==== Front J Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Medknow Publications & Media Pvt Ltd India JFMPC-7-61810.4103/jfmpc.jfmpc_56_18Case ReportSpontaneous intracranial hemorrhage associated with dengue fever: An emerging concern for general physicians Singh Abhijeet 1Balasubramanian Viswesvaran 2Gupta Nitesh 21 Department of Pulmonary, Critical Care and Sleep Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India2 Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, IndiaAddress for correspondence: Dr. Abhijeet Singh, Department of Pulmonary, Critical Care and Sleep Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029, India. E-mail: appu.abhijeet@gmail.comMay-Jun 2018 7 3 618 628 Copyright: © 2018 Journal of Family Medicine and Primary Care2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Dengue fever (DF) is an arboviral disease caused by a positive-sense RNA virus of the genus Flavivirus. The overall incidence of DF has increased exponentially worldwide over the last three decades. The atypical clinical manifestations of DF grouped under expanded dengue syndrome (EDS), have also been reported more frequently for the last decade. These unusual manifestations are usually associated with coinfections, comorbidities, or complications of prolonged shock. Intracranial hemorrhage (ICH) is one of the rare manifestations of the central nervous system involvement by dengue as a part of EDS. The pathogenesis and treatment of this manifestation also remain controversial. Therefore, we report a case of a previously healthy 65-year-old female who developed ICH as a part of EDS along with a brief review of literature. Dengue feverexpanded dengue syndromeintracranial hemorrhage ==== Body Introduction Dengue fever (DF), an arboviral illness, is caused by a positive-sense RNA virus of the genus Flavivirus.[1] The incidence of dengue has increased exponentially around the world over the last three decades.[2] The atypical or unusual manifestations recently grouped under expanded dengue syndrome (EDS) with neurological, hepatic, renal, and other isolated organ involvement, have also increased for the last decade. These manifestations are usually associated with coinfections, comorbidities, or complications of prolonged shock. Intracranial hemorrhage (ICH) is one of the rare manifestations of the central nervous system (CNS) involvement by dengue as a part of EDS. The pathogenesis is multifactorial attributed to the complex interplay of vasculopathy, coagulopathy, platelet dysfunction, and thrombocytopenia. There is a scarcity of knowledge on prevention and management of ICH secondary to DF. The role of prophylactic platelet transfusion and the need for elaborate assessment of hemostasis parameters remains uncertain. We are reporting a case of a previously healthy 65-year-old female who developed ICH as a part of EDS with a brief review of the literature. Case Report A 65-year-old previously healthy female was admitted to the hospital with chief complaints of high-grade fever, generalized body ache, and decreased appetite for 3 days, followed by breathlessness and altered sensorium for 2 days. Her vital parameters recorded on examination were pulse – 140/min, blood pressure – 90/60 mmHg, respiratory rate – 60/min, temperature 102°F, and pulse oximetry 60% on room air. She also had diffuse erythematous macular rash on the trunk and peripheral extremities. Neurological examination revealed Glasgow Coma Score (GCS) of 10 without any signs of meningeal irritation. Pupillary size and reaction were normal with bilateral extensors plantars. Other systemic examinations were unremarkable. She was found to have anemia (hemoglobin 8 g/dl), hematocrit 41%, and thrombocytopenia (90,000/cm3) with normal total leukocyte count and coagulation profile. Dengue nonstructural (NS1) antigen (ELISA kit, PanBio Diagnostics, Brisbane, Australia) as well as IgM dengue antibody (Immunochromatographic kit, Standard Diagnostics Inc., Yongin, Korea) tests were detected positive in blood, whereas IgG antibody was negative. Serologies for malaria, chikungunya, leptospira, typhoid, and scrub typhus were negative. Rest all laboratory investigations were unremarkable. Her chest skiagram revealed bilateral infiltrates involving all zones suggestive of acute respiratory distress syndrome (ARDS). She was immediately placed on invasive mechanical ventilation in view of acute hypoxemic respiratory failure. The working diagnosis of ARDS secondary to dengue infection was established. Fluid resuscitation was started along with hemodynamic monitoring followed by subsequent resuscitation with vasopressor support. She was managed with ventilator strategy that comprised low tidal volume and high positive end-expiratory pressure settings with target fraction of inspired oxygen (FiO2) ≤0.6 to maintain SaO2 above 90%. On the 2nd day of hospital stay, her general condition further worsened as her GCS dropped to 5, bilateral pupils sluggishly reacting to light, and vasopressor requirement further increased. She also had two episodes of generalized tonic–clonic seizure. Serial platelet count was 65,000/cm3. She was given one unit of packed red blood cells and six units of random donor platelets. Emergency noncontrast computed tomography revealed dilated bilateral lateral, third, and fourth ventricles showing hyperdense content of blood attenuation suggestive of intraventricular hemorrhage along with linear hyperdensities along bilateral sulcal spaces diffusely and along tentorium cerebelli as well as falx cerebrum suggestive of subarachnoid hemorrhage shown in Figure 1a–c. There was no midline shift. Fundus examination revealed no evidence of papilledema. Contrast magnetic resonance imaging including angiography excluded other sources of ICH, such as arteriovenous malformations, aneurysm, or dural fistulas. The patient was managed conservatively to maintain hemodynamic stability and repeat platelet transfusions were done. However, there was progressive deterioration and succumbed to death on the 3rd day of hospital stay. Figure 1 (a-c) Noncontrast computed tomography of head: Dilated bilateral lateral, third, and fourth ventricles showing hyperdense content of blood attenuation suggestive of intraventricular hemorrhage along with linear hyperdensities along bilateral sulcal spaces diffusely and along tentorium cerebelli as well as falx cerebrum suggestive of subarachnoid hemorrhage Discussion Dengue virus infection is a common mosquito vector-borne arboviral disease that may present with a varied spectrum of clinical manifestations. The infection may be asymptomatic or may cause undifferentiated febrile illness (viral syndrome), DF without hemorrhage or with unusual hemorrhage, dengue hemorrhagic fever (DHF) including shock known as dengue shock syndrome and EDS or isolated organopathy.[2] CNS involvement as a part of EDS continues to remain underrecognized and underreported. The various CNS manifestations include febrile seizures in young children, encephalopathy, encephalitis/aseptic meningitis, subdural effusions, mononeuropathies/polyneuropathies/Guillain–Barre Syndrome, and transverse myelitis.[12] These CNS manifestations are having pathogenetic mechanisms such as direct neurotrophic effects of virus, systemic manifestations of DF, and postinfectious immune complex-mediated mechanism. ICH, a potential life-threatening complication of dengue, is of uncommon occurrence in patients with severe dengue.[3] The incidence of dengue encephalopathy is estimated to range from 0.5% to 6.2%.[456] However, the incidence of ICH associated with DF is still uncertain. In a study by Cam et al., of the 5400 patients with DF, only one had ICH.[4] There is a scarcity of data regarding the incidence, pathogenesis, and treatment modalities available to prevent and treat patients of dengue with ICH. A literature review of case reports as well as series describing demographic and clinical profile including the outcome of ICH in patients with DF are listed in Tables 1 and 2, respectively.[378910111213141516171819202122232425] Presence of fever, reduced or altered consciousness, vomiting, seizures, and headache are common chief complaints in patients with ICH. The occurrence of ICH associated with DF can be localized or diffuse involving commonly cerebrum, ventricles, and less commonly cerebellum. Subdural, extradural, as well as subarachnoid hemorrhages were also reported. Various issues need to be considered in managing such complication of DF. Table 1 Demographic profile of cases of dengue fever associated intracranial hemorrhage from various case reports and series reported by different authors Table 2 Clinical profile of cases including the outcome of dengue fever associated intracranial hemorrhage from various case reports and series reported by different authors Platelet counts did not correlate with the incidence of ICH suggesting a complex interplay of multifactorial pathogenetic mechanisms for the occurrence of ICH.[3] The various postulated mechanisms include vasculopathy, coagulopathy, platelet dysfunction, and thrombocytopenia.[26] Detection of dengue IgM, IgG, and NS1 Ag in cerebrospinal fluid (CSF) of patients with dengue suggests breach of blood–brain barrier and blood–CSF barrier and vasculopathy secondary to immunopathological-related mechanisms.[27] Coagulopathy secondary to NS1 antigen-induced production of plasminogen cross-reactive antibodies leading to increased plasmin through plasminogen activation of fibrinolysis is also reported.[28] Thrombocytopenia and platelet dysfunction can be attributed to exhaustion from platelet activation triggered by immune complexes.[29] The lack of treatment guidelines for prevention and early recognition of ICH contributes to significant morbidity and mortality. High-risk population for EDS includes infants and the elderly, obesity, pregnant women, peptic ulcer disease, women who have menstruation or abnormal vaginal bleeding, hemolytic diseases such as glucose-6-phosphatase dehydrogenase deficiency, thalassemia and other hemoglobinopathies, congenital heart disease, chronic diseases such as diabetes mellitus, hypertension, asthma, ischemic heart disease, chronic renal failure, liver cirrhosis, and patients on steroid or nonsteroidal anti-inflammatory drug treatment.[2] Factors such as older patients, high baseline hematocrit levels, low platelet levels, prolonged APTT, female gender, vomiting, high absolute lymphocyte count, duration of shock, and high aspartate aminotransferase level are associated with severe bleeding in dengue patients.[3031] It is not possible to advise screening CT head in every patient with DF to detect ICH. CT should be considered only there is high index of suspicion based on clinical findings. Clinical experience from prior studies suggests that patients with secondary dengue infection identified by the detection of IgG early in the course of the disease with a positive NS1 antigen test and negative IgM are at higher risk of ICH carrying poor prognosis and should be monitored more closely with lower thresholds for diagnostic CT of the brain when suspicion of ICH is present.[3] In the present case report, though the patient was a female without any comorbidities, presence of risk factors of profound shock requiring vasopressor support, seizures, low platelet, and viremia, suggested by positive NS-1 antigen along with altered sensorium prompted early CT scan which revealed suggesting ICH. The efficacy of platelet and fresh-frozen plasma transfusions for prevention of ICH and their role in the outcome of patients with ICH are controversial and debatable. The British Committee for Standardization in Haematology Guidelines and Directorate of National Vector Borne Diseases Control Programme, Government of India, recommend a trigger of 10,000/μl for platelet transfusion for stable thrombocytopenic patients without additional risk factors for bleeding.[3233] These guidelines also recommend prophylactic platelet transfusions are not required in stable patients with platelet count below 20,000/μl. Studies have observed lack of benefit with prophylactic platelet transfusion. This has been attributed to lack of correlation between clinical bleed and platelet count indicating defects in alternate coagulation pathways, lack of sustained effect of platelet due to transient increment in platelet count with return to pretransfusion levels within 5 h of transfusion, risk of pulmonary edema, prolongation of hospitalization, and cost.[343536] However, the role of prophylactic transfusion of platelets in the prevention of ICH remains contentious and debatable taking into consideration the significant morbidity and mortality associated with this rare event. In the present case, the patient was transfused 6 units of platelets. Despite that patient's intracranial bleed progressed and the patient succumbed. The role of other blood products such as fresh-frozen plasma, cryoprecipitate, and factor VIIa in prevention and treatment of ICH remain equally contentious and are generally administered by discretion of the physician taking into consideration the clinical condition of the patient.[37] Since complex multifactorial pathogenic mechanisms are involved in bleeding manifestations of dengue, monitoring of platelet count and routine coagulation profile would not be sufficient, and a global assessment of efficiency of hemostatic mechanisms are warranted. Thromboelastography which involves rapid assessment of hemostatic clot stability based on the assessment of viscoelastic changes in clotting whole blood under low shear conditions after adding a specific coagulation activator might be helpful in determining a subset of dengue patients that may benefit from prophylactic transfusions to prevent life-threatening hemorrhages.[38] Other modalities such as thromboelastometry and platelet aggregometry may also aid in assessing the need for prophylactic transfusions. Although these studies are validated for goal-directed transfusion therapy in bleeding patients in major surgery and trauma and in bleeding hemophilic patients, their role in patients of dengue is unknown due to lack of clinical trials.[3] Surgical management of dengue infection with ICH such as hematoma evacuation is often delayed and difficult as vasculopathy, coagulopathy and platelet dysfunction necessitate correction of platelets and other coagulation parameters with blood transfusions.[3] These factors may persist even after surgery. Factors such as availability of neurosurgical centers, surgeons’ experience, disease severity, comorbid illnesses, and distance for transportation of critically ill patients can affect the outcome. Neurosurgical procedures can be undertaken if platelets are above 100 × 109/L and international normalized ratio is maintained from 1.5 to 1.7.[383940] Timely surgical intervention if performed within 8 h of hemorrhage was associated with improved outcome.[4142] These recommendations need to be validated for ICH associated with dengue infection. However, in the present case, deteriorated rapidly before decision for surgery could be undertaken and finally succumbed to death on the 3rd day of illness indicating fulminant course of illness. The expanding literature regarding incidence and outcome of DF associated with atypical CNS manifestations such as ICH predicts high morbidity and mortality. It is very difficult and even challenging for general physicians to take action even if diagnosed early as there is still uncertainty in management. This warrants health-care delivery systems to revise existing guidelines and frame strict protocols for managing such complications to reduce morbidity as mortality worldwide. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs 1 World Health Organization. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control- New Edition. (WHO/HTM/NTD/DEN/2009.1) 2009 Last accessed on 2017 Nov 28 Geneva World Health Organization Available from: http://www.who.int/rpc/guidelines/9789241547871/ 2 World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. Revised and Expanded Edition 2011 Last accessed on 2017 Nov 28 Regional Office for South-East Asia WHO Available from: http://www.apps.who.int/iris/bitstream/10665/204894/1/B4751.pdf 3 Sam JE Gee TS Nasser AW Deadly intracranial bleed in patients with dengue fever: A series of nine patients and review of literature J Neurosci Rural Pract 2016 7 423 34 27365962 4 Cam BV Fonsmark L Hue NB Phuong NT Poulsen A Heegaard ED Prospective case-control study of encephalopathy in children with dengue hemorrhagic fever Am J Trop Med Hyg 2001 65 848 51 11791985 5 Hendarto SK Hadinegoro SR Dengue encephalopathy Acta Paediatr Jpn 1992 34 350 7 1509881 6 Solomon T Dung NM Vaughn DW Kneen R Thao LT Raengsakulrach B Neurological manifestations of dengue infection Lancet 2000 355 1053 9 10744091 7 Wafa SR Jamsari S Karis BM A case report: Intracranial haemorrhage in a patient with probable dengue fever Med J Malaysia 1999 54 273 6 10972043 8 de Souza LJ Martins AL Paravidini PC Nogueira RM Gicovate Neto C Bastos DA Hemorrhagic encephalopathy in dengue shock syndrome: A case report Braz J Infect Dis 2005 9 257 61 16224633 9 Kumar J Kumar A Gupta S Jain D Dengue hemorrhagic fever: An unusual cause of intracranial hemorrhage J Neurol Neurosurg Psychiatry 2007 78 253 17308289 10 Jensenius M Berild D Ormaasen V Maehlen J Lindegren G Falk KI Fatal subarachnoidal haemorrhage in a Norwegian traveller with dengue virus infection Scand J Infect Dis 2007 39 272 4 17366065 11 Kumar R Prakash O Sharma BS Intracranial hemorrhage in dengue fever: Management and outcome: A series of 5 cases and review of literature Surg Neurol 2009 72 429 33 19328535 12 Wani AM Mejally MA Hussain WM Maimani WA Hanif S Khoujah AM Skin rash, headache and abnormal behaviour: Unusual presentation of intracranial haemorrhage in dengue fever BMJ Case Rep 2010 2010 pii: bcr06.2009.1949 13 Mathew S Pandian JD Stroke in patients with dengue J Stroke Cerebrovasc Dis 2010 19 253 6 20434057 14 Gera C George U Acute disseminating encephalomyelitis with hemorrhage following dengue Neurol India 2010 58 595 6 20739799 15 Khanna A Atam V Gupta A A case of dengue encephalitis with intracerebral hemorrhage J Glob Infect Dis 2011 3 206 20 21731315 16 Mittal M Jain N Subdural haematoma and axonal polyneuropathy complicating dengue fever BMJ Case Rep 2011 2011 pii: bcr1220103672 17 Assir MZ Jawa A Ahmed HI Expanded dengue syndrome: Subacute thyroiditis and intracerebral hemorrhage BMC Infect Dis 2012 12 240 23033818 18 Singh M Garg K Bisht A Sharma BS Singh PK Pandia M Spinal epidural hematoma with myelitis and brainstem hemorrhage: An unusual complication of dengue fever Neurol India 2013 61 541 3 24262469 19 Singh RK Ghatak T Baronia AK Garg P Intracranial hemorrhage in a patient coinfected with dengue and leptospirosis J Neurosci Rural Pract 2013 4 366 7 24250191 20 Vargas-Sánchez A Chiquete E Gutiérrez-Plascencia P Castañeda-Moreno V Alfaro-Castellanos D Paredes-Casillas P Cerebellar hemorrhage in a patient during the convalescent phase of dengue fever J Stroke 2014 16 202 4 25328880 21 Singh J Dinkar A Atam V Misra R Kumar S Gupta KK Patel ML Intracranial hemorrhage in dengue fever: A case series JMSCR 2015 3 4447 52 22 Nadarajah J Madhusudhan KS Yadav AK Gupta AK Vikram NK Acute hemorrhagic encephalitis: An unusual presentation of dengue viral infection Indian J Radiol Imaging 2015 25 52 5 25709166 23 Jayasinghe NS Thalagala E Wattegama M Thirumavalavan K Dengue fever with diffuse cerebral hemorrhages, subdural hematoma and cranial diabetes insipidus BMC Res Notes 2016 9 265 27165581 24 Mehta M Sharma PK Garg RK An uncommon complication of dengue J Stroke Cerebrovasc Dis 2018 27 e46 7 29103866 25 Sam JE Gee TS Wahab NA Fatal intracranial hemorrhage in a patient with severe dengue fever Asian J Neurosurg 2018 13 56 8 29492121 26 Chuansumrit A Tangnararatchakit K Pathophysiology and management of dengue hemorrhagic fever Transfus Altern Transfus Med 2006 8 3 11 27 Puccioni-Sohler M Rosadas C Cabral-Castro MJ Neurological complications in dengue infection: A review for clinical practice Arq Neuropsiquiatr 2013 71 667 71 24141501 28 Chuang YC Lin J Lin YS Wang S Yeh TM Dengue virus nonstructural protein 1-induced antibodies cross-react with human plasminogen and enhance its activation J Immunol 2016 196 1218 26 26712948 29 Boonpucknavig S Vuttiviroj O Bunnag C Bhamarapravati N Nimmanitya S Demonstration of dengue antibody complexes on the surface of platelets from patients with dengue hemorrhagic fever Am J Trop Med Hyg 1979 28 881 4 384817 30 Tee HP How SH Jamalludin AR Safhan MN Sapian MM Kuan YC Risk factors associated with development of dengue haemorrhagic fever or dengue shock syndrome in adults in hospital Tengku Ampuan Afzan Kuantan Med J Malaysia 2009 64 316 20 20954558 31 Chamnanchanunt S Kanagaraj D Thanachartwet V Desakorn V Rojnuckarin P Early predictors of clinically significant bleeding in adults with dengue infection Southeast Asian J Trop Med Public Health 2012 43 890 9 23077811 32 British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions Br J Haematol 2003 122 10 23 12823341 33 Dutta AK Biswas A Baruah K Dhariwal AC National guidelines for diagnosis and management of dengue fever/dengue haemorrhagic fever and dengue shock syndrome J Indian Med Assoc 2011 109 30 5 21888156 34 Chaudhary R Khetan D Sinha S Sinha P Sonker A Pandey P Transfusion support to dengue patients in a hospital based blood transfusion service in North India Transfus Apher Sci 2006 35 239 44 17097349 35 Stanworth SJ Dyer C Choo L Bakrania L Copplestone A Llewelyn C Do all patients with hematologic malignancies and severe thrombocytopenia need prophylactic platelet transfusions? Background, rationale, and design of a clinical trial (trial of platelet prophylaxis) to assess the effectiveness of prophylactic platelet transfusions Transfus Med Rev 2010 24 163 71 20656185 36 Lum LC Abdel-Latif Mel-A Goh AY Chan PW Lam SK Preventive transfusion in dengue shock syndrome-is it necessary? J Pediatr 2003 143 682 4 14615749 37 Bolliger D Seeberger MD Tanaka KA Principles and practice of thromboelastography in clinical coagulation management and transfusion practice Transfus Med Rev 2012 26 1 3 21872428 38 Chan KH Mann KS Chan TK The significance of thrombocytopenia in the development of postoperative intracranial hematoma J Neurosurg 1989 71 38 41 2738639 39 Matevosyan K Madden C Barnett SL Beshay JE Rutherford C Sarode R Coagulation factor levels in neurosurgical patients with mild prolongation of prothrombin time: Effect on plasma transfusion therapy J Neurosurg 2011 114 3 7 20815699 40 Szczepiorkowski ZM Dunbar NM Transfusion guidelines: When to transfuse Hematology Am Soc Hematol Educ Program 2013 2013 638 44 24319244 41 Mendelow AD Gregson BA Rowan EN Murray GD Gholkar A Mitchell PM Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): A randomised trial Lancet 2013 382 397 408 23726393 42 Gregson BA Broderick JP Auer LM Batjer H Chen XC Juvela S Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage Stroke 2012 43 1496 504 22511006