Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment

Abstract

Sixty relapsing-remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.

Keywords

4-aminopyridine evoked potentials fatigability fluoxetine fatigue multiple sclerosis transcranial magnetic stimulation

Get full access to this article

View all access options for this article.

References

Colosimo C , Millefiorini E , Grasso MG , Vinci F , Fiorelli M , Koudriavtseva T et al. Fatigue in MS is associated with specific clinical features . Acta Neurol Scand 1995; 92: 353-355 .

Fisk JD , Pontefract A , Ritvo PG , Archibald CJ , Murray TJ. The impact of fatigue on patients with multiple sclerosis . Can J Neurol Sci 1994; 21: 9-14 .

Iriarte J , Subira ML , Castro P. Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors . Mult Scler 2000; 6: 124-130 .

Krupp LB , LaRocca NG , Muir-Nash J , Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus . Arch Neurol 1989; 46: 1121-1123 .

Krupp LB. Fatigue in multiple sclerosis: definition, pathophysiology and treatment . CNS Drugs 2003; 17: 225-234 .

Iriarte J , Katsamakis G , de Castro P. The Fatigue Descriptive Scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis . Mult Scler 1999; 5: 10-16 .

Djaldetti R , Ziv I , Achiron A , Melamed E. Fatigue in multiple sclerosis compared with chronic fatigue syndrome: a quantitative assessment . Neurology 1996; 46: 632-635 .

Sheean GL , Murray NM , Rothwell JC , Miller DH , Thompson AJ. An electrophysiological study of the mechanism of fatigue in multiple sclerosis . Brain 1997; 120: 299-315 .

Iriarte J , de Castro P. Correlation between symptom fatigue and muscular fatigue in multiple sclerosis . Eur J Neurol 1998; 5: 579-585 .

10.

Schreurs KM , de Ridder DT , Bensing JM. Fatigue in multiple sclerosis: reciprocal relationships with physical disabilities and depression . J Psychosom Res 2002; 53: 775-781 .

11.

Krupp LB , Coyle PK , Doscher C , Miller A , Cross AH , Jandorf L et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo . Neurology 1995; 45: 1956-1961 .

12.

Moresco RM , Volonte MA , Messa C , Gobbo C , Galli L , Carpinelli A et al. New perspectives on neurochemical effects of amantadine in the brain of parkinsonian patients: a PET- [(11)C]raclopride study . J Neural Transm 2002; 109: 1265-1274 .

13.

Rossini PM , Pasqualetti P , Pozzilli C , Grasso MG , Millefiorini E , Graceffa A et al. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine . Mult Scler 2001; 7: 354-358 .

14.

Smith KJ , Felts PA , John GR. Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension . Brain 2000; 123: 171-184 .

15.

Zifko UA , Rupp M , Schwarz S , Zipko HT , Maida EM. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study . J Neurol 2002; 249: 983-987 .

16.

Ishizuka T , Sakamoto Y , Sakurai T , Yamatodani A. Modafinil increases histamine release in the anterior hypothalamus of rats . Neurosci Lett 2003; 339: 143-146 .

17.

Poser CM , Paty DW , Scheinberg L , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 1983; 13: 227-231 .

18.

Bergamaschi R , Romani A , Versino M , Poli R , Cosi V. Clinical aspects of fatigue in multiple sclerosis . Funct Neurol 1997; 12: 247-251 .

19.

Hamilton M. Development of a rating scale for primary depressive illness . Br J Soc Clin Psychol 1967; 6: 278-296 .

20.

Beck AT , Beck RW. Screening depressed patients in family practice: a rapid technique . Postgrad Med 1972; 52: 81-85 .

21.

Stroop JR. Studies of interference in serial verbal reactions . J Exp Psychol 1935; 18: 643-672 .

22.

Wechsler D. Manual of the Wechsler Adult Intelligence Scale revised. New York, NY: Psychological Corporation , 1981.

23.

Corrigan JD , Hinkeldey NS. Relationships between part A and part B of the trail making test . J Clin Psychol 1987; 43: 402-409 .

24.

Novelli G , Papagno C , Capitani E , Laiacona M , Vallar G , Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali . Arch Psicol Neurol Psichiat 1986; 47: 577-586 .

25.

Lloyd AR , Gandevia SC , Hales JP. Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome . Brain 1997; 114: 83-98 .

26.

Schwid SR , Covington M , Segal BM , Goodman AD. Fatigue in multiple sclerosis: current understanding and future directions . J Rehabil Res Dev 2002; 39: 211-224 .

27.

Mathiowetz V. Test-retest reliability and convergent validity of the Fatigue Impact Scale for persons with multiple sclerosis . Am J Occup Ther 2003; 57: 389-395 .

28.

Kroencke D , Lynch SG , Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability and disease pattern . Mult Scler 2000; 6: 1131-1136 .

29.

Amato MP , Ponziani G , Rossi F , Liedl CL , Stefanile C , Rossi L. Quality of life in multiple sclerosis: the impact of depression, fatigue and disability . Mult Scler 2001; 7: 340-344

30.

Vercoulen JH , Hommes OR , Swanink CM , Jongen PJ , Fennis JF , Galama JM et al. The measurement of fatigue in patients with multiple sclerosis: a multidimensional comparison with patients with chronic fatigue and healthy subjects . Arch Neurol 1996; 53: 642-649 .

31.

Rao SM , Leo GJ , Bernardin L , Unverzagt F. Cognitive dysfunction in multiple sclerosis: I Frequency, patterns and prediction . Neurology 1991; 41: 685-691 .

32.

Beatty WW , Goodkin DE , Monson N , Beatty PA. Cognitive disturbances in patients with relapsing-remitting multiple sclerosis . Arch Neurol 1989; 46: 1113-1119 .

33.

Krupp LB , Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis . Neurology 2000; 55: 934-939 .

34.

Sandroni P , Walker C , Starr A. ‘Fatigue’ in patients with multiple sclerosis. Motor pathway conduction and event-related potentials . Arch Neurol 1992; 49: 517-524 .

35.

Roelcke U , Kappos L , Lechner-Scott J , Brunnschweiler H , Huber S , Ammann W et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a F-fluorodeoxyglucose positron emission tomography study . Neurology 1997; 48: 1566-1571 .

36.

Filippi M , Rocca MA , Colombo B , Falini A , Codellaa M , Scotti G et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis . NeuroImage 2002; 15: 559-567 .

37.

George MS , Wassermann EM , Kimbrell TA , Little JT , Williams WE , Danielson AL et al. Mood improvement following daylileft prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial . Am J Psychiatry 1997; 12: 1752-1756 .

38.

Rossini PM , Marciani MG , Caramia M , Roma V , Zarola F. Nervous propagation along ‘central’ motor pathways in intact man: characteristics of motor responses to ‘bifocal’ and ‘unifocal’ spine and scalp non invasive stimulation . Electro-enccephalog Clin Neurophysiol 1985; 61: 272-286 .

39.

Rollink JD , Schubert M , Albrecht J , Wohlfarth K , Dengler R. Effects of somatosensory input on central fatigue: a pilot study . Clin Neurophysiol 2000; 111: 1843-1846 .

40.

Bashir K , Whitaker JN. Handbook of multiple sclerosis. Philadelphia, PA: Lippincott Williams and Wilkins , 2002: 143-143.

41.

Stefoski D , Davis FA , Fitzsimons WE , Luskin SS , Rush J , Parkhurst GW.

4-Aminopyridine in multiple sclerosis: prolonged administration

Neurology 1991; 41: 1344-1348 .

42.

Van Diemen HAM , Polman CH , Koetsier JC , Van Loenen AC , Nauta JJP , Bertelsmann FW. 4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy . Clin Neuropharmacol 1993; 16: 195-204 .

43.

Isolda WC , Segal JL. Effects of 4-aminopyridine on cardiac repolarization, PR interval and heart rate in patients with spinal chord injury . Pharmacotherapy 2003; 23: 133-136 .