Fat embolism syndrome in Duchenne muscular dystrophy: Report on a novel case and systematic literature review.

We report a non-ambulatory 13-year-old boy with Duchenne muscular dystrophy who experienced severe acute respiratory distress syndrome and cerebral fat embolism following elective soft tissue surgery. Post-surgery radiological examination revealed bilateral femoral fractures and marked osteopenia that were believed to have caused disseminated pulmonary and cerebral fat embolism. The patient had never been on glucocorticoid treatment. Five months post-surgery, he remained in a state of minimal consciousness. A literature review was performed and eleven publications included, providing case reports of a total number of 23 patients with Duchenne muscular dystrophy with fat embolism syndrome. The most common causes were falls from the wheelchair that predominantly resulted in femoral fractures. Median age at the event was around 14 years. Seven patients succumbed to complications of fat embolism. No event was described in the context of surgery. We want to raise awareness that spontaneous unnoticed fractures may occur especially in adolescents with DMD from traumatic injury of large bones and also during elective surgery with a high risk of causing fat embolism with severe sequelae.

Mortality Rates and autopsy findings in fat embolism syndrome complicating sickle cell disease.

Fat embolism syndrome is a rare but underdiagnosed complication of sickle cell disease associated with high morbidity and mortality. It affects predominantly patients with a previously mild course of their illness and those of non-SS genotypes while there is possibly an association with infection with human parvovirus B19 (HPV B19). Here, we present the mortality rates and autopsy findings of all reported cases to date. A systematic review has revealed 99 published cases in the world literature with a mortality rate of 46%. Mortality varied greatly according to the time of reported cases with no survivors in the 1940s, 1950s or 1960s and no deaths since 2020. 35% of cases had previously undiagnosed sickle cell disease and the latter was only identified at autopsy after developing fat embolism with a fatal outcome. 20% of cases reported after 1986 tested positive for HPV B19 with an associated mortality of 63% whereas in cases that have not documented HPV B19 infection the mortality was 32%. The organs most often staining positive for fat were the kidneys, lungs, brain and heart whereas ectopic haematopoietic tissue was found in 45% of the examined lung specimens.

Fat Embolism Syndrome in Sickle Cell ß-Thalassemia Patient With Osteonecrosis: An Uncommon Presentation in a Young Adult.

Fat embolism syndrome is a relatively infrequent presentation in sickle cell thalassemia patients. It most commonly occurs in long bone fractures in the setting of trauma. However, nonorthopedic trauma and nontraumatic cases have been reported to contribute to fat embolism. The fat embolic syndrome is an underdiagnosed, life-threatening, and debilitating complication of sickle-ß-thalassemia-related hemoglobinopathies. It is primarily seen in milder versions of sickle cell disease, including HbSC and sickle cell ß-thalassemia, with the mild prior clinical course without complications; hence, diagnosis can be easily missed. Pathogenesis of fat embolic syndrome is a combination of mechanical obstruction from fat globules released into systemic circulation at the time of bone marrow necrosis and direct tissue toxicity from fatty acids and inflammatory cytokines released from fat globules. Prompt diagnosis and early initiation of treatment can reduce morbidity and mortality and result in better outcomes and prognosis. Red cell exchange transfusion is the mainstay of therapy with mortality benefits. Overall mortality and neurological sequelae continue to be high despite increased red cell exchange transfusion in the last few years. In this article, we discussed a case of a 34-year-old male patient with a history of sickle cell thalassemia and avascular necrosis of the hip, who presented with fever, hypoxia, encephalopathy, and generalized body aches, found to have thrombocytopenia and punctate lesions on magnetic resonance imaging brain, which led to the diagnosis of the fat embolism syndrome. Only a few sickle cell ß-thalassemia with fat embolic syndrome cases have been reported.

Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening disease with a high mortality rate, which was a common complication of fat embolism syndrome (FES). Ursodeoxycholic acid (UDCA) has been reported to exert potent anti-inflammatory effects under various conditions. In vivo, perinephric fat was injected via tail vein to establish a rat FES model, the anti-inflammatory effects of UDCA on FES-induced lung injury were investigated through histological examination, ELISA, qRT-PCR, Western blot and immunofluorescence. In vitro, human lung microvascular endothelial cells (HPMECs) were employed to understand the protective effects of UDCA. The extent of ALI/ARDS was evaluated and validated by reduced PaO2 /FiO2 ratios, increased lung wet/dry (W/D) ratios and impaired alveolar-capillary barrier, up-regulation of ALI-related proteins in lung tissues (including myeloperoxidase [MPO], vascular cell adhesion molecule 1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1]), elevated protein concentration and increased proinflammatory cytokines levels (TNF-α and IL-1ß) in bronchoalveolar lavage fluid (BALF). Pre-treatment with UDCA remarkably alleviated these pathologic and biochemical changes of FES-induced ALI/ARDS; our data demonstrated that pre-treatment with UDCA attenuated the pathologic and biochemical changes of FES-induced ARDS, which provided a possible preventive therapy for lung injury caused by FES.

[Purtscher's retinopathy as a complication to a cemented resection tumour prosthesis].

In this case report, a 53-year-old female with a pathological subtrochanteric femur fracture received a cemented resection tumour prosthesis. The patient was post-operatively diagnosed with Purtscher's retinopathy due to fat embolisation. Purtscher's retinopathy has previously been described in trauma patients, however, no previous reports exist with patients treated with prosthesis. No treatment guideline is available. There is a risk of permanent visual impairment, and it is recommended, that patients presenting reduced vision post-operatively are referred to an ophthalmologist without delay for correct diagnosis.

VEGF mediates fat embolism-induced acute lung injury via VEGF receptor 2 and the MAPK cascade.

Fat embolism (FE) is a lethal medical emergency often caused by fracture of long bones and amputation of limbs. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increases vascular permeability. We tested the hypothesis that VEGF plays a critical role in FE-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Fat tissues were collected from male Sprague-Dawley rats, and animal oil was extracted and mixed with water to form fatty micelles. The micelles were then injected into the tail vein to produce FE and ALI in rats. Lung weight gain was measured as the index of pulmonary edema. The expression of pulmonary VEGF was evaluated by real-time PCR and western blot analysis. Inducible nitric oxide synthase (iNOS) and phosphorylation of mitogen-activated protein kinase (MAPK) were determined by western blot analyses. Interleukin-1ß (IL-1ß) was quantified by ELISAs. Hematoxylin and eosin staining was used to evaluate the pathological damage of ALI. In this study, we found that animal oil-induced FE significantly increased pulmonary VEGF expression and MAPK phosphorylation. We also evaluated the inflammatory response after FE and found that iNOS and IL-1ß significantly increased after FE. Systemic administration of SU-1498, an antagonist of VEGF receptor 2 (VEGFR-2), significantly attenuated the FE-induced inflammatory response and histological damage. This study suggested that VEGF is involved in FE-induced ARDS via the VEGFR-2 and MAPK cascades, which induce IL-1ß release and iNOS upregulation. Blockade of could be used to treat FE-induced pulmonary damage.

[A case of bone marrow necrosis and fat embolism in a sickle-cell disease patient]. / Un cas de nécrose médullaire compliquée d'embolie graisseuse chez un patient drépanocytaire.

We report here a case of bone marrow necrosis and fat embolism syndrome in a 23-year-old sickle-cell disease (HbSS) patient. A brutal and severe bicytopenia conducted to suspect bone marrow necrosis, confirmed by bone marrow aspiration and analysis. This was the first life-threatening medical event for this patient. In the present case, a complex alloimmunization against blood group antigens complicated the treatment because of the risks associated with the transfusion strategy. These rare complications of sickle-cell disease may be fatal, but an efficient symptomatic treatment generally allows for recovery. Medical biologists should be aware of the danger of bone marrow necrosis in sickle-cell disease, so that they can help clinicians and accurately diagnose this serious complication.

Sudden death caused by pulmonary fat embolism in a patient with miliary tuberculosis

An 84-year-old Japanese woman with myelodysplastic syndrome was admitted with pyrexia and dyspnea, but died suddenly during diagnostic evaluation. The autopsy revealed miliary tuberculosis in addition to myelodysplastic syndrome in the bone marrow. The immediate cause of the patient's sudden death was pulmonary fat embolism derived from bone marrow necrosis. This case shows that the infiltration of the myelodysplastic bone marrow by tuberculosis and consequent bone marrow necrosis and fat embolism can be the cause of sudden death. In this article, we report the autopsy results of this unusual cause of sudden death, and discuss tuberculosis-related sudden death with a review of the literature.

Un caso de síndrome de embolia grasa: tratamiento y rehabilitación neurológica y cognitiva / A case report off at embolism syndrome: Treatment and neurological and cognitive rehabilitation

Resumen Se reporta el proceso de recuperación y rehabilitación neurológica y cognitiva de una mujer joven que desarrolló un síndrome de embolia grasa con repercusiones neurológicas, después de sufrir un politraumatismo. La paciente era una mujer de 21 años de edad con fractura cerrada de húmero y fémur izquierdos, que presentó un síndrome de embolia grasa, neumotórax izquierdo e hipertensión pulmonar, en las primeras 24 horas después de un accidente. Estuvo hospitalizada un mes y quedó con varios déficits neurológicos centrales, como infartos 'lacunares' y necrosis cortical laminar occipital, así como limitaciones en la bipedestación, la marcha, la visión y las funciones cognitivas. A partir del primer mes después del alta hospitalaria, se comenzó un proceso integral de rehabilitación neurológica y cognitiva en casa, y posteriormente, en una unidad médica de rehabilitación. Durante los primeros dos años después del accidente, la paciente recibió estimulación sensorial, sensoperceptiva y motora, así como rehabilitación motora y visual intensiva. Una vez se recuperó físicamente, se inició un proceso de rehabilitación neuropsicológica. Seis años después del accidente, la paciente terminó sus estudios universitarios y hoy está laboralmente activa. El proceso de rehabilitación neurológica es complejo, individual y difícil, aunque no imposible, y no se puede estandarizar un patrón de recuperación para todos los pacientes. Si bien existe la recuperación espontánea, la cual se da en los primeros seis meses, el caso aquí reportado demuestra que, en la fase crónica, la recuperación se puede lograr, pero requiere de evaluaciones y técnicas coordinadas de rehabilitación neurológica.

Abstract We report the neurological and cognitive recovery and rehabilitation process in a young woman who developed a fat embolism syndrome with neurological repercussions secondary to multiple trauma. The patient was a 21-year-old woman with a closed fracture of the left humerus and femur. She developed fat embolism syndrome, left pneumothorax and pulmonary hypertension in the first 24 hours after the accident. After one month of hospitalization, the patient had several central neurological deficits such as lacunar infarcts and occipital laminar cortical necrosis, as well as limitations in standing, walking, vision, and cognitive functions. An integral process of neurological and cognitive rehabilitation--first at home and later in a medical rehabilitation unit-- was carried out from the first month after being released from the hospital. During the first two years after the accident, the patient received sensory and motor stimulation, motor rehabilitation, and intensive visual rehabilitation. Once recovered physically, a process of neuropsychological rehabilitation began. Six years after the accident, the patient finished her university studies and she is working actively. The neurological rehabilitation process is complex, individual and difficult, but not impossible, and a recovery pattern cannot be standardized for all patients. Although there is spontaneous recovery, which occurs in the first six months, the case here reported shows that in the chronic phase recovery can be achieved but requires evaluations and coordinated techniques of neurological rehabilitation.

Rapamycin alleviated pulmonary injury induced by fat embolism syndrome in rats.

Fat embolism syndrome (FES) is a serious complication after trauma, surgery and fat emulsion input and can lead to serious pulmonary injury. Autophagy controls the cell survival and homeostasis by removing the mis-folded proteins and damaged organelles as well as intracellular pathogens through a lysosomal degradation pathway. Increasing research documented that autophagy was wildly involved in variety of human diseases and had huge therapeutic potential. However, the role and mechanism of autophagy in FES remains largely unknown. The rat model of FES was established by tail vein injection with fat and was assessed by Wet-to-Dry (W/D) ratio analysis, hematoxylin-eosin (HE) analysis, staining Oil red staining analysis and qPCR analysis. Western blots were employed to detect the expression of autophagy markers. The changes of pulmonary injury were observed after premedication of rapamycin (an autophagy activator). The alveolar structural damage, red free fat substances in the blood vessels of lung, increased the lung ratio, and the up-regulated MPO expression and activity were showed in the FES models. The expressions of autophagy markers were decreased and meanwhile, apoptosis markers were increased in the FES model. Rapamycin restored the expression of autophagy markers and inhibited the apoptosis and further, resulting in the improvement of the pulmonary injury. Thus, our study demonstrated that autophagy was inhibited and apoptosis was promoted in FES and further Rapamycin alleviated the pulmonary damage in FES via restoring the autophagy and inhibiting the apoptosis.

Síndrome de hiperatividade simpática paroxística causada por síndrome da embolia gordurosa / Paroxysmal sympathetic hyperactivity syndrome caused by fat embolism syndrome

RESUMO A hiperatividade simpática paroxística representa uma complicação incomum, com potencial risco à vida, de lesões cerebrais graves, mais comumente de origem traumática. Seu diagnóstico clínico se baseia na manifestação recorrente de taquicardia, hipertensão, diaforese, taquipneia e, às vezes, febre, além de posturas distônicas. Os episódios podem ser induzidos por estímulos ou ocorrer de forma espontânea. É comum que ocorra subdiagnóstico desta síndrome, e o retardamento de seu reconhecimento pode aumentar a morbidade e a incapacidade em longo prazo. Evitar os desencadeantes e a farmacoterapia podem ter muito sucesso no controle desta complicação. A síndrome da embolia gordurosa é uma complicação rara, mas grave, das fraturas de ossos longos. Sinais neurológicos, petéquias hemorrágicas e insuficiência respiratória aguda são as características que constituem seu quadro clínico. O termo "embolia gordurosa cerebral" é estabelecido quando predomina o envolvimento neurológico. O diagnóstico é clínico, porém achados específicos de neuroimagem podem confirmá-lo. As manifestações neurológicas incluem diferentes graus de alteração da consciência, défices focais ou convulsões. Seu tratamento é de suporte, porém são possíveis desfechos favoráveis, mesmo nos casos com apresentação grave. Relatamos dois casos de hiperatividade simpática paroxística após embolia gordurosa cerebral, uma associação muito incomum.

ABSTRACT Paroxysmal sympathetic hyperactivity represents an uncommon and potentially life-threatening complication of severe brain injuries, which are most commonly traumatic. This syndrome is a clinical diagnosis based on the recurrent occurrence of tachycardia, hypertension, diaphoresis, tachypnea, and occasionally high fever and dystonic postures. The episodes may be induced by stimulation or may occur spontaneously. Underdiagnosis is common, and delayed recognition may increase morbidity and long-term disability. Trigger avoidance and pharmacological therapy can be very successful in controlling this complication. Fat embolism syndrome is a rare but serious complication of long bone fractures. Neurologic signs, petechial hemorrhages and acute respiratory failure constitute the characteristic presenting triad. The term cerebral fat embolism is used when the neurological involvement predominates. The diagnosis is clinical, but specific neuroimaging findings can be supportive. The neurologic manifestations include different degrees of alteration of consciousness, focal deficits or seizures. Management is supportive, but good outcomes are possible even in cases with very severe presentation. We report two cases of paroxysmal sympathetic hyperactivity after cerebral fat embolism, which is a very uncommon association.

Cerebral Fat Embolism: Recognition, Complications, and Prognosis.

Fat embolism syndrome (FES) is a rare syndrome caused by embolization of fat particles into multiple organs including the brain. It typically manifests with petechial rash, deteriorating mental status, and progressive respiratory insufficiency, usually occurring within 24-48 h of trauma with long-bone fractures or an orthopedic surgery. The diagnosis of FES is based on clinical and imaging findings, but requires exclusion of alternative diagnoses. Although there is no specific treatment for FES, prompt recognition is important because it can avoid unnecessary interventions and clarify prognosis. Patients with severe FES can become critically ill, but even comatose patients with respiratory failure may recover favorably. Prophylactic measures, such as early stabilization of fractures and certain intraoperative techniques, may help decrease the incidence and severity of FES.

Fat embolism: a rare cause of perioperative renal transplant dysfunction.

Fat embolism is a recognised complication of bony injury and orthopaedic surgery, commonly involving the long bones and pelvis. We report on the case of a 68-year-old renal transplant recipient who developed acute kidney injury following surgical stabilisation of metastatic carcinoma of the acetabulum and replacement of the proximal femur. A CT renal angiogram demonstrated a large fat embolus in the inferior vena cava (IVC) and left iliac veins below the level of IVC filter, with impaired renal perfusion. The risks of open or endovascular lipothrombectomy were felt to outweigh the potential benefits. The patient was managed with systemic anticoagulation and prepared for transplant failure. Subsequently, there was spontaneous improvement in urine output and 4 months postoperatively her transplant function had returned to her baseline level and this has remained stable at 1 year postsurgery.

Cerebral Fat Embolism: Clinical Presentation, Diagnostic Steps and Long-Term Follow-Up.

OBJECTIVE: Symptomatic cerebral fat embolism (CFE) is a rare complication that occurs after a traumatic injury or orthopaedic surgery and is diagnostically challenging. No data is currently available concerning long-term follow-up. METHODS: We identified from medical records 9 patients with CFE and revised the clinical signs and the diagnostic process. We then analysed long-term follow-up data, targeting clinical course after discharge, neurological impairment, and current quality of life, using the Barthel index and the modified Rankin Scale. RESULTS: All 9 patients initially showed severe neurological deficits, including disturbance of consciousness ranging from somnolence to coma. During the follow-up period for 3-58 months after the insult 2 patients had died. The 7 patients who remained alive had either recovered completely or showed only minor neurological deficits after rehabilitation. They were nearly independent in daily life and needed only minimal assistance. We performed the first brain biopsy in a patient with CFE. CONCLUSION: Most patients had a good outcome after long-term follow-up. In patients with an unexplained altered state of consciousness after a traumatic injury or an orthopaedic surgery, an MRI with diffusion-weighted imaging must be performed to uncover the characteristic pattern of disseminated hyperintense lesions in the white matter that are associated with CFE.

Timing of definitive fixation of major long bone fractures: Can fat embolism syndrome be prevented?

Fat embolism is common in patients with major fractures, but leads to devastating consequences, named fat embolism syndrome (FES) in some. Despite advances in treatment strategies regarding the timing of definitive fixation of major fractures, FES still occurs in patients. In this overview, current literature is reviewed and optimal treatment strategies for patients with multiple traumatic injuries, including major fractures, are discussed. Considering the multifactorial etiology of FES, including mechanical and biochemical pathways, FES cannot be prevented in all patients. However, screening for symptoms of FES should be standard in the pre-operative work-up of these patients, prior to definitive fixation of major fractures.

Inhalational Ciclesonide found beneficial in prevention of fat embolism syndrome and improvement of hypoxia in isolated skeletal trauma victims.

BACKGROUND: Many studies have established intravenous corticosteroid as an effective prophylactic therapy in fat embolism syndrome (FES). However, its use is limited among surgeons because of systemic side effects. Inhalational steroids have least systemic effects and are widely used for several chest conditions (i.e., asthma), but their effectiveness in FES has not been established. QUESTION/PURPOSE: This study was sought to evaluate the (1) efficacy and (2) safety of inhalational Ciclesonide (CIC) in prevention of FES and treatment of hypoxemia in isolated skeletal trauma victims. METHODS: A nonrandomized prospective control trial was designed in which all patients between 18 and 40 years with isolated skeletal injury who presented within 8 h of injury were allocated to either Trial group or control group. Trial group patients received 640 mcg of inhalational CIC with a metered-dose inhaler at the time of admission, and at 24 h. Control group patients did not receive any prophylactic therapy. Both groups were evaluated for development of FES (Gurd's criteria) and hypoxemia (PaO2 <70 mmHg) for 72 h. The complications related to CIC administration were evaluated in trial group patients during their hospital stay. RESULTS: Of 35 patients in each group, two patients in Trial group and nine patients in control group developed FES (P = 0.022). Eight patients in Trial group had hypoxemia at the time of admission, six of them improved and one additional patient developed hypoxemia after inhalational CIC administration. In control group, ten patients had hypoxia at the time of admission, only one of them improved and remaining nine patients had persistent hypoxemia even after 72 h. Additionally, three patients developed hypoxemia. A significant improvement in hypoxemia and a significant decrease in the incidence of FES were observed in Trial group (P < 0.05) compared to control group. None of the patients presented with any complications or adverse effects of steroid in Trial group. CONCLUSION: Inhalational CIC is a safe and effective therapy for prevention of FES and also an effective drug for treatment of hypoxemia in orthopedic trauma victims. LEVEL OF EVIDENCE: Level III, therapeutic study.

Severe fat embolism in perioperative abdominal liposuction and fat grafting / Embolia gordurosa grave no peroperatório de lipoaspiração abdominal e lipoenxertia

ABSTRACT BACKGROUND AND OBJECTIVES: Fat embolism syndrome may occur in patients suffering from multiple trauma (long bone fractures) or plastic surgery (liposuction), compromising the circulatory, respiratory and/or central nervous systems. This report shows the evolution of severe fat embolism syndrome after liposuction and fat grafting. CASE REPORT: SSS, 42 years old, ASA 1, no risk factors for thrombosis, candidate for abdominal liposuction and breast implant prosthesis. Subjected to balanced general anesthesia with basic monitoring and controlled ventilation. After 45 min of procedure, there was a sudden and gradual decrease of capnometry, severe hypoxemia and hypotension. The patient was immediately monitored for MAP and central catheter, treated with vasopressors, inotropes, and crystalloid infusion, stabilizing her condition. Arterial blood sample showed pH = 7.21; PCO2 = 51 mmHg; PO2 = 52 mmHg; BE = -8; HCO3 = 18 mEq L-1, and lactate = 6.0 mmol L-1. Transthoracic echocardiogram showed PASP = 55 mmHg, hypocontractile VD and LVEF = 60%. Diagnosis of pulmonary embolism. After 24 h of intensive treatment, the patient developed anisocoria and coma (Glasgow coma scale = 3). A brain CT was performed which showed severe cerebral hemispheric ischemia with signs of fat emboli in right middle cerebral artery; transesophageal echocardiography showed a patent foramen ovale. Finally, after 72 h of evolution, the patient progressed to brain death. CONCLUSION: Fat embolism syndrome usually occurs in young people. Treatment is based mainly on the infusion of fluids and vasoactive drugs, mechanical ventilation, and triggering factor correction (early fixation of fractures or suspension of liposuction). The multiorgânico involvement indicates a worse prognosis.

RESUMO JUSTIFICATIVA E OBJETIVOS: A Síndrome da Embolia Gordurosa (SEG) pode acontecer em pacientes vítimas de politrauma (fratura de ossos longos) ou operações plásticas (lipoaspiração), comprometendo circulação, respiração e/ou sistema nervoso central. O presente relato mostra evolução de SEG grave após lipoaspiração e lipoenxertia. RELATO DO CASO: SSS, 42 anos, ASA 1, sem fatores de risco para trombose, candidata a lipoaspiração abdominal e implante de prótese mamária. Submetida à anestesia geral balanceada com monitorização básica e ventilação controlada. Após 45 minutos de procedimento, houve queda súbita e progressiva da capnometria, hipoxemia e hipotensão grave. Imediatamente foi monitorizada com PAM e cateter central, tratada com vasopressores, inotrópicos e infusão de cristaloides, obtendo estabilização do quadro. Amostra sanguínea arterial mostrou pH = 7,21; PCO2 = 51 mmHg; PO2 = 52 mmHg; BE = -8; HCO3 = 18 mEQ/l e lactato = 6,0 mmol/l. Ecocardiograma transtorácico mostrou PSAP = 55 mmHg, VD hipocontrátil e FEVE = 60%. Diagnóstico de embolia pulmonar. Após24 h de tratamento intensivo, a paciente evoluiu com anisocoria e coma com escala de glasgow 3. Realizada TC de encéfalo que evidenciou isquemia cerebral grave, hemisférica, com sinais de êmbolos de gordura em A. cerebral média D; o ecocardiograma transesofágico mostrou forame oval patente. Finalmente, após 72 h de evolução, a paciente evoluiu para morte encefálica. CONCLUSÃO: A SEG ocorre geralmente em jovens. O tratamento baseia-se principalmente na infusão de líquidos e drogas vasoativas, ventilação mecânica e correção do fator desencadeante (fixação precoce de fraturas ou suspensão da lipoaspiração). O comprometimento multiorgânico indica pior prognóstico.