Fabry disease 'The New Great Imposter': results of the French Observatoire in Internal Medicine Departments (FIMeD).

Fabry disease (FD) is an X-linked lysosomal storage disorder due to α-galactosidase A deficiency. It is associated with a broad range of clinical symptoms, resulting in frequent misdiagnosis and diagnostic delay, which may impact on patient outcomes. This retrospective observational study of 58 FD patients referred to 10 internal medicine departments in France aimed to review differential diagnoses received prior to diagnosis and examines diagnostic delay. The average age at the time of diagnosis was 27.6 years (range: 10-60) and 42.2 years (range: 9-77) among the 23 males and 35 females analyzed, respectively. Most common symptoms that led to FD diagnosis were family history of FD (12 males and 27 females), followed by pain in extremities (10 males and 5 females), and angiokeratoma (8 males and 4 females). Eighteen patients had received alternative diagnoses prior to FD diagnosis, including a female patient with four previous diagnoses. Four case reports are presented, which illustrate the diagnostic 'odyssey' and delayed diagnosis often experienced by patients. Clinicians should consider a diagnosis of FD when presented with a wide range of symptoms, thus helping to shorten the diagnostic delay and facilitating early therapy with enzyme replacement therapy to improve patient outcomes.

Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients.

OBJECTIVE: This study was undertaken to assess the characteristics and outcome of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) and to determine variables predictive of ILD deterioration in PM/DM. METHODS: Among 348 consecutive patients with PM/DM, 107 patients with ILD were identified by medical records search in 4 medical centers. All patients underwent pulmonary function tests (PFTs) and pulmonary high-resolution computed tomography (HRCT) scan. RESULTS: ILD onset preceded PM/DM clinical manifestations in 20 patients, was identified concurrently with PM/DM in 69 patients, and occurred after PM/DM onset in 18 patients. Patients with ILD could be divided into 3 groups according to their presenting lung manifestations: patients with acute lung disease (n = 20), patients with progressive-course lung signs (n = 55), and asymptomatic patients with abnormalities consistent with ILD evident on PFTs and HRCT scan (n = 32). We observed that 32.7% of the patients had resolution of pulmonary disorders, whereas 15.9% experienced ILD deterioration. Factors that predicted a poor ILD prognosis were older age, symptomatic ILD, lower values of vital capacity and diffusing capacity for carbon monoxide, a pattern of usual interstitial pneumonia on HRCT scan and lung biopsy, and steroid-refractory ILD. The mortality rate was higher in patients with ILD deterioration than in those without ILD deterioration (47.1% versus 3.3%). CONCLUSION: Our findings indicate that ILD results in high morbidity in PM/DM. Our findings also suggest that more aggressive therapy may be required in PM/DM patients presenting with factors predictive of poor ILD outcome.

Vertebral fractures in Gaucher disease type I: data from the French "Observatoire" on Gaucher disease (FROG).

UNLABELLED: Gaucher disease type 1 (GD1), results in a range of skeletal complications including osteopenia, osteoporosis, and osteonecrosis, but there is little published information regarding vertebral fractures. Findings from this observational study indicated that the prevalence of vertebral fractures in a cohort of adult French GD1 patients is approximately 15%. INTRODUCTION: The aim of the study was to assess the prevalence and characteristics of vertebral fractures in a cohort of adult patients with GD1. METHODS: This study was performed in adult patients with GD1 based on a detailed and complete clinical examination. For all patients for whom vertebral fractures were reported, a specific questionnaire was sent to physicians, and imaging data were collected, when available, for centralized analysis. RESULTS: Data were collected from a total of 105 adult GD1 patients. Bone complications were reported in 85% of patients, among whom vertebral fractures were diagnosed in 16 (15%); seven women and nine men (mean age, 45 years). We observed five patients with multiple vertebral fractures and one patient in whom the T3 vertebra was fractured. Most of these patients did not report fracture-related back pain. CONCLUSIONS: The prevalence of vertebral fractures in this cohort of adult patients with GD1 was 15%. Greater awareness of the natural history of vertebral fractures in GD1, and rigorous monitoring of bone fragility and spine involvement in affected patients, should allow earlier detection and initiation of treatment tailored toward improving bone status.

The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG).

BACKGROUND: Gaucher disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity. Type 1 GD (GD1), the most common variant, is classically considered non-neuronopathic. METHODS: We performed a national cross-sectional observational survey-the French Observatoire on Gaucher Disease (FROG)-in patients with GD1 between March 2005 and September 2006. The study included all patients over 18 years of age with confirmed GD1 who attended participating centers for regular follow-up. RESULTS: One hundred and five patients were included, in whom we studied the prevalence and characteristics of relevant neurological symptoms associated with the neuraxis. Of these, 51 (49%) GD1 patients presented at least one neurological symptom. Four patients (4%) had Parkinson disease and 22 (21%) presented with at least one parkinsonian sign or at least one sign frequently associated with Parkinson disease. Five patients (5%) had a previous diagnosis of peripheral neuropathy. Other central nervous system symptoms were recorded in 20 (19%) patients and other peripheral nervous system symptoms in 39 (37%) patients. CONCLUSIONS: These data challenge the current classification of GD, and suggest that the three forms of GD each involve a different profile of neurological manifestations.

[Diagnostic journey of type 1 Gaucher Disease patients: A survey including internists and hematologists]. / Parcours diagnostique des patients atteints de maladie de Gaucher de type 1 : enquête auprès de médecins internistes et hématologues.

INTRODUCTION: Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by a beta-glucocerebrosidase deficiency and responsible for a lysosomal storage disorder. GD is characterized by haematological, visceral and bone involvements. The aim of this study was to describe the diagnostic journey of type 1 GD patients as well as the role of the internist. METHODS: A retrospective multicentric study involving type 1 GD patients has been conducted in 16 centers, between 2009 and 2011. RESULTS: Fifty-five type 1 GD patients were included, under the care of an internist or an haematologist. They were originally hospitalized in 8 different specialized units. Diagnosis was established by bone-marrow aspiration in 22 patients (40%), by enzymatic assay of glucocerebrosidase activity in 15 patients (27%), and by bone-marrow biopsy in 9 patients (16%). The use of enzymatic assay became more frequent after 1990. The delay between first hospitalization due to GD symptoms and definitive diagnosis was less than one year for 38 patients. Patients with suspected GD were mainly referred to an internist physician. CONCLUSION: GD seems to be better recognized and quickly diagnosed since 1990 in spite of the multiplicity of journeys. The role of the internist seems important.

[Current therapy for polymyositis and dermatomyositis]. / Actualités thérapeutiques dans les polymyosites et dermatomyosites.

Polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM) are severe inflammatory muscle disorders of unknown cause, which may present life-threatening complications. Prognosis and response to medications may be predicted not only from the clinical and pathologic diagnostic group into which a patient belongs, but also from the patient's myositis-specific antibody status, extraskeletal muscle involvement, and the interval between onset of muscle weakness, and the start of the treatment. Corticosteroids remain the mainstay of treatment in PM and DM. In patients refractory or intolerant to corticosteroids, another therapy, often an immunosuppressive agent, or intravenous immunoglobulin (IVIg), is added. IVIg seems the treatment of choice in severe myositis with dysphagia. New molecules, anti-TNF and monoclonal antibodies anti-CD20 justifies randomised trial and long term follow up.

[Management of adverse effects related to human immunoglobulin therapy: Recommendations for clinical practice]. / Prise en charge des événements indésirables chez les patients sous traitement par immunoglobulines : recommandations pour la pratique clinique.

Both intravenous and subcutaneous immunoglobulins are therapeutic modalities approved in various conditions, including primary and secondary immune deficiencies and autoimmune disorders. To date, immunoglobulins have more often been considered as a safe medication, with minor adverse effects such as hypertension, fever and chills, nausea, myalgia or headache. However, with the wider use of immunoglobulins in the treatment of autoimmune diseases, severe side effects have also been reported to occur in immunoglobulin-treated patients, especially anaphylaxis, aseptic meningitis, acute renal impairment, thrombotic events as well as haematological manifestations. This paper reviews all the potential adverse events related to immunoglobulin therapy and establishes a comprehensive guideline for the management of these events.

[Neurological manifestations of type 1 Gaucher's disease: Is a revision of disease classification needed?]. / Les manifestations neurologiques de la maladie de Gaucher de type 1: vers une remise en cause de la classification actuelle?

INTRODUCTION: Gaucher's disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity. The resulting accumulation of glucocerebrosides in lysosomes of macrophages leads to hepatosplenomegaly, anemia, thrombocytopenia, and various bone manifestations. Gaucher's disease is classified into 3 types based on the nature of its effects on the central nervous system. Type 1, the most common variant, is classically nonneuronopathic. However, the occurrence of Parkinsonism seems to be more frequent in type I Gaucher's disease than in the general population. Furthermore, heterozygotes for certain glucocerebrosidase gene mutations have a higher risk to develop Parkinson's disease. OBSERVATIONS: We report our experience about 9 patients with Gaucher's disease and their association with neurological manifestations. CONCLUSION: These recent data may discuss Gaucher's classification and the existence of a continuum between neurologic and non-neurologic forms of the disease.

[Intramuscular vascular malformations as a differential diagnosis of focal myositis]. / Les malformations vasculaires à développement intramusculaire: un diagnostic différentiel rare de myosite focale.

INTRODUCTION: Focal myositis constitutes an original and rare pathological entity, characterized by a localized inflammation within skeletal muscle, presenting as a soft tissue painful tumefaction. Diagnosis requires histological confirmation because of its non-specific clinical feature and the numerous differential diagnoses. EXEGESIS: We report a 27 year-old man who presented with suggestive symptoms of focal myositis. MR imaging and echography were compatible with this diagnosis but also demonstrated the existence of a vascular component within the tumefaction. The diagnosis of a benign vascular malformation with intramuscular development was made by a surgically guided biopsy. CONCLUSION: Vascular malformations are histologically heterogeneous with extremely variable clinical expressions. When they develop within skeletal muscle, they may mimic focal myositis. Hence, their diagnosis has to be evoked before performing muscle biopsy, because of the potential hemorrhagic risk.

Does the route of immunoglobin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort "Visages".

BACKGROUND: IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients' satisfaction regarding IgRT and quality of life (QoL) in real-life conditions. METHODS: The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire. RESULTS: The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT. CONCLUSION: PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient's expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.

A phase I/II dose-escalation study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for metastatic melanoma. Study Group on Gene Therapy of Metastatic Melanoma.

We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1 thymidine kinase (HSV-1-TK) suicide gene therapy for metastatic melanoma. HSV-1 TK expression, which specifically sensitizes transduced and bystander cancer cells to ganciclovir (GCV) toxicity, was mediated by one (four patients, first dose step) to three (four patients, second dose step) injections of "M11" retrovirus vector-producing cells in melanoma cutaneous nodules. After a 7-day period allowed for cancer cell transduction, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by tumor measurements and histology. M11 doses ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse events were mild and transient, limited to inflammatory skin reactions at injection and fever on repeated injections. Plasma GCV was in the active range (>0.2 microg/ml); transgene was detected by polymerase chain reaction in three of six patients; treated tumor size was moderately affected under GCV as compared with untreated tumors, although 2 weeks after GCV administration important (>50%) treated-tumor necrosis was evidenced on histology in three of eight patients. All patients showed disease progression on long-term follow-up. Thus, M11-mediated HSV-1 TK gene therapy was well tolerated over a wide dose range. The limited tumor response is likely to be related to poor gene transfer efficiency. However, necrosis following GCV administration in transduced tumors indicates a potential for treatment efficacy.

Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients.

PURPOSE: Polymyositis and dermatomyositis are inflammatory muscular diseases of unknown cause. Many interventions are available to treat patients with these conditions including corticosteroids, immunosuppressive drugs, plasmapheresis, and total body irradiation. However, these therapies are not always effective, and they may be associated with certain serious side effects. An attempt was made to evaluate the efficacy of polyvalent intravenous immunoglobulin (IVIG) in patients with polymyositis or dermatomyositis refractory to traditional treatment. PATIENTS AND METHODS: Twenty patients (16 women and 4 men; mean age 43 [16 SD] years), 14 with chronic refractory polymyositis and six with dermatomyositis, received high doses of IVIG because of the failure of traditional treatments (prednisone [19], methotrexate [10], azathioprine [6], cyclophosphamide [3], cyclosporine [3], chlorambucil [1], plasmapheresis [8], lymphopheresis [1], and total body irradiation [1]). In one patient with positive results on picornavirus serologic testing, IVIG was the first treatment choice. IVIG therapy was given with prednisone in 15 patients, with methotrexate in six patients, and with plasmapheresis in one patient. There were no changes in treatment in the 2 months before the introduction of IVIG therapy and no increases in dose during this treatment. Preparations of polyvalent human intravenous gammaglobulins with increased intact immunoglobulin G were used. Thirteen patients received 1 g/kg daily for 2 days each month, and seven patients received 0.4 g/kg daily for 5 days each month. The mean duration of treatment was 4 months. RESULTS: Clinical assessment, which consisted of the measurement of proximal muscle power, and biochemical studies were carried out before each treatment period. Significant clinical improvement was noted in 15 of the 20 patients. Mean muscle power estimated for the 20 patients before and after IVIG therapy was statistically significantly reduced (p less than 0.01). Eighteen patients showed biochemical improvement, and two patients with normal initial serum creatine kinase levels showed clinical improvement. Mean creatine kinase levels for the 20 patients during IVIG therapy showed a statistically significant decrease from the first IVIG perfusions (p less than 0.01). Side effects of IVIG therapy were noted in four patients; however, these effects were mild. During IVIG therapy, steroid doses were significantly reduced from the second or the third IVIG infusion (p less than 0.05). CONCLUSION: IVIG is an efficacious new therapy for polymyositis and dermatomyositis and should play a role in the treatment of these diseases, replacing or reducing steroid and immunosuppressive medications.

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.

Recognition and management of myositis.

Polymyositis and dermatomyositis are severe inflammatory muscle disorders of unknown cause, with possible life-threatening complications. Prognosis and response to therapy may be predicted not only from the clinical and pathological diagnostic group to which a patient belongs, but also from the patient's myositis-specific antibody status, extraskeletal muscle involvement, and the interval between onset of muscle weakness and the start of the treatment. Corticosteroids are the mainstay of treatment, providing recovery of normal muscular function in about 60% of patients. However, adequate dose, duration of therapy and gradual tapering of corticosteroids are required to produce favourable biochemical and clinical outcomes. In patients refractory to or intolerant of corticosteroids, additional therapy, often involving an immunosuppressive agent or intravenous immunoglobulin, is required. The potential roles of plasmapheresis and total body irradiation must be balanced by their inconclusive efficacies and adverse effects.

Risk of syncope in the elderly and consumption of drugs: a case-control study.

A multicenter case-control study (588 cases and 1807 controls) was performed to assess the risk of syncope in the elderly according to drug consumption within the three days before syncope, controlling the underlying cardiovascular diseases. Pair-matched and non-pair-matched analyses using logistic regression were performed, providing consistent results. After adjustment for age, sex, and cardiovascular disease, cases were shown to consume more often than non-cases drugs in classes of non-tricyclic antidepressants, neuroleptic drugs, and antiparkinsonians. A detailed analysis has shown that only four drugs were significantly associated with an excess risk of syncope: fluoxetine (OR = 2.6; 95% CI: [1.8-3.5]), aceprometazine (OR = 2.0; [1.5-2.5]), haloperidol (OR = 2.8; [2.0-3.6]), and L-dopa (OR = 2.8; [2.2-3.7]). This analysis shows that these drugs should be prescribed with special caution in the elderly.

Hyperchloremic acidosis during grand mal seizure lactic acidosis.

OBJECTIVE: To evaluate the prevalence and the mechanism of hyperchloremic acidosis component (HClA) during lactic acidosis secondary to grand mal seizures. DESIGN: Retrospective study. SETTING: Medical intensive care unit in a university hospital. PATIENTS: 35 patients admitted for grand mal seizures with lactic acidosis (pH < 7.35, TCO2 < 20 mmol/l and PaCO2 < 8 kPa). MEASUREMENTS: HClA was defined by the ratio: excess anion gap/HCO3 deficit (delta AG/delta TCO2) < 0.8. A difference in the distribution space of protons and their accompanying anion, i.e., a displacement of chloride from cells by the entering lactate, was evaluated by the ratio natremia/chloremia (Na+/Cl-). RESULTS: Immediately after seizures, a profound lactic acidosis was observed (pH = 7.22 +/- 0.17 (mean +/- SD), AG: 23.8 +/- 7.1 mmol/l, TCO2 = 14.5 +/- 5.3 mmol/l, lactate: 14.6 +/- 6.9 mmol/. HClA was present on admission in 11 patients (31.5%). Its prevalence increased to 73% after recovery. delta AG/delta TCO2 ratios were unrelated to creatinine, level and PaCO2, but dependent on the ratio Na+/Cl- (r = 0.803; p < 0.001, delta AG/delta TCO2 = 6.4 x (Na+/Cl-)-7.9). These data demonstrate that HClA is not a respiratory or renal phenomenon and suggest differences in the distribution spaces of hydrogen ions and their accompanying anions. CONCLUSION: HClA component may be associated with lactic acidosis in grand mal seizures and appears to be secondary to a lactate antiport. This phenomenon could be an immediate physiological response to a sudden metabolic acidosis.

Association of macrophagic myofasciitis and fibromuscular dysplasia with renal fibromuscular dysplasia: first case report.

Two rare muscular diseases, macrophagic myofasciitis and fibromuscular dysplasia, are associated in the patient reported here. Their respective etiologies are unknown. The possible link has to be discussed.

Features of polymyositis and dermatomyositis in the elderly: a case-control study.

OBJECTIVE: Polymyositis (PM) and dermatomyositis (DM) are uncommon idiopathic inflammatory myopathies (IIM). Little is known about these diseases in the elderly. We attempted to define the characteristics of PM/DM in the elderly by a case-control study involving the retrospective review of medical files of PM/DM patients. METHODS: We drew from among 200 PM/DM patients being followed in our Internal Medicine Department 21 patients (14 F/7 M), aged > or = 65 years at the onset of myositis (17 PM/4 DM) (mean: 69.9 +/- 4.8 yrs.). They were compared with 21 (15 F/6 M) randomly selected younger patients with IIM: PM (14) and DM (7) (mean: 46.4 +/- 12.4 yrs). Clinical, biological, electrophysiological and pathologic features, treatment regimens and side-effects in the 2 groups were collected. RESULTS: Clinical features were similar for the 2 groups. Elderly patients tended to have a higher frequency of cancer (24% vs 9.5%, p = 0.06), particularly of rectal adenocarcinoma. The time from disease onset to diagnosis was significantly longer in older patients (26 +/- 37 months vs 9 +/- 15 months; p = 0.02), normal CK levels were more frequent (40% vs 5%; p = 0.02) and serum CK levels were lower than for the population as the whole (11.5 N vs 22 N, p < 0.03). Electromyography features were more frequently suggestive of a chronic form of the disease in elderly patients. Treatment regimens and short-term side-effects were similar for the 2 groups. CONCLUSION: PM and DM are often diagnosed late in the elderly. Biological data and electromyography features argue for a chronic form of the disease in this age group. Clinical and endoscopic rectal examinations should be carried out in elderly patients with PM/DM.

[Muscle, fatigue, sports and infection]. / Muscle, fatigue, sport et infection.

PURPOSE: Skeletal muscle can be considered as motors which convert chemical energy into mechanical energy. We can evaluate the intracellular pH and energy state of phosphate-containing metabolites in skeletal muscle of patients complaining fatigue or asthenia, using phosphorus MRS. MAIN POINTS: Acute infectious disease and extreme endurance exercise may induce a loss of oxidative capacity of muscle tissue. Muscle fatigue is not due only to an insufficient supply of ATP to the energy consuming mechanisms. Phosphorus MRS show a muscle production of toxic metabolites such as lactates, protons and ammonia. These metabolic features induced excessive intracellular acidosis of skeletal muscle and systemic hyperammonia, responsible of fatigue and asthenia. PERSPECTIVES: Reversal of the excessive acidosis and improvement of the capacity for oxidative ATP synthesis might help to relieve the symptoms of exhaustion/fatigue in these patients.