International Journal of Neuroscience ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: https://www.tandfonline.com/loi/ines20 “Intraventricular hemorrhage as clinical presentation of herpes simplex virus encephalitis. A case report and review of the literature.” FJ Alvarez-Perez, F Paiva & CA Lino To cite this article: FJ Alvarez-Perez, F Paiva & CA Lino (2020): “Intraventricular hemorrhage as clinical presentation of herpes simplex virus encephalitis. A case report and review of the literature.”, International Journal of Neuroscience, DOI: 10.1080/00207454.2020.1787409 To link to this article: https://doi.org/10.1080/00207454.2020.1787409 Accepted author version posted online: 27 Jun 2020. Submit your article to this journal Article views: 4 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ines20 “Intraventricular hemorrhage as clinical presentation of herpes simplex virus encephalitis. A case report and review of the literature.” Alvarez-Perez FJ1,2, Paiva F1, Lino CA1. 1 Stroke Unit, Cova da Beira University Hospital (Covilhã, Portugal). 2 Health Sciences Research Center. Medicine Department. Health Sciences Faculty, Beira Interior University (Covilhã, Portugal). ip t franciscoplus@hotmail.com cr Abstract us Herpes simplex virus encephalitis (HSVE) represents the most common cause of sporadic encephalitis in humans. The development of intracerebral hematomas is rare and late during the course of HSVE. Objective: to report a case of a patient with HSVE who initially presented a diffuse intracranial hemorrhage with predominant intraventricular bleeding. ed M an Case report: A 66-year-old man was admitted to the Emergency Department with acute headache. Antecedents: alcohol consumption and ethylic hepatopathy. The brain computed tomography showed acute tetraventricular hemorrhage and hydrocephalus. The blood analysis showed pancytopenia and alteration of all hepatic parameters. After external drainage of cerebrospinal fluid the patient presented a worsening of headache, disorientation, mild left hemiparesis, neck stiffness and temperature of 37.6°C. The cerebrospinal fluid was hemorrhagic, with 3 lymphocytes/mm3, 60 mg/dL of proteins and PCR positive for Herpes simplex virus type 1. The patient improved with intravenous acyclovir, however he experienced several medical complications which caused his dead. ce pt Discussion: The patient presented an atypical cerebral bleeding related to HSVE because the development of hematoma was early and the topography of hemorrhage was basically intraventricular. Probably, both atypical characteristics were related to thrombocytopenia and severe coagulation disorder. This case expands the spectrum of cerebrovascular disorders associated with HSVE. Ac Keywords: Intraventricular bleeding, Cerebral haemorrhage, Herpetic encephalitis, Stroke Herpes simplex virus encephalitis (HSVE) is an acute necrotizing encephalitis which represents the most common cause of sporadic encephalitis in humans1-4. This encephalitis causes perivascular edema and hemorrhagic necrosis of the brain parenchyma with a predominantly orbitofrontal and temporal topography. This edema may be observed in imaging studies performed during acute phase, specially magnetic resonance, in the mesiotemporal, orbitofrontal and insular cortex5-8. However, the development of macroscopic intracerebral hematomas is rare and usually occurs late during the course of HSVE. A recent work reported 2.7% of intracranial bleedings in 4.871 patients admitted by HSVE between 2002 and 2014 in United States9. The objective of the present work is to report a case of a male patient with HSVE who presented initially a diffuse intracranial hemorrhage with a predominant intraventricular bleeding. Case presentation A 66-year-old man was admitted to the Emergency Department of University Hospital of Covilha (UHC) with intense acute holocranial headache after the lunch, without vomit or seizures. He was not hypertensive and he was not taking any drug. The main previous antecedent was heavy alcohol consumption and an alteration of hepatic parameters in blood analysis and weight loss which his general practitioner was assessing during last months. t The physical examination showed that the patient was drowsy but could be woken up with minimum stimuli. He was confuse, disoriented in time and space, and not collaborative. The patient had not motor asymmetries in members, cranial nerve paresis, neck rigidity or fever (body temperature on admission 35.6°C). Ac ce pt ed M an us cr ip The brain computed tomography (CT) scan showed an acute tetraventricular hemorrhage, which predominated in the right lateral ventricle, and was associated to acute hydrocephalus. A discrete parenchymatous bleeding in medial aspect of the right temporal lobe was also identified (Figure 1). An Angio-CT examination was performed, excluding aneurisms and vascular malformations. The blood analysis showed pancytopenia (1.800 leucocytes/mm3, 3.170.000 erythrocytes/mm3, 30.000 platelets/mm3), elevation of bilirrubine (total 2.81 mg/dL, direct 1.17 mg/dL, indirect 1.64 mg/dL), glutamic oxaloacetic transaminase (66 U/L), lactate dehydrogenase (493 U/L) and gamma glutaryl transpherase (197 U/L), a prolongation of prothrombine time (19.7 seconds) and hypoalbuminemia (2.8 g/dL), compatible with hepatic failure. The patient was transferred to the Neurosurgical Unit in the reference hospital to perform an external drainage of cerebrospinal fluid and blood. After 8 days he returned to the Stroke Unit of UHC. The discharge report of Neurosurgery Unit did not relate any complication during this time. The first day after readmission (ninth day of disease) the patient presented a worsening of frontal headache. He was conscious and not collaborative and showed time and space disorientation, anosognosia of deficits, and right ocular preference. A mild left hemiparesis, neck stiffness and signals of Lassegue, Kernig and Brudzinski were evident. Body temperature was 37.6°C. The CT scan showed minimal rests of subarachnoid blood in the convexity of the brain, without images of parenchymatous hematoma or hydrocephalus (Figure 2). The electroencephalographic study showed a diffuse slowing of activity without evidence of periodic or epileptic discharges. A cerebrospinal fluid examination was done, showing an hemorrhagic liquor with 3 lymphocytes/mm3 and 60 mg/dL of proteins. Microbiological study was negative (Gram and Ziehl-Neelsen stains, culture, VDRL, and polymerase chain reactions [PCR] for Escherichia coli K1, Streptococcus agalactiae, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenza, Listeria monocytogenes, Cryptococcus neoformans, Enterovirus, Human parechovirus, Varicela zoster, Human herpesvirus 6, Herpes simplex type 2, and Cytomegalovirus), except PCR for Herpes simplex virus type 1. The patient was treated with intravenous acyclovir during 14 days, showing a good evolution of confusion, fever, and headache. However, he experienced a fistulization in the point of insertion of the intraventricular catheter, and several medical complications (respiratory and urinary infections, hepatic encephalopathy) which prolonged the admission during 3 months. Finally, the patient dead in a chronic care unit due to complications of hepatic disease. Discussion The herpes virus infection causes a necrotizing inflammatory process which affects mainly the medial temporal lobe in cortical and subcortical areas. Secondarily, insula, cingulated cortex, posterior orbital frontal cortex, and other extra-temporal areas may be affected3. The mechanism of lesion combines viral replication and immune response mediated by T cells, cytokines, chemokines, and proteases like matrix metalloproteinase-9. Histologically, the tissue presents cytotoxic and vasogenic edema, necrosis and petechial hemorrhages4. Although this petechial bleeding is a frequent phenomenon in HSVE, the development of a macroscopic hematoma in the infected parenchyma is rare and it was reported in 2.7% of patients in a large series9. On the other hand, the development of ischemic stroke is still less frequent and it was reported in a reduced number of patients with HSVE caused by type 2 virus. These ischemic strokes were usually multifocal and related to large vessel vasculitis7. A recent review showed that the bleeding usually appears during the second week (median 10 days) after the clinical onset of HSVE7. Because some patients receiving acyclovir therapy may experience thrombocytopenia induced by the drug10,11 and most hematomas developed during the antiviral therapy, it has been suggested that it could be a predisposing factor for bleeding in these patients. The Table 1 summarizes the cases of intracerebral bleeding related to HSVE reported in adult and pediatric patients. The presence of a bleeding is related to worse prognosis in these patients and there has been suggested that anticoagulants could be avoided16. ed M an us cr ip t The reported patient presents an atypical cerebral bleeding related to HSVE because the development of hematoma was very early and the topography of hemorrhage was basically intraventricular. There was a minimum parenchymatous bleeding in the medial aspect of the right temporal lobe which was relatively occulted by the diffuse presence of blood in the 4 ventricles. The diagnosis of primary intraventricular hemorrhage is uncommon and this topography, representing only the 3.9% of all intracerebral hemorrhages diagnosed during a 10-years period in a big series39. The atypical characteristics present in this patient may be explained by the thrombocytopenia and the severe coagulation disorder found in the patient due to chronic hepatopathy, which probably helped to increase the petechial bleeding that usually may be found in the affected parenchyma. Because the clinical presentation was an acute hydrocephalus, the clinical manifestations related to HSVE were undervalued. Indeed, it is possible that this patient was subencephalopathic before or in the moment of admission, state that could be hided by the acute bleeding and hydrocephalus. The in-hospital mortality of intraventricular hemorrhage is high, being reported in 41.7% of all patients and 60% of those older than 85 years40. Although the death of the reported patient was finally caused by complications related to the chronic hepatic disorder, is probably that the previous cerebral bleeding was a relevant factor for this outcome causing a state of extreme dependence and lack of mobility. Ac ce pt In conclusion, the reported patient expands the spectrum of cerebrovascular disorders associated with type 1 HSVE because represents one of the few reported cases of early cerebral bleeding related to HSVE and the first with a diffuse intraventricular hemorrhage as the initial clinical presentation. This suggests that HSVE could be considered between the causes of acute diffuse intraventricular hemorrhage, especially when the parenchymatous bleeding is in medial temporal lobe or it is not clearly identified and the intraventricular blood shows an asymmetric and predominantly temporal distribution. Author contributions: Alvarez-Perez FJ did majority of the writing and prepared the figures and table, Paiva F and Lino C provided the guidelines for writing the manuscript, provided scientific knowledge and reviewed the language of the manuscript. Conflict-of-interest statement: There is no conflict of interest associated with any of the authors. Financial sources: none. 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Site of bleeding and early outcome in primary intracerebral hemorrhage. Acta Neurol Scand 2002: 105: 282-8. 40. Arboix A, Garcia-Eroles L, Vicens A, Oliveres M, et al. Spontaneous primary intraventricular hemorrhage: clinical features and early outcome. ISRN Neurol. 2012;2012:498303. t ip cr us Ac ce pt ed M an Figure 1. Computed tomography on day 1 showing diffuse intraventricular bleeding affecting 4 ventricles and causing acute hydrocephalus. Ac ce pt ed M an us cr ip t Figure 2. Computed tomography on day 9 showing the practically complete resolution of bleeding and hydrocephalus. Case number Age Sex Days onsetadmission Days onsethaemorrhage (reference) 1 36 M 4 10 Relation antiviral therapy bleeding Left medial temporal lobe No During F NA On admission Right medial temporal lobe NA NA M 2 days 23 days Petechial in left insula and left frontal lobe No After M 17 days On admission Left insula No During 14 months F 4 days On admission Right parietal lobe No Before 38 M 1 day 7 days Right frontal and temporal lobes No M 10 days On admission Left parietal lobe M 1 day 9 days (after anticoagulation) Right medial temporal lobe M 2 days 13 days Left medial temporal lobe M 2 days 18 days Left medial temporal lobe M 7 days On admission (15) 6 (16) 7 years (17) 8 years (18) 9 years (19) years 10 26 (20) 11 years (21) 12 years (22) 13 years (23) 14 years (24) 15 years (25) 16 years (26) 17 years (26) years 3 27 22 46 56 30 54 38 45 53 After cr years No us (14) 5 6 After Yes During Yes During No After No Before Left medial temporal lobe Yes During 10 days Left medial temporal lobe Yes During an years M (14) 4 15 ed years Subcortical adjacent to the posterior pt (13) 3 53 body of the left lateral ventricle M 14 days F 5 days 20 days ce years Ac (12) 2 Topography of bleeding t IV bleeding ip Table 1. Cases of intracerebral bleeding related to HSVE reported in adult and pediatric patients M 2 days 12 days Right medial temporal lobe No During F 3 days 9 days Left medial temporal lobe Yes During F NA 9 days Left medial temporal lobe No During F 6 days 14 days Left medial temporal lobe No During 10 days Left medial temporal lobe Yes During M NA On admission Right lateral temporal lobe No After 4 months M 2 days Admission Bilateral postcentral gyrus No Before 28 F NA 15 days Subtentorial, right side No After M 4 days 19 days Left medial temporal lobe No During M 5 days On admission Bilateral occipital No Before F NA 18 days Left medial temporal lobe Yes F 7 days 14 days Right medial temporal lobe No M 2 days 12 days Right medial temporal lobe F 8 days 14 days Right medial temporal medial F 1 day On admission F 14 days 18 days Right medial temporal lobe years (32) 24 years (33) 25 years (34) 26 years (35) 27 years (36) 28 years (37) 29 years (38) years 71 53 40 49 71 78 34 During ip (31) 23 23 During cr years us (30) 22 No During Yes During Right lateral temporal lobe No Before No During an years M (28) 20 64 ed years t 7 days pt (27) 19 (29) 21 M ce 46 Ac 18