Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: A pilot analysis

https://doi.org/10.1016/j.clineuro.2011.02.018Get rights and content

Abstract

Objective

Mitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS).

Methods

In an open-label, retrospective analysis, we investigated effects of MX therapy on parameters of cognitive functions in patients with progressive MS and significant disability. Twenty patients received a total of 42 mg/m2 MX in 4 cycles. Six patients who fulfilled the criteria for MX therapy, yet did not receive this treatment, served as controls. Before initiation of therapy and after a mean observation period of 24 months, neurological examination and a neuropsychological test battery were performed. Neuropsychological analyses comprised tests for cognitive flexibility as a part of executive functioning, and verbal as well as non-verbal tests for memory and attention. Additionally, intelligence and symptoms of depression were investigated.

Results

While there was stability of EDSS over time, there were no differences in cognitive functions before and after MX treatment. In contrast, patients not receiving MX showed a worsening of verbal short term memory and cognitive flexibility over the same time period.

Conclusion

In conclusion, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis.

Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) in young adults. It is characterized by demyelination, gliosis as well as neurodegenerative features and involves primarily the white, but more recently in the focus of interest, also the grey matter. While MS symptoms typically comprise optic neuritis, sensory and motor symptoms as well as bladder dysfunction, the impairment of neuropsychological functions is increasingly recognized. Indeed, cognitive dysfunction has an estimated prevalence of 65% in MS patients and constitutes a major cause of disability [1], [2], [3]. It is not strictly correlated with disease duration [4], [5] and may develop irrespective of disease subtype or stage [6], [7], including patients with “benign” MS [8], early MS [9] or even clinically isolated syndrome [10], [11]. Available data from studies on the natural history of MS suggest that remission of existing cognitive dysfunction is unlikely and that cognitive performance may decrease with worsening disability [2], [12], [13], [14]. In particular, worsening cognitive function may indicate progressive disease in patients with stable physical symptoms [13], [15] and cognitive impairment may predict physical disability and the rate of future disability progression [13], [15]. Typically, cognitive dysfunction in MS involves the domains of memory, learning, attention, executive functions and information processing activities and there is a common comorbidity with fatigue and depression [16], [5], [17], [18].

While cognitive impairment is highly prevalent in MS patients, effective treatment strategies have not yet been well established. Non-pharmacological interventions, such as occupational therapy, psychotherapy and cognitive rehabilitation may at least transiently improve cognition, but probably do not prevent the long-term decline of cognitive functions [19]. Disease-modifying drugs such as interferon beta preparations and glatiramer acetate significantly reduce relapse rates and MRI parameters of inflammation and may also prevent or delay cognitive impairment as shown in some smaller studies [20], [21]. Yet, the definitive cognitive benefits of all these compounds in MS have not yet been elucidated [16], [22].

Mitoxantrone (MX) is an anthracenedione that exerts potent cytotoxic effects, including induction of B cell apoptosis and reduction of T cell numbers [23]. In clinical trials, MX showed a statistically significant effect on the reduction of relapse rate and disability progression [24] and, in 2000, the FDA approved the use of MX for the treatment of active relapsing–remitting MS, secondary progressive MS and progressing relapsing MS [25]. Generally, MX treatment is well tolerated, yet the risk of leukaemia and dose-dependent cardiotoxicity limit its use in clinical practice [26]. So far, only a small French study investigated the impact of MX on cognitive functions in patients with very active MS. In 15 MS patients who received monthly intravenous MX pulses combined with methylprednisolone, a significant improvement in global cognitive functions was observed over 6 months [27].

Here we studied neuropsychological functions in significantly disabled patients with progressive MS under MX therapy and show stability of cognitive functions over a mean observation period of 2 years.

Section snippets

Patients

Charts from MS patients who were treated with mitoxantrone since 2006 at the Neurology Department, St. Josef Hospital Bochum, Germany, were reviewed. Out of these patients, 30 individuals with available data of neuropsychological testing were identified. After thorough review of all available information, data from 20 patients with progressive or relapsing-progressive MS who received testing with a standardized protocol before and after 4–5 cycles of MX treatment were included in the

Neuropsychological functions at baseline

For neuropsychological testing, patients were first subjected to routine screening for depression, dementia or mental retardation. To this end, a battery including Beck's depression inventory, clock drawing test as well the MWT-B and LPS subtest 3 for IQ testing were employed. As seen in Table 1, these tests excluded major symptoms of depression as well as dementia. IQ testing revealed an average intelligence in the investigated MS patients. In summary, tests on cognitive functions under MX

Discussion

Here we investigated cognitive functions under MX therapy and show a slightly improved EDSS as well stability of cognitive functions over an observation period of 2 years. While beneficial effects of MX on motor functions are well characterized [25], these data suggest that aggressive immunotherapy may also exert some positive effects on cognitive functions, as already described for immunomodulatory drugs such as interferon beta preparations or glatiramer acetate. Indeed, MX may display a

Conclusion

In summary, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis. Further studies on the impact of MS immunotherapies on cognitive functions are needed. Such investigations may not only comprise early MS, but also patients with already existing disability.

Acknowledgement

We are indebted to Christian Prehn for help with the neuropsychological assessment.

References (39)

  • S.C. Huijbregts et al.

    Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS

    Neurology

    (2004)
  • C.G. Haase et al.

    The influence of immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis

    Neuroimmunomodulation

    (2004)
  • M.P. Amato et al.

    Cognitive impairment in early-onset multiple sclerosis Pattern, predictors, and impact on everyday life in a 4-year follow-up

    Arch Neurol

    (1995)
  • L. Feuillet et al.

    Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis

    Mult Scler

    (2007)
  • B.I. Glanz et al.

    Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis

    Mult Scler

    (2007)
  • S.M. Rao et al.

    Cognitive dysfunction in multiple sclerosis I. Frequency, patterns, and prediction

    Neurology

    (1991)
  • S.G. Lynch et al.

    The association between cognitive impairment and physical disability in multiple sclerosis

    Mult Scler

    (2005)
  • A. Achiron et al.

    Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves

    J Neurol Neurosurg Psychiatry

    (2005)
  • M.P. Amato et al.

    Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years

    Arch Neurol

    (2001)
  • 1

    Present address: Department of Neurology, University Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.

    View full text