3. Treatment algorithm for HAMS
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* Figure taken from: Continuum (Minneap Minn) 2016;22(3):761–784. Contin Lifelong Learn Neurol. 2016;22(3):761–84. (20)
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Images cases
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Clinical case 1
B A
C
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A
E
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D
Clinical case 1: 30-year-old male patient with no relevant history who was admitted for a clinical picture of 6 days of diplopia. Neurological examination with finding of mesencephalic syndrome and left pyramidal motor. Normal cerebrospinal fluid. Oligoclonal bands positive pattern II. Brain MRI study shown in images:
F
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Panel A. Axial FLAIR and sagittal. Panel B sequence with evidence of more than 40 hyper-intense ovoid lesions, scattered in white matter of both cerebral hemispheres (predominantly peri-ventricular), thalamus, left basal nuclei and cortical. Panel C.
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Panel D. Compromise of the corpus callosum in the region of the callous-septal interface. Panel E. Lesions in mid-cerebellar peduncles and less numerous in the white matter of both cerebellar hemispheres.
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Panel F. After the injection of intravenous gadolinium, we identified peripheral enhancement of 4 of the supratentorial lesions, the greater of 10 mm in the anterior
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subcortical region of the right frontal lobe.
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Clinical case 2: 27-year-old female patient diagnosed with HAMS. Panel A and B: Axial and sagittal FLAIR sequence: shows more than 30 hyperintense
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lesions located in the periventricular supratentorial white matter (some involving the parasagittal fibers of the corpus callosum), in the white matter of the semioval centers and less numerous in the subcortical white matter of both cerebral hemispheres.
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Panel C: Axial T2 sequence: lesions in both middle cerebellar peduncles.
F and G: Small eccentric hyperintense lesion, whose length does not exceed 5 mm, involving the left lateral aspect at C3-C4 level, without enhancement after gadolinium
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injection.
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C
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B
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E
F
Highly Active Multiple Sclerosis: An update Cindy D´ıaz , Luis Zarco , Diego M. Rivera PII: DOI: Reference:
S2211-0348(19)30038-0 https://doi.org/10.1016/j.msard.2019.01.039 MSARD 1145
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
9 November 2018 21 January 2019 23 January 2019
Please cite this article as: Cindy D´ıaz , Luis Zarco , Multiple Sclerosis: An update, Multiple Sclerosis and https://doi.org/10.1016/j.msard.2019.01.039
Diego M. Rivera , Highly Active Related Disorders (2019), doi:
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights •
Multiple sclerosis is the most prevalent chronic inflammatory disease of the central
nervous system There are the relapsing remitting MS (RRMS), primary progressive MS (PPMS),
and secondary progressive MS (SPMS) phenotypes. •
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•
There is a subgroup of RRMS patients who have a more aggressive disease course
marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more disease modifying drugs (DMTs).
In the past, this disease phenotype was called “aggressive” MS (AMS); it is now
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•
called highly active MS (HAMS). •
It is generally agreed that the severe nature of this phenotype requires different
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treatment decisions. Unfortunately, there is no consensus on the definition of AMS or the
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treatment algorithm.
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Highly Active Multiple Sclerosis: An update
Authors: Cindy Díaz1 Luis Zarco2
Neurological Resident. Department of Neurology, Hospital Universitario San Ignacio,
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1.
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Diego M. Rivera3
Universidad Javeriana, Bogotá, Colombia.
Neuroimmunologist, Director of the Neurology Service, Hospital Universitario San
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2.
Ignacio, Universidad Javeriana, Bogotá, Colombia. Neuroradiológo; Hospital Universitario San Ignacio; Universidad Pontifica Javeriana,
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3.
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Bogotá, Colombia.
Corresponding author: Cindy Díaz
Email: [email protected]
Highly Active Multiple Sclerosis: An update
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Cindy Díaz1, Luis Zarco2, Diego M. Rivera3
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Abstract: Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system (CNS), affecting more than 2 million people worldwide. It is characterized by brain and spinal cord involvement. There are the relapsing remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) phenotypes. There is a subgroup of RRMS patients who have a more aggressive disease course marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more disease modifying drugs (DMTs). In the past, this disease phenotype was called "aggressive" MS (AMS); it is now called highly active MS (HAMS). It is generally agreed that the severe nature of this phenotype requires different treatment decisions. Unfortunately, there is no consensus on the definition of AMS or the treatment algorithm. In this article we review HAMS in relation to its definition and the treatments available.
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Keywords: Review, Multiple Sclerosis, Highly Active Multiple Sclerosis
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Introduction
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Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central
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nervous system (CNS), affecting more than 2 million people worldwide. (1)
It is characterized by brain and spinal cord involvement.(2)(3) There are the relapsingremitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) phenotypes.(4)
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After 10 to 20 years, a progressive clinical course develops in many of the persons affected, leading to impaired mobility, loss of sphincter control and slowed cognitive processing.(5) Approximately 4-15% of patients have a highly active course from the onset.
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Tissue damage in MS results from a complex and dynamic interaction between the immune system, glia (oligodendrocytes and their precursors, microglia and astrocytes) and neurons. There is an associated immune process, with the participation of helper lymphocytes (CD4+ T) that are more concentrated in the peri-vascular cuffs, cytotoxic (CD8+ T) widely
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distributed within the brain parenchyma, B lymphocytes, antibodies and innate immune system cells.(6)(7)
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The inflammatory response leads to demyelination and early neuronal transection.(8) Late in the natural course of the disease, there is a neurodegenerative process with more diffuse
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inflammation.(9)(10) The inflammatory and neurodegenerative processes can occur in parallel. MS lesions may appear in gray or white matter (WM);(11)(12) however, they are
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more easily recognized in WM as focal areas of demyelination, inflammation and glial
CE
reaction. In early stages, WM demyelination (known as early active WM lesions) is heterogeneous(13) and evolves over the course of months. Regardless of the particular
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immunological pattern of early demyelination, analysis of active lesions, over both time and space, suggests that there is a single dominant immune-effector mechanism in each person.(14) Consistent with this notion, the plasmapheresis (PPH) that removes pathogenic antibodies from the circulation, ameliorates relapses that are refractory to initial treatment with glucocorticoids in patients whose active lesions contain immunoglobulin and complement.(15) It is not known what determines the long-term evolution of the lesion,
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whether the resolution, chronification or remyelination of the lesion. Recent data from longitudinal studies suggest that lesions in young people may repair more effectively; (16) findings from pre-clinical studies indicate that age strongly modulates immune-mediated
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regenerative processes.(17)(18)
Treatment of MS is based on disease modifying drugs (DMTs) for the classic RRMS phenotype; several treatment algorithms have been proposed. Often, a first line treatment (platform) is started that has moderate effectiveness but is relatively safe, and according to
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the response and/or tolerance it is modified to a second or third line. There is a subgroup of RRMS patients who have a more aggressive disease course marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more DMTs. In
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the past, this disease phenotype was called “aggressive” MS (AMS); it is now called highly active MS (HAMS). It is generally agreed that the severe nature of this phenotype requires
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different treatment decisions. Unfortunately, there is no consensus on the definition of
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AMS or the treatment algorithm.
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In this article we review HAMS in relation to its definition and the treatments available.
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Definition of Highly Active Multiple Sclerosis
HAMS is defined as an RRMS phenotype with one or more of the following characteristics:
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1. EDSS scale of 4 points at 5 years of onset of the disease 2. Multiple relapses (two or more) with incomplete recovery in the ongoing year 3. More than 2 brain magnetic resonance imaging (MRI) studies demonstrating new
gadolinium despite treatment (Clinical case 1 and 2).
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lesions or increase in the size of the lesions in T2, or lesions that enhance with
4. No response to treatment with one or more DMTs for at least one year.
There are risk factors that help identify patients at risk of EMA; they must be identified at
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the onset of the disease and during follow-up, in the RRMS (19)(20) phenotypes (Figure 1). These factors include demographic, clinical (type of relapse, severity of attacks, frequency of relapses) and imaging characteristics that also provide important prognostic markers both
at
the
onset
and
during
the
follow-up
of
the
disease.
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(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)
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Importance of early identification of HAMS
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RRMS relapses that occur in the first 2 years lead to an early progression of the disease, with a lower contribution of subsequent relapses (after year 3 (third)). The predictors of
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rapid conversion to SPMS are: (36) Short time to accumulate 3 points in EDSS (independent time predictor to achieve an EDSS of 6, 8 and 10 points 1. High rates of early relapses in the course of the disease 2. Short intervals between attacks
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By identifying risk factors and predictors of aggressive behavior within the RRMS phenotype, it is possible to predict, by identifying them in the early phases of the disease, which patients are at higher risk of developing a HAMS phenotype. In long-term follow-up studies of patients presenting with optic neuritis, a high lesion load in the brain MRI leads
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to greater disability in the next 20 years, and in those who convert from RRMS to SPMS, the rate of changes in the volume of lesions was 3 times higher than in those that did not experienced conversion.(37)
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In the natural course of the disease, there is a “window of opportunity” for an effective treatment of RRMS patients, which covers the period of greatest CNS inflammation. (38) This window starts after the first demyelinating attack, and probably closes early after the development of SPMS. It is quite challenging to identify in which part of the window a
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particular patient is, especially in patients with the HAMS phenotype, who have a short
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window of opportunity that can close quickly. Currently, the DMTs target the early attack of the CNS inflammatory process, which
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contributes substantially to demyelination and axonal damage. These therapies are more effective when the inflammatory process is greater, as in the early stages of the disease. The
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severity of inflammation in the first few years after the onset of the disease is what causes
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early disability, which eventually evolves into a chronic neurodegenerative process, and the disease-modifying therapies have no major effect on that process. The goal of treatment is to minimize the accumulation of irreversible disability and, ultimately, decrease or stop the progression of the disease, minimizing long-term disability, which allows having a good quality of life. The treatment algorithms are different in the HAMS patient scenario. Conventional treatments should be reconsidered in this group of patients, in order to avoid
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missing the window of opportunity, with greater irreversible disability.(39)
Highly Active Multiple Sclerosis: Induction vs. Escalating Therapy
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Patients who meet the HAMS diagnostic criteria have a high risk of imminent disease progression, and their window of therapeutic opportunity closes rapidly. Therefore, a definitive and not temporary treatment is justified, that is, they require a powerful induction therapy instead of the standard immunomodulated escalating therapy. The concept of “early
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treatment is best” changes to “maximum effectiveness in early treatment”.
Induction therapy(39) represents a more aggressive therapy with potent immunosuppressive drugs that are used from the beginning of therapeutic management to stop the inflammatory
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process. Figure 2. The goal is to “reset” the immune system to prevent the spread of epitopes and prevent early structural damage. Potent immunosuppressants are used for a
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short period of time and, once disease control is achieved, the change is made to maintenance therapy with immunomodulatory drugs that are better tolerated. The success
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of this approach is to use immunosuppressants for the shortest time possible to achieve and
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maintain control of disease activity (rapid remission). The advantage of the induction therapy is that it makes it easier to achieve NEDA (no evidence of disease activity) earlier
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or “the closest thing to NEDA”, which is the “gold standard” of MS treatment for some schools of thought. Induction therapy (IT) protocols include: 1. Limited-dose agents: mitoxantrone, cladribine and cyclophosphamide
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2. Continuous use agents: natalizumab 3. Agents used during a limited time: alemtuzumab, rituximab(40)(41)(42)(43), ocrelizumab 4. Definitive ablative agents: autologous hematopoietic stem cell transplantation
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(AHSCT)(44)
First-line agents (platform treatment) are not effective in controlling the high inflammatory
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power in the HAMS phenotype; second-line agents, such as fingolimod, have a low efficacy, as observed in clinical trials. (45)(46)(47) Third-line agents such as natalizumab, allow controlling the inflammatory process, as long as its use is maintained; if they are interrupted, the disease becomes active again. (48)
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The classic paradigm of maintenance versus escalating therapy, which prioritizes safety
ED
over efficacy, is appropriate for most RRMS patients, always with close monitoring to detect sub-optimal response. The approach of starting with first-line agents and then
PT
escalating to second or third line agents, in cases of inadequate response, is not suitable for HAMS patients. Since these patients have a short window of opportunity to receive
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treatment, the opportunity to control the disease would be missed. In this context it is
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important to take into account the new treatment algorithms for the HAMS phenotype, which ensure greater efficacy and aggressive control of the inflammatory process. This is why when treating HAMS, the “escalation” paradigm is changed to an “induction” treatment approach, with the premise of “hitting hard and early”; this involves highly potent agents that allow an early control of the severe inflammatory process in patients with the
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HAMS phenotype; however, the potential for serious and irreversible toxicity makes it critical to use the appropriate patient selection criteria for this type of disease modifying agents. Hence the importance of suspecting and identifying patients with HAMS early.
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The duration of IT is often limited due to specific toxicity, cumulative dose and the selection of an “exit strategy”. The response to treatment should be closely monitored for
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an early and timely identification of patients with therapeutic failure.(39)
Specific treatments for HAMS
Agents available for HAMS (Table 1) share the characteristic of substantially depleting the autoimmune cells that cause the disease. In many cases, they do not remove all cells, and
M
different medications are distinguished by the time required before immune cells return and
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disease activity returns. In some cases, a second treatment cycle may be possible, but in other cases combined treatments may lead to a new toxicity. Given the risk of MS rebound
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activity, it may be appropriate to use a first-line DMT after treatment, in order to extend the
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benefit obtained with aggressive treatment. Treatment algorithm for HAMS
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Currently there are no treatment algorithms for HAMS patients. (39) Rush et al proposed a specific practical treatment model for these patients (Figure 3). With the limitations given by: 1. There is no optimal strategy for the sequence of these therapies
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2. The availability of the various therapies varies from one center to another, depending on familiarity, experience and hematological support.
The choice of treatment often depends on risk tolerance, which varies widely between
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patients and their neurologists. Different studies have shown that MS patients are willing to take more risks than their treating neurologists, possibly due to the impact of the disease on their quality of life. (49)(50)(51)(52) Alemtuzumab has demonstrated efficacy and manageable adverse effects in HAMS patients. However, in the CARE-MS II trial, the
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annualized relapse rate after treatment with alemtuzumab was 0.26, and 13% of patients continued to progress. Although this treatment was significantly better than the comparator, high dose IFN-β, this level of efficacy might not be acceptable in certain cases of HAMS.
M
(53)(54) AHSCT has been used to treat HAMS, but its availability varies around the world. It should only be considered in centers with hematological and neurological experience.
ED
(55)
In the treatment algorithm, if alemtuzumab maintains a good disease control during the first
PT
2 years of treatment, we recommend to use it intermittently afterwards. However, if the
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drug fails to control the disease during the first year, we suggest moving quickly to AHSCT. (56)(57)(58)(59)(60)(61) If AHSCT is not available, we recommend switching to
AC
another
form
of
potent
immunosuppression,
cyclophosphamide,(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)
such
as
mitoxantrona
(73)(74)(75)(76)(77)(78)(79) or even cladribine(80)(81)(82)(82), to induce remission. It remains uncertain whether the use of these immunosuppressants after alemtuzumab failure provides an additional benefit. In theory, these options could be used as a last resort. Cyclophosphamide and mitoxantrone have limited utility due to their cumulative toxicity,
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but if it is possible to control the disease activity, the benefit can be maintained later with a safer first-line agent. In regions where AHSCT and alemtuzumab are not available, the immunosuppressive agents cladribine, cyclophosphamide and mitoxantrone would be the first logical consideration in the therapeutic algorithm, always bearing in mind the risk-
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benefit equation, and evaluating toxicity and cumulative doses. Patients can stabilize or continue to show a sub-optimal response. If it is clear that the disease is refractory, a second immunosuppression cycle could be attempted.
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If after a period of clinical stability after treatment with alemtuzumab or cladribine, patients experience a resurgence of disease activity, either of these agents could be used again (a 3day treatment with alemtuzumab or two treatments every 6 months with cladribine), to induce remission. If relapse occurs after treatment with cyclophosphamide or mitoxantrone,
M
alemtuzumab, cladribine or AHSCT may be used.
ED
To evaluate the response to treatment in patients with aggressive MS, we recommend low
PT
thresholds of acceptable disease activity. Strict monitoring is essential to achieve a timely sub-optimal response. However, there is no consensus regarding the frequency with which
CE
patients should be monitored. The literature suggests a clinical evaluation every 3 months and a radiological evaluation every 6 months. We should accept only minimal evidence of
AC
disease activity (such as relapse, MRI activity or EDSS progression) as a reason to further intensify treatment: in other words, we must strive to achieve NEDA.
Conclusion
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Early detection of HAMS is essential, since these patients have a much higher risk of early progression than other MS patients. In addition, HAMS tends to be refractory to conventional DMTs. A timely and adapted implementation of specific treatment strategies
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for this group of patients can have a positive impact on the severity of the disease and the disability. The use of more aggressive treatment agents will require closer continuous
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Tables
Table 1. Specific treatments for HAMS
from:
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Drug
Protocol
Mechanism of Action
Alemtuzumab
DI: IV infusion 12 Humanized monoclonal directed
(93%)
Monitoring
Related
against infusion:
mild
to No
specific
to recommendation
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mg per day for 5 ab
Side Effects
days followed by 2 CD52, high levels of moderate
(>90%),
cycles of 12 mg for surface antigen present in serious reactions (3%). 3 days after 12 T and B lymphocytes
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months
(71%)
infections:
Serious
cerebral No milk, seafood listeria consumption.
nocardiosis, meningitis,
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tuberculosis, pancolitis due to E. coli (2.7%). PML Nasopharyngitis. ARI. UTI. (36%)
TSH
every
3
months. Monthly Thyroid monitoring
of
hypo- symptoms
disorders: hyperthyroidism,
Serious Dis., thyroid
No
specific
recommendation
ophthalmopathy. Thyroid cancer. (12%)
Superficial
Annual screening
for
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fungal infections: oral- HPV vaginal candidiasis. (3%)
Herpes
Monthly
virus monitoring with
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infections: HPV (2%), blood count and oral herpes simplex, blood VZV (0.3%).
differential.
(1%) Haematological
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disorders: ITP, other cytopenias
(neutropenia, hemolytic
M
pancytopenia)
ED
(0.3%)
for 4 days every 6 nucleoside months
urinalysis
and
creatinine,
and
48 months posttreatment
Nephropathy:
Membranous
PT CE
0.875 mg/kg daily Synthetic
AC
Cladribine
anemia,
Monthly
GN,
anti-glomerular membrane purine Risk
of
long-term Screening
and malignancy
antimetabolite that acts as an antineoplastic agent with immunosuppressive
Infectious: zoster
cancer herpes
for
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effect. It reduces the number of CD4+ and CD8+ T lymphocytes Induction protocol: Nonspecific
cytotoxic (33-47%) infertility
de
600mg/m2 daily for agent of the cell cycle 5 days + MTP, that exerts its effect on T
(800-1000mg/m )
suppresses humoral and cystitis
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2
monthly for every cellular immunity, broad 12-24 months; with spectrum. or without MTP.
(120-200
M
High dose protocol mg/kg
specific
recommendation
protocol and B lymphocytes, it (7-15%) Hemorrhagic
pulse
No
CR IP T
Cyclophosphami
(5-7%) Bladder cancer
Urinalysis
and
cytology every 6 months.
If
cytology
is
abnormal, annual
Brain atrophy
cystoscopy
ED
daily for 5 days).
PT
Maximum lifetime cumulative
dose:
12mg/m2 every 3 It is an anthracenedione (22-26%)
AC
Mitoxantrone
CE
80-100 g.
months
for
24 similar to doxorubicin.
months. Maximum lifetime cumulative dose: 140mg/m
amenorrhea
It inhibits proliferation of (12%)
Permanent No
specific
recommendation Systolic Annual
T and B lymphocytes. It dysfunction
echocardiogram
suppresses
or CAT scan for
2
cytokines
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secreted
by
Th1 (10%) Cardiotoxicity
lymphocytes (TNF, IL-
(0.4%) Heart failure
12)
5
years
post-
treatment. Complete blood
(1%) Leukemia
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count every 6 months for 10 years
Initial dose: 1 g and Partially again after 15 days. Maintenance dose: 1 g every 6 months
monoclonal
humanized Infusion
reactions
antibody 7.8%:
headache,
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Rituximab
against CD20 antigen in malaise, chills, nausea. B lymphocytes, leading
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to B cell depletion.
Bacterial
systemic
infections
(1.7%):
pneumonia
(2.3%),
otitis
(1.5%)
pyelonephritis, sepsis, sinusitis
(1.2%),
appendicitis, enteritis, bronchitis
(0.5%),
erysipelas , intestinal abscess, tubulointerstitial nephritis)
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Cardiac
alterations
0.1% (acute coronary syndrome)
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Respiratory alterations 0.1%:
interstitial
pneumonitis
CNS alterations 0.1%:
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bilateral
facial
paralysis
Alterations
of
the
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immune system 0.1%: rheumatoid arthritis. Alterations 0.1%: syndrome,
in
skin
Sweet’s herpes
0.7% Neoplasms: basal cell carcinoma 0.2% and pyoderma gangrenosum 0.1%
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Progressive multifocal leukoencephalopathy Methodology:
Transplantation
-Mobilization
of hematopoietic
-Immunoablation
cells -Autograft
lymphoid
viremia of EB
system spectrum
vivo
B
cell
depletion comprises
cells
post-transplant
is
eliminated, adaptive
system cells [B and T
Transient alopecia
preventive
cells
[cells:
ED
Permanent infertility
and Secondary with
a autoimmune diseases
cytotoxic new one derived from (3.6-6.4%): thyroiditis
PT
chemotherapy with HSCs. cyclophosphamide
HSCs
are Cancer
obtained by allogeneic or
2-4g/m2SC autologous
combined
with transplantation. and
hyperhydration for bladder protection)
increase
system
monocytes
HSC:
mesna
and in case of
viremia,
A. Mobilization of granulocytes])
dose
Viral infections
lymphocytes] and innate Amenorrhea
4 natural killer, dendritic,
steps:
and CMV in the first 3 months
M
It
of
Sepsis
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-Serotherapy for in
(a
of
lymphoid and myeloid Urinary infection
including
CE
(HSCs)
Monitoring
broad
AC
stem
It replaces the blood and Febrile neutropenia
CR IP T
AHSC
It eliminates the aberrant adaptive immune system, reconstituting
the
treatment required.
in
is
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associated
with immune
granulocyte colony achieve stimulating
system
to
immunological
factor tolerance.
5-10ug/kg/day until the
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completing
collection of HSC. B. HSC extraction
AN US
(leukapheresis). C. Ablation. D. Reinfusion
or
Duration:
extraction:
ED
1.Mobilization and 5-15
PT
days 2. Ablation: begins 2-4 weeks
CE
after A-B step.
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transplant.
Abbreviation: ID, initial dose.
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Figures
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Figure 1: Risk factors for HAMS
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Figure 2. Induction therapy in HAMS
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Figure 3. Treatment algorithm for HAMS
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* Figure taken from: Continuum (Minneap Minn) 2016;22(3):761–784. Contin Lifelong Learn Neurol. 2016;22(3):761–84. (20)
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Images cases
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Clinical case 1
B A
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A
E
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Clinical case 1: 30-year-old male patient with no relevant history who was admitted for a clinical picture of 6 days of diplopia. Neurological examination with finding of mesencephalic syndrome and left pyramidal motor. Normal cerebrospinal fluid. Oligoclonal bands positive pattern II. Brain MRI study shown in images:
F
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Panel A. Axial FLAIR and sagittal. Panel B sequence with evidence of more than 40 hyper-intense ovoid lesions, scattered in white matter of both cerebral hemispheres (predominantly peri-ventricular), thalamus, left basal nuclei and cortical. Panel C.
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Panel D. Compromise of the corpus callosum in the region of the callous-septal interface. Panel E. Lesions in mid-cerebellar peduncles and less numerous in the white matter of both cerebellar hemispheres.
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Panel F. After the injection of intravenous gadolinium, we identified peripheral enhancement of 4 of the supratentorial lesions, the greater of 10 mm in the anterior
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subcortical region of the right frontal lobe.
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Clinical case 2: 27-year-old female patient diagnosed with HAMS. Panel A and B: Axial and sagittal FLAIR sequence: shows more than 30 hyperintense
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lesions located in the periventricular supratentorial white matter (some involving the parasagittal fibers of the corpus callosum), in the white matter of the semioval centers and less numerous in the subcortical white matter of both cerebral hemispheres.
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Panel C: Axial T2 sequence: lesions in both middle cerebellar peduncles.
F and G: Small eccentric hyperintense lesion, whose length does not exceed 5 mm, involving the left lateral aspect at C3-C4 level, without enhancement after gadolinium
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injection.
A
C
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B
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G
E
F