Macrophagic myofasciitis in childhood: a controversial entity

Macrophagic myofasciitis is an unusual inflammatory myopathy, which has been almost exclusively reported in French adults with diffuse arthromyalgias and asthenia. It is characterized by an infiltrate of densely packed macrophages, with granular periodic-acid-Schiff positive content, on muscle biopsies at the site of vaccination. The presence of aluminum inclusions in these macrophages points to an inappropriate reaction to aluminum used as an adjuvant in some vaccines. Although in adults this entity is well defined, less than 15 cases have been reported in children. This study describes seven children, younger than 3 years of age, with typical lesions of macrophagic myofasciitis on quadriceps muscle biopsy. In five cases, biopsies were performed to exclude mitochondrial pathology. All the children developed hypotonia and motor or psychomotor delay, associated with others symptoms. Abnormal neuroimaging was evident in six cases. Spectrometry studies detected elevated levels of aluminum in muscle in three of four cases tested. Despite the wide use of vaccines in childhood, macrophagic myofasciitis was rarely observed in children and its characteristic histologic pattern could not be correlated with a distinctive clinical syndrome.     

Macrophagic myofasciitis: an infantile Italian case

Macrophagic myofasciitis is a recently identified inflammatory myopathy mostly described in adult French patients complaining of arthro-myalgias and fatigue. It is probably due to intramuscular injection of aluminium-containing vaccines and is characterized by a typical muscular infiltrate of large macrophages with aluminium inclusions. We report a 1-year-old Italian child presenting irritability, delayed motor development, hyperCKemia (up to 10 times the normal value), and typical features of macrophagic myofasciitis on muscle biopsy. The child recovered fully after steroid therapy. Macrophagic myofasciitis is a new treatable cause of motor retardation and hyperCKemia in children, and is probably more common than reported. Diagnosis requires a high index of suspicion and can be missed if biopsy is performed outside the vaccination site.     

Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome

Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients. One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.     

Inflammatory myopathy with abundant macrophages (IMAM): a condition sharing similarities with cytophagic histiocytic panniculitis and distinct from macrophagic myofasciitis

We describe the unreported pattern of inflammatory myopathy with abundant macrophages (IMAM) as a main differential diagnosis of postimmunization aluminum hydroxide-induced macrophagic myofasciitis (MMF). IMAM was mainly detected among patients with a dermatomyositis (DM)-like disease. Among 113 muscle biopsies from DM patients collected from 1974 to 2000, intensity of macrophage infiltration was highly variable: 41.5% (-/+); 34.5% (+); 17% (++): and 7% (+++). The 27 patients from groups (++) and (+++) had a similar pattern of macrophagic infiltration and were considered to have IMAM. They were compared to 40 MMF patients. In IMAM, macrophage infiltrates were diffuse and correlated positively with both T cell infiltrates and acute muscle fiber damage, and showed pictures of hemophagocytosis (21/27). Connective tissue structures were infiltrated by noncohesive, ribbon-forming collections of large basophilic macrophages containing no crystalline inclusions. In MMF, macrophage infiltrates were focal and formed compact well-delineated aggregates of granular PAS+ cells, loaded with crystalline aluminum hydroxide particles, in the absence of either hemophagocytosis or conspicuous muscle damage. Review of the literature indicates similarities between IMAM and "cytophagic histiocytic panniculitis" (CHP), a condition characterized by T cell-triggered macrophage hyperactivation. Both IMAM and CHP, but not MMF, may be associated with a life-threatening hemophagocytic syndrome.     

Childhood macrophagic myofasciitis-consanguinity and clinicopathological features

Macrophagic myofasciitis has been almost exclusively detected in adults only. We describe six children of Arab Moslem origin with this disorder. Three presented with hypotonia, developmental delay and seizures and were evaluated for a mitochondrial disorder. The other three children had hypotonia and predominantly motor delay. Five of the six families were consanguineous. A massive collection of macrophages was present in the fascia and adjacent epimysium in all biopsies. The macrophages were periodic-acid-Schiff positive and immunoreactive for CD68. One biopsy which was evaluated by electron microscopy and energy-dispersive X-ray microanalysis showed crystalline structures containing aluminum in macrophages. Two children with motor delay and hypotonia were treated with oral prednisone for 3 months with no clinical improvement. Genetic predisposition probably accounts for the variability in the prevalence of macrophagic myofasciitis in different populations. At least in childhood, there seems to be no connection between macrophagic myofasciitis as a pathological entity and the clinical symptoms and signs.     

Intérêt de la biopsie musculaire chez l’enfant en 2012

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5 years; 155 (37%) biopsies were obtained before the child was 5 years old. Final histopathological diagnoses were: congenital myopathy (n = 193, including 15 structural congenital myopathies); progressive muscular dystrophy (n = 75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n = 17, including six primary merosinopathies); dermatomyositis (n = 11); spinal muscular atrophy (n = 9, including six atypical spinal muscular atrophies); metabolic myopathy (n = 32, including 19 mitochondrial myopathies); encephalomyopathy (n = 53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.     

FHL1-related myopathy may not be classified by reducing bodies in muscle biopsy

FHL1-related myopathies, including reducing body myopathy (RBM), X-linked scapulo-axio-peroneal myopathy, rigid spine syndrome, X-linked myopathy with postural muscle atrophy (XMPMA), X-linked Emery–Dreifuss muscular dystrophy and hypertrophic cardiomyopathy, are clinically and pathologically heterogeneous disorders caused by FHL1 gene mutations. According to previous reports, the first three types are myopathies with reducing bodies observed in biopsies, and the last three are myopathies without reducing bodies. We report four FHL1-related myopathy patients, including an XMPMA patient and a RBM family with three patients. Clinical information, muscle biopsies, electromyograms and genetic testing were obtained. Muscle weakness and atrophy, spinal rigidity, and joint contracture were present in the RBM family. The XMPMA patient showed a pseudoathletic appearance with muscle weakness and atrophy, spinal rigidity and deformity. The index patient of the RBM family underwent two muscle biopsies to find reducing bodies. Interestingly, these muscle biopsies revealed reducing bodies and rimmed vacuoles not only in the RBM family but also in the XMPMA patient. Next-generation sequencing identified a reported single missense mutation c.448 C>T (p. C150R) in the RBM family and a novel mutation c.814T>C (p. S272P) in the XMPMA patient. Therefore, FHL1-related myopathies overlap substantially and may not be simply classified into subtypes depending on reducing bodies. Biopsies of additional affected muscles can aid in finding reducing bodies. We report the first XMPMA patient with a novel FHL1 mutation and reducing bodies in a muscle biopsy in China.     

Anti-vimentin staining in muscle pathology

The intermediate filaments of immature muscle fibres contain desmin and vimentin; vimentin is lacking in mature fibres. Regenerating fibres react with anti-vimentin antibodies and more intensely for desmin than mature fibres. The aim of the present study was to evaluate anti-vimentin staining for muscle pathology. Anti-vimentin-reactive fibres were found in 40 of 89 biopsies assessed. Fifteen patients with progressive destructive myopathy, infantile spinal muscular atrophy, clinically suspected Leigh's disease or unclassifiable congenital myopathy had between 1% and 95% vimentin-positive fibres. Less than 1% positive fibres were found in 25 patients with neuropathy with secondary myopathy or chronic myopathic conditions. Vimentin-positive fibres were lacking in 20 normal biopsies, in eight biopsies with neuropathic and in 21 biopsies with mild or non-destructive myopathic changes. We conclude that staining with anti-vimentin antibodies is a useful indicator for muscle fibre regeneration; it may help establish the diagnosis in infantile spinal muscular atrophy when the histopathology is non-characteristic. The high incidence of reactive fibres in some congenital or early-onset disorders may indicate developmental arrest.     

Pediatric macrophagic myofasciitis associated with motor delay

BACKGROUND: Macrophagic myofasciitis (MMF) is a rare inflammatory myopathy characterized by accumulation of perifascicular macrophages without muscle fiber necrosis. Few sporadic pediatric cases have been described, and MMF is recognized as a possible reaction to intramuscular injections of aluminum-containing vaccines. The association of MMF and motor delay is unclear in the pediatric population. We report the clinical evaluation and follow-up of 4 young children with MMF and review of 4 cases previously reported of sporadic, pediatric MMF to better determine the possible association of sporadic MMF in children presenting with motor delay. PATIENTS AND METHODS: Described our 4 case reports in which we observed children presenting for evaluation of motor delay with unrevealing clinical and laboratory evaluations for common causes of motor delay and histopathological evaluations consistent with macrophagic myofasciitis. Muscle data was obtained by quadriceps muscle biopsy. RESULTS: Clinical presentations were similar in all children and were characterized by motor delay, hypotonia, and failure to thrive with an unrevealing evaluation for central nervous system disease, congenital, and mitochondrial myopathies. CONCLUSIONS: Our cases and those previously reported in the literature demonstrate MMF should be considered in the evaluation of children with failure to thrive, hypotonia, and muscle weakness, as clinical outcome appears to be favorable.     

Macrophagic myofasciitis associated with inclusion body myositis: a report of three cases

We describe three patients with macrophagic myofasciitis and inclusion body myositis. All patients fulfilled diagnostic criteria for inclusion body myositis and myopathologic criteria for macrophagic myofasciitis. In the three cases macrophagic myofasciitis complicated the evolution of a known and painless inclusion body myositis and was diagnosed in a repeated deltoid biopsy because of the appearance of myalgia during the course of inclusion body myositis in all cases. The unexpected appearance of myalgia during the course of painless inclusion body myositis must arouse the suspicion of an association of another inflammatory muscle disease, macrophagic myofasciitis.     

Differential diagnosis of limb-girdle muscular dystrophy and spinal muscular atrophy

Neuromuscular biopsies from 18 patients with proximal muscle weakness were classified electromyographically as myopathy (11 cases), denervation (3 cases), or inconclusive (4 cases). Myopathic changes of muscle fibers occurred in all biopsies. Small angular dark fibers were observed in nine biopsies, and small-group atrophy in four biopsies from the three above-mentioned groups. Two biopsies classified as denervation showed large-group atrophy. Terminal innervation ratio (TIR) was increased only in the three cases classified as denervation and in one inconclusive case. TIR, which is more closely correlated with electromyographic (EMG) results than are muscle fiber changes, may help differentiate spinal muscular atrophy from limb-girdle muscular dystrophy.     

Predictive value of electromyography in diagnosis and prognosis of the hypotonic infant.

To investigate the diagnostic validity of electromyography in the hypotonic infant, 79 children aged 0 to 12 months, seen over a 20-year period, were studied retrospectively. The diagnoses using clinical, muscle biopsy, and laboratory characteristics were: 25 central hypotonia, 20 spinal muscular atrophy, 20 myopathy, four myotonic dystrophy, four benign congenital hypotonia, two congenital muscular dystrophy, two myasthenia gravis, one infantile inflammatory myopathy, and one arthrogryposis multiplex congenita. Using strict criteria, electromyography accurately predicted the final diagnosis in 65% of infants with spinal muscular atrophy and was consistent with the diagnosis in another 25%. In contrast, electromyography accurately predicted the final diagnosis in only 10% of infants with myopathy and was normal in 88% of infants with central hypotonia. In infants with spinal muscular atrophy, there was no difference in the predictive value of electromyography when performed in the newborn compared to older infants. Normal distal nerve conduction velocities in infants with spinal muscular atrophy may predict prognosis, since these infants had a longer survival. Electromyography thus has a high predictive value for infantile spinal muscular atrophy but not for myopathy.     

Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies

Summary A histochemical assay was routinely performed of myoadenylate deaminase (MAD) in muscle biopsy specimens. MAD was absent in 13 cases, i.e. 2.9% of the specimens. In 10 cases the deficiency was confirmed biochemically. The diagnoses in the 13 patients were: polyneuropathy (n=5), infantile spinal muscular atrophy (n=3), congenital myopathy with type 2 fibre atrophy, facioscapulohumeral myopathy, polymyositis, myotonic dystrophy and hyperornithinaemia with gyrate atrophy of the retina. In contrast, 35 unrelated patients presenting with exercise-related muscle cramps or pains showed normal histochemical MAD activity. The biopsy specimens in all of these patients were essentially normal and in none of them was the diagnosis of a neuromuscular disease made. The results failed to confirm the association of MAD deficiency with aches, cramps and pains or exertional myalgia.     

Patients with severe muscle wasting are prone to develop hypoglycemia during fasting

The authors investigated whether hypoglycemia develops during 23 hours of fasting in patients with Duchenne dystrophy (7 patients), spinal muscular atrophy (4 patients), and congenital myopathy (2 patients), all with residual muscle mass <10% of body weight. All patients with spinal muscular atrophy and congenital myopathy and one patient with Duchenne dystrophy, but none of six healthy subjects, developed hypoglycemia. Skeletal muscle is an important source of gluconeogenic substrates during fasting. Hypoglycemia must be considered in patients with low muscle mass, especially during surgery and febrile episodes.     

Toxic myopathies: muscle biopsy features

Several drugs and toxic substances can cause muscular abnormalities and are frequent causes of acquired myopathies. We present a series of 32 patients, predominance of young adult patients, diagnosed with toxic myopathy. The most common substances inducing myopathy were corticosteroids (56.2%) followed by the propoxyphene, neuroleptics, zidovudine and drug-induced hypokalemia. The investigation showed normal serum creatine kinase levels in 65.4%, myopathic pattern of the needle electromyography in 40% and the more frequent histological diagnosis of the muscle biopsy was type 2 fiber atrophy (59.3%). Clinical features, etiology, course of the disease, serum levels of muscular enzymes, electromyographic features and, especially, muscle biopsy features are discussed.     

Neurogenic muscle involvement in myasthenia gravis: A clinical and histopathological study

An investigation was made into the occurrence of muscular atrophy and muscular pathology in a series of 170 patients with myasthenia gravis. The results can be summarized as follows: (1) Of the 148 patients with generalized myasthenia gravis, 14 showed local muscular atrophies. Of 10 biopsies from atrophic muscles, eight showed neurogenic changes, with or without lymphocytic infiltrations. One biopsy showed lymphocytic infiltrations only, and one showed type II-fibre atrophy (Table 1). No relationship was demonstrable between the presence of clilnical muscular atrophy and age, sex, duration of the disease, severity of the disease, presence of a thymoma, or drug resistant ophthalmoplegia. (2) In this group of patients 61 biopsies were examined from 46 individuals; 40 of these biopsies were taken from the quadriceps muscle. A thymoma was present in 17 patients. Examination disclosed neurogenic changes in 17 biopsies, lymphocytic infiltrates in 21, and myositis in one biopsy (Table 2). A distinct correlation was established between the presence of a thymoma and lymphocytic infiltrates, but none was demonstrable between thymoma and neurogenic changes (Table 3). (3) An enzyme-histochemical study was carried out in 35 cases, including 12 with neurogenic changes. A normal differentiation of type I- and type II-fibres was observed in eight instances, type grouping of type II-fibres in three, and type II-fibre atrophy in two cases. (4) In 21 patients and 19 controls, the smallest mean diameter was determined in the quadriceps muscle. Both type I- and type II-fibres proved to have a smaller mean diameter in the female patients than in the controls. In the male patients this could not be proven. (5) Of the eight patients who had died without disorders of ventilation, 90 muscle specimens were examined postmortem. Four of these patients had a thymoma. Lymphocytic infiltrations, found in 32 biopsy specimens, were mostly observed in the presence of a thymoma. Neurogenic changes were apparently unrelated to the presence of a thymoma (Tables 5 and 6). The post mortem examination included the spinal cord in five, and peripheral nerves in three cases. No abnormalities were found. (6) The muscular atrophy found in patients with myasthenia is not a myopathy but an affection of the lower motor neurone. Neurogenic changes were regularly found in the muscles of patients with myasthenia, even without muscular atrophy. The finding of these changes is no reason to reject the diagnosis. It is postulated that denervation occurs at the neuromuscular junction as a result of permanent absence of acetylcholine.     

Emery-dreifuss humeroperoneal muscular dystorphy: An X-linked myopathy with unusual contractures and bradycardia

Clinical, electromyographic, and muscle biopsy findings in the two largest known families with emery-Dreifuss humieroperoneal muscular dystorphy indicate that this is an X-linked recessive muscle disease with stereotyped clinical manifestations but with variable pathological and electromyographic characteristics. Elbow contractures, involvement of humeral muscles, Hyporeflexia, and abnorman electorcardiograms are present in our patients. The disorder is associated with a potentially lethal cardiac arrhythmia that should be managed by pacemaker insertion. The skeletal muscle disease is slowly progressive and is usually not life threatening. Muscle biopsy commonly shows type I fiver atrophy. Electromyogrphy usually indicates myopathy, though the classic findings of myopathy may not be present in every muscle.     

Predominant fiber atrophy and fiber type disproportion in early ullrich disease

Ullrich disease (congenital muscular dystrophy type Ullrich, UCMD) is a severe congenital disorder of muscle caused by recessive and dominant mutations in the three genes that encode the alpha-chains of collagen type VI. Little is known about the early pathogenesis of this myopathy. The aim of this study was to investigate early histological changes in muscle of patients with molecularly confirmed UCMD. Muscle biopsies were analyzed from 8 UCMD patients ranging in age from 6 to 30 months. Type I fiber atrophy and predominance were seen early, together with a widening of the fiber diameter spectrum, whereas no dystrophic features were apparent. A subpopulation of more severely atrophic type I fibers was apparent subsequently, including one biopsy that fulfilled the formal diagnostic criteria of histopathological fiber type disproportion (FTD). Thus, early in the disease, UCMD presents as a non-dystrophic myopathy with predominant fiber atrophy. Collagen VI mutations also qualify as a cause of fiber type disproportion.     

The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders

To determine the incidence of selective type 1 fiber atrophy (hypotrophy) and its possible significance in various muscle diseases of childhood, we reviewed 2212 muscle biopsies from children which we had examined in the past 20 years histochemically with ATPase staining. Type 1 fiber atrophy was seen in a variety of neuromuscular disorders, but predominantly in congenital myopathies, including all patients with congenital fiber type disproportion myopathy (20 patients), central core disease (12 patients) and multicore disease (four patients). Although type 1 fiber atrophy was not a constant feature in nemaline myopathy and myotubular myopathy, all patients with these diseases had abnormal fiber type distribution which included type 1 fiber predominance both with and without type 2B fiber deficiency. Together with abnormal fiber type distribution, type 1 fiber atrophy was a common finding in childhood neuromuscular disorders, especially congenital myopathies.     

Anti-Signal Recognition Particle Myopathy in the First Decade of Life

Autoantibodies to signal recognition particle have been associated with juvenile and adult-onset necrotizing myopathy. However, only a few teenage patients with anti-signal recognition particle myopathy have been reported, and to date, to our knowledge, no patient younger than 10 years has been documented. We describe 2 Japanese girls with anti-signal recognition particle myopathy who developed symptoms from the ages of 5 and 9 years, respectively. Both patients had progressive muscle weakness and atrophy without myalgia. Facioscapulohumeral muscular dystrophy was initially suspected because of asymmetric shoulder girdle muscle involvement in one patient, and limb girdle muscular dystrophy due to proximal limb muscle weakness in the other. There were no extramuscular manifestations, including fever or arthritis. Serum creatine kinase levels were elevated to 2,467-4,629 IU/L. Results of muscle biopsy revealed necrotizing myopathy with minimal to mild endomysial fibrosis but without inflammatory infiltrates. Immunosuppressive agents were not effective for muscle weakness, resulting in marked disability. Anti-signal recognition particle myopathy can occur in the first decade of life and should be included in the differential diagnosis for children with progressive limb girdle muscle weakness and high creatine kinase levels.