Haemophagocytic syndrome as a cause of subacute encephalopathy

Hernández Ramos, Francisco José; Palomino García, Alfredo; Jiménez Hernández, María Dolores

doi:10.1016/j.medcle.2019.10.016

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Subcorneal bullae of hematic content (black arrows). 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Unidad de Gestión Clínica de Neurología y Neurofisiología, Hospital Regional Universitario, Virgen del Rocío de Sevilla, Sevilla, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome hemofagocítico como causa de encefalopatía subaguda" ] ] "textoCompleto" => "Hemophagocytic syndrome is a rare entity with an annual incidence of one case per 800,000 people<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>. There is a genetic form, and it is more common in Japan and in children. Its pathogenesis is unknown. It is an entity with a high mortality rate and affects multiple organs, including the nervous system<a class="elsevierStyleCrossRef" href="#bib0015">3</a>. It has been associated with infections, neoplasms, autoimmune diseases, immunomodulatory treatment of multiple sclerosis, haematological transplants, and there is an idiopathic form. The diagnosis is based on clinical, laboratory and immunological markers and it is pathologically confirmed. The diagnostic criteria have been defined by the Histiocytosis Society (2004). Management consists of life support measures, concomitant disease treatment and specific treatment (salvage and induction)<a class="elsevierStyleCrossRef" href="#bib0020">4</a>.We report the case of a 56-year-old man, with no relevant family, personal, and epidemiological history, whose symptoms began in March 2018 with fever, generalized weakness, toxic syndrome, dry cough, evanescent hives-like skin lesions, drowsiness and seizures, reason why he was admitted to the infectious disease department, ruling out microbiological causes and haematological causes after a bone marrow study. A brain MRI scan showed anomalies in white matter, resulting in admission to the neurology department. The examination showed: general malaise, pyretic, paleness, hepatosplenomegaly and from a neurological point of view, tendency to sleep, with ocular opening to verbal stimuli, disorientation to time and place, bradypsychia, understands simple commands responding with disyllables and motor perseveration. There appears to be cortical blindness, ocular tracking in horizontal rapid eye movements, bilateral lower facial weakness, spastic tetraparesis with extensor plantar reflexes, attitude tremor in hands with occasional myoclonic jerks. Among the anomalies found in the complementary tests performed, the following stand out: pancytopenia, LDH 1,926U/l, ferritin 1.309μg/l, CD25 18.64U/mL, and negative autoimmunity. Body PET/CT scan with splenomegaly, electroencephalogram with diffuse slowing in theta frequency range, cerebrospinal fluid with elevated protein count and negative cultures, serologies, PCR and flow cytometry. A new brain MRI was performed which showed progression of the white matter abnormality with activity data in diffusion sequences.From a topographic and syndromic point of view, we propose a subacute encephalopathy with white matter damage, elevated protein count in cerebrospinal fluid, diffuse slowing in the electroencephalogram, together with the systemic and analytical clinical data described. In the differential diagnosis, the demyelinating aetiology of the hemorrhagic leukoencephalitis was considered, but the lack of red blood cells, negative oligoclonal banding in cerebrospinal fluid, absence of oedema and hemorrhagic component in the MRI rule out this aetiology. There are no epidemiological data for the toxic aetiology, and the infectious cause is ruled out after the extensive study in this regard. We ruled out inflammatory amyloid angiopathy due to the lack of bleeding and hemosiderin deposits in spin-echo sequences on MRI. Vasculitis of the nervous system, in this case secondary to the accompanying systemic symptoms, is ruled out because it does not present pleocytosis or data on autoimmune or infectious diseases. Fever, pancytopenia, and white matter involvement would work in favour of lymphoma with nervous system involvement, but a negative cerebrospinal fluid flow cytometry would work against it.Despite a first negative bone marrow biopsy, the clinical and laboratory findings pointed to the hemophagocytic syndrome as the cause of the patient's symptoms. We insisted on the need for a second bone marrow biopsy showing hemophagocytosis and abnormal lymphocytes compatible with germinal centre B-cell non-Hodgkin lymphoma in a percentage lower than 5% on cytometry. Despite starting treatment with corticosteroid pulse therapy and subsequently cyclophosphamide, the patient died in the ICU, unable to perform autopsy due to family refusal, being the final diagnosis that of idiopathic hemophagocytic syndrome, not ruling out that it was secondary to lymphoma, although a percentage of abnormal lymphocytes below 5% do not allow its confirmation.When the hemophagocytic syndrome affects the nervous system, it can manifest as subacute encephalopathy, meningoencephalomyelitis, hematomas, Guillain-Barré or cauda equina syndrome. The differential diagnosis is narrowed if it is accompanied by systemic data such as fever, lymphadenopathy, hepatosplenomegaly, skin lesions, and laboratory abnormalities such as pancytopenia and elevated LDH, triglycerides, ferritin, and CD25. It is a disease with a high mortality rate, but it can respond to treatment.This case has the peculiarity that, despite a first negative bone marrow biopsy, the neurological manifestations, ancillary tests, systemic data and laboratory abnormalities allowed us to suspect the hemophagocytic syndrome, which was confirmed in the second bone marrow biopsy.It is important to bear in mind that we, neurologists, should not only assess "pure" neurological manifestations, but also those that are accompanied by systemic manifestations, since we provide insight into the diagnosis and treatment of diseases such as hemophagocytic syndrome, which can enable us to increase our knowledge of these diseases." 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Robb-Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1939" "volumen" => "2" "paginaInicial" => "194" "paginaFinal" => "198" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2885645" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adult haemophagocytic syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Ramos-Casals" 1 => "P. Brito-Zerón" 2 => "A. López-Guillermo" 3 => "M.A. Khamashta" 4 => "X. Bosch" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(13)61048-X" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2014" "volumen" => "383" "paginaInicial" => "1503" "paginaFinal" => "61516X" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24290661" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The expanding spectrum of haemophagocytic lymphohistiocitosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.H. Filipovich" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Curr Opin Allergy Clin Inmunol" "fecha" => "2011" "volumen" => "11" "paginaInicial" => "512" "paginaFinal" => "516" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in diagnosis and treatment of hemophagocytic lymphohistiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.F. Bode" 1 => "K. Lehmberg" 2 => "A. Maul-Pavicic" 3 => "T. Vraetz" 4 => "G. Janka" 5 => "U. zur Stadt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/ar3843" "Revista" => array:5 [ "tituloSerie" => "Arthritis Res Ther" "fecha" => "2012" "volumen" => "14" "paginaInicial" => "213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22682420" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015600000001/v1_202101070942/S2387020620305982/v1_202101070942/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015600000001/v1_202101070942/S2387020620305982/v1_202101070942/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620305982?idApp=UINPBA00004N"]

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Vol. 156. Issue 1.