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Magnetic Resonance Imaging and ³¹P Magnetic Resonance Spectroscopy Investigations of Muscle Function Disclose No Abnormality in Macrophagic Myofasciitis

To the Editor:

Macrophagic myofasciitis (MMF) has been recently described as a localized inflammatory muscle disease on the basis of histological investigations. MMF might be triggered by aluminum hydroxide used as adjuvant in hepatitis A, hepatitis B, and tetanus toxoid vaccines in order to enhance anti-vaccine antigen immune responses. Muscle biopsy performed on the vaccination site typically shows infiltration of connective tissue by large, grossly rounded, and densely packed CD68+ macrophages¹. Various clinical symptoms such as diffuse myalgia, arthralgia, marked asthenia, muscle weakness, fever, and symptomatic demyelinating central nervous system disorder have been reported to date, while no clear link has been established with myofasciitis^1,2. Although it has been suggested that aluminum hydroxide-containing vaccine might account for histological changes of MMF in the context of the HLA-DRB1*01 genetic background^3,4, a link between aluminum hydroxide injections and clinical symptoms has not been established. Considering the skeletal muscle signs, the existence of an underlying or vaccine-induced myopathy could be suspected, but no data regarding muscle function have been available to date. We investigated whether muscle energy metabolism and muscle anatomy are altered in patients with MMF similarly to what has been observed in other inflammatory diseases^5-8.

Nine patients with MMF (7 men, 2 women, mean age 40.7 ± 8.7 yrs) were studied, and the diagnosis of MMF was performed according to histopathological results⁹. Using ³¹P magnetic resonance spectroscopy (MRS), high-energy phosphate compound concentrations and pH values were recorded throughout a rest-exercise-recovery protocol as described¹⁰. Control subjects (n = 27, 12 women) were free from chronic or acute muscle disease. Conventional magnetic resonance imaging (MRI) sequences (T1 and T2 weighted and inversion-recovery techniques) were performed on thigh muscles. The statistical distribution of sex and age was similar in the 2 groups.

In all patients, inflammatory infiltrates containing macrophages were observed within muscle and fascia. Intracytoplasmic spiculated inclusions were detected by electron microscopy. Two clinical patterns were observed in the patient group, i.e., central and/or peripheral nervous system involvement in 4 patients and myalgias and chronic fatigue in the remaining 5. In the latter group, no particular MRI abnormality was observed, whereas in the former group signs of muscle atrophy with fatty infiltration were found (Figure 1). At rest, the ratios of metabolite concentrations (PCr/ATP, Pi/ATP, and PCr/Pi) and pH values were not different between groups. Accordingly, as shown in Figure 2, the average absolute PCr concentration measured at rest was similar in both groups (33.4 ± 4.5 mM in the MMF group vs 34.3 ± 3.1 mM in controls), while the scattering of data was also identical. Exercise-induced PCr and pH changes were of similar magnitude in both groups. As expected, muscle contraction led to PCr consumption (17.9 ± 7.1 mM in MMF patients vs 23.8 ± 10 mM in controls) and intracellular acidosis (0.41 ± 0.26 pH unit in MMF patients vs 0.50 ± 0.22 pH unit in controls). In the early period of exercise, intracellular alkalosis was recorded as a result of H⁺ consumption through PCr breakdown. Thereafter, pH decreased, indicating a net H⁺ production related to anaerobic glycogenolysis coupled to ATP hydrolysis¹¹. Accumulation of ADP (calculated from PCr and pH changes) was similar in both groups. The initial rate of PCr recovery did not differ between groups, indicating, when taking account of end-exercise ADP values, normal involvement of aerobic ATP production in patients.

In light of these results, an impairment of muscle energy metabolism could clearly be ruled out in patients with MMF. Oxidative and anaerobic energy production during exercise was similar in MMF patients and controls. This is in contrast to the increased energy cost previously reported in dermatomyositis, thereby excluding such a myopathy or even a glycogenolytic disorder as a cause of myalgias in MMF^5,8. Regarding a potential oxidative disorder, the rate of PCr changes in the initial recovery period provides unquestionable evidence of normal aerobic function, thereby excluding a mitochondrial impairment in MMF patients¹². Considering the MRI results, the signs of atrophy and fatty infiltration observed in patients with neurological symptoms are very common and are nonspecific for a particular neuromuscular disease. They might only reflect a deconditioning phenomenon due to reduced physical activity¹³. Apart from a metabolic muscle disorder, other physiopathological hypotheses have been put forth, considering MMF either as a fortuitous association with other connective tissue disorders or as a new clinical syndrome related to a chronic immune response induced by aluminum granulomas persisting at the sites of prior immunization¹⁴. The existence of a genetic predisposition has also been described⁴, and all these issues will be more precisely documented in the future.

It can be concluded from our study combining ³¹P MRS and MRI that neither alterations of mitochondrial function nor modifications in glycolytic or glycogenolytic pathways can account for muscle signs in patients with MMF, indicating that no primary or secondary underlying anomaly of muscle energy metabolism is responsible for the observed clinical symptoms.

SANDRINE GUIS, MD, PhD, Associate Professor in Rheumatology; JEAN-PIERRE MATTEI, MD, PhD, Senior Consultant in Rheumatology, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS no. 6612, Service de Rhumatologie, Hôpital La Conception; JEAN-FRANÇOIS PELLISSIER, MD, Professor of Pathology, Service d'Anatomie-Pathologie et de Neuropathologie, Hôpital la Timone; FRANÇOIS NICOLI, MD, PhD, Professor of Neurology, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS no. 6612, Service de Neurologie, Hôpital Sainte Marguerite; DOMINIQUE FIGARELLA-BRANGER, MD, PhD, Professor of Pathology, Service d'Anatomie-Pathologie et de Neuropathologie, Hôpital la Timone; YANN LE FUR, PhD, CNRS Research Engineer, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS no. 6612; GILLES KAPLANSKI, MD, PhD, Professor of Internal Medicine, Service de Médecine Interne, Hôpital La Conception; JEAN PELLETIER, MD, Professor of Neurology, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS no. 6612, Service de Neurologie, Hôpital de la Timone; JEAN-ROBERT HARLE, MD, Professor of Internal Medicine, Service de Médecine Interne, Hôpital La Conception; PATRICK J. COZZONE, PhD, Professor of Biophysics; DAVID BENDAHAN, PhD, CNRS Research Director, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS no. 6612, Faculté de Médecine, Marseille, France.

Address reprint requests to Dr. D. Bendahan, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13005 Marseille, France. E-mail: david.bendahan@medecine.univ-mrs.fr

Supported by CNRS (UMR CNRS 6612) and Programme Hospitalier de Recherche Clinique.

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