The i.m. injection of a dose of a vaccine adsorbed on aluminum hydroxide is sufficient to induce MMF lesions in rats (3), macaque (10), and mouse (11). The biopersistence of such a lesion is much longer than originally thought. In rats, these lesions persist 1 year (3) and elimination kinetics depends on the genetic background. In macaques, 50% of injected animals had detectable lesions at 1 year. In human beings, the persistence time of post-vaccinal physiological tissue damage is not known. As long as we do not have non-invasive and reliable imaging technique to visualize MMF lesions with certainty, and that can substitute for biopsy, this data will be impossible to determine, and can only be based on projections, derived from experimental data obtained in animals. In 1999, the WHO asked for the mechanisms involved in the persistence of MMF lesion. It proposed that “A plausible possibility is the existence of a predisposed subset of individuals with impaired ability to clear aluminum from the deltoid muscle. Whether this reflects a macrophagic dysfunction of either genetic or acquired origin, or the tail end of a normal distribution describing the kinetics of aluminum clearance and the local tissue response to it in the general population, has not yet been defined” (9). In the current state of knowledge, it can be assumed that the presence of lesions MMF has no formal pathological significance if the biopsy was performed within one year after vaccination (provided that the biopsied muscle is the actual site of vaccine injection). If the delay is superior to 2 years, the presence of MMF lesions can be considered pathological. If one considers that the detection of MMF lesion is purely fortuitous phenomenon, the probability to find this lesion would be higher as the date of biopsy would be close to the date of vaccination. Examination of the distribution histograms of vaccination-biopsy delays goes against this hypothesis (Figure 1). The median delay elapsed between last vaccination and biopsy was found at 53 months (12) and the distribution profile shows a peak between 4 and 5 years after vaccination, in complete opposition to the model of “the tail of the normal distribution” (9). It must be noted that, in the small subset of patients, the delay was <1 year. In these cases, MMF lesion can not be considered pathological.

Aluminum salts other than aluminum hydroxide are used as vaccine adjuvants. For example, quadrivalent anti-human papilloma virus (HPV) vaccine available in France contains aluminum hydroxyphosphate. Several observations of girls developing fatigue/myalgias syndrome after HPV vaccination raised the question of possible MMF induced by this vaccine. At electron microscopy, the structure of aluminum hydroxyphosphate differs from that of aluminum hydroxide (13) suggesting different physicochemical properties. Macrophages in lesion were fluorescent with Morin technique, indicating the presence of aluminum. Time persistence of granuloma after quadrivalent HPV vaccine i.m. injection has not yet been determined in mouse to our knowledge. Moreover, further studies are needed to evaluate whether HPV vaccine may actually induce full-blown MMF in human beings.

The evidence of an abnormally prolonged persistence (several years) of aluminum hydroxide in muscle tissue after i.m. injection, has led some authors to speak of “vaccination tattoo” (14, 15), considering MMF lesion as an inert vaccine scar. However, data from literature contradict this view and it seems somewhat unwise to regard protracted persistence of aluminum hydroxide within body as trivial. First, the majority of aluminum-containing vaccine receivers do not have long-standing MMF at muscle biopsy (7), considering MMF and non-MMF patients similar for age, sex-ratio, the number of aluminum-containing vaccines, and the delay between last vaccine injection and biopsy. Second, histopathological investigation indicates that MMF lesion is immunologically active (2), a finding consistent with the immunostimulant properties of aluminum hydroxide (16). Third, although it is true that MMF histological lesions have been observed only at usual sites of vaccinations so far, experiments performed in rodents (rabbits, mice) showed that the i.m. injection of aluminum hydroxide is accompanied by the diffusion of aluminum in the entire body, including a fraction of the aluminum that penetrates and persists in brain (11, 17).

The analysis of data from the literature (Table 2) and Henri Mondor database (Table 1) allows defining most representative features of MACS. The development of symptoms is usually slow, over several months. Diffuse myalgias were observed with a prevalence ranging from 55 to 96%. Myalgias have been recognized as cardinal symptoms since first description. The InVS study (18) showed that myalgias most often began distally in lower limbs, with subsequent progressive extension to the whole body. At physical examination, patients usually exhibit only few tender point sites, if not none. The tenderness at specific tender point sites is a characteristic feature of fibromyalgia, which are included in the clinical criteria for fibromyalgia proposed in 1990 by the American College of Rheumatology (ACR) (20). Logically, most MMF patients did not meet the 1990 ACR criteria for fibromyalgia (7). In a minority of patients, myalgias are the only functional complaints. Arthralgias are less frequently reported (14–84% depending on the series) and may sometime represent the only complaint. Spinal pain, especially dorsal, is also frequently observed. Finally, MMF patients typically present with diffuse arthromyalgias affecting both proximal and distal parts of lower and upper limbs and spine, pain being usually present at waking up and exacerbated by exercise and daily activity, leading to marked disability. At physical examination, muscle strength is usually normal, and the presence of a true deficit must prompt a search for a diffuse muscular inflammatory/dysimmune process (e.g., inclusions body myositis or autoimmune necrotizing myopathy) that may associates with MMF.

Chronic fatigue is the second cardinal symptom, with a prevalence ranging from 36 to 100% depending on the study (91% in InVS study). In a study conducted in 30 MMF patients (25), we found chronic (duration >6 months) fatigue in 28/30 patients (93%). Fatigue was considered severe and debilitating in 26/30 patients (87%), caused a significant reduction of activities in 24/30 (80%), was present more than half the time in 19/30 patients (63%), affected both physical and mental functioning in 16/30 patients (53%), and was not alleviated by rest in 13/30 patients (43%). The majority of patients (16/30, 53%) met the 1991 Oxford or 1994 CDC international criteria for chronic fatigue syndrome (25). In some patients, chronic fatigue may be the only symptom at onset and it may precede pain by several months.

The third cardinal clinical manifestation in MMF is cognitive impairment (5, 6). This item has been neglected for a long time and was incorrectly considered as non-specific. Indeed, chronic pain, chronic fatigue states, and depressive syndromes are known to impair intellectual or cognitive performance, especially attention and concentration. In most studies, cognitive disturbances were not mentioned. The prevalence of cognitive complaints ranged from 20 to 68% (5, 12, 23–25). In a first comprehensive study (5), we demonstrated that all MMF patients had quantifiable neuropsychological involvement. MMF-associated cognitive dysfunction (MACD) is usually severe, and did not correlate to pain, fatigue, depression, disease duration, or drug intake (5, 6). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. The cognitive profile combines a dysexecutive syndrome, memory impairment, and signs of inter-hemispherical disconnection (5). Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment (MCI) (Figure 2), even if some cognitive deficits seem unusually severe (6). MACD is probably the most disabling feature of MMF but seems stable with time, despite marked fluctuations (6). Long-term follow-up is needed to determine the evolution of patients.

Psychiatric manifestations are unusually frequent in MMF patients, often leading physicians to consider physical complaints as psychosomatic. When checked on, the prevalence of mood disorders ranged from 50 to 60% (6, 25). MMF-associated psychiatric manifestations have not been specifically investigated, to date, but plausibly they could be consubstantial with the disease and contribute to alter the relations of patients with physicians. Various other complaints are reported by MMF patients, most regularly encountered being dyspnea and headache (12).