脳静脈血栓形成の臨床的な総括

//Background//---
 In the sequela and the concurrent disease in SARS-CoV-2, the cerebrovascular disease, which is Cerebral Venous Thrombosis, is rarely diagnosed. In 57 cases, mean interval is 13 days, deep venous system and parenchymal hemorrhage was affected in 37%, 42% patients, respectively(3). This disease differs from the usual form of ischemic stroke caused by occlusion of arterial vessels.
 Allan H. Ropper, and Joshua P. Klein review anatomy, pathophysiology, clinical manifestation, causes, diagnosis criteria, treatment, outcome, guideline already set about Cerebral Venous Thrombosis including SARS-CoV-2 case(1). I would like to share a small part of this reviews with the global important readers.
 
//Anatomical manifestation(1)//---
*Occlusion site: Both dural clots and cortical vein
Dural clot: in large, dural venous conduits / Cortical clot: on the surface of the cortex
 
//Pathophysiology(1,2)//---
*Cortical venous infarction with focal neurologic syndromes
*Raised intracranial pressure.
 The clinical syndrome by these causes usually evolve over a period of hours or days, but can progress for weeks.
 
//Clinical manifestation(1)//---
((Dural sinus thrombosis))
*Acute or subacute headache
⇒(detailed symptoms)
Epidemiologically 70 to 90% of patients, T
Typically 1 to 3 days duration,
Unilateral pain(1/3 patients), Localized pain(1/5 patients)(4)
Throbbing headache may occur, but differ from usual migraine headache.
Coughing, bending over, heat movement tend to worsen the headache.
*Seizures (34%/1281 patients(5))
*Focal convulsions
*Stroke-like deficits (If cortical infarction occurs)
*Papilledema
*Paresis both legs or hemiparesis from infarction
*Aphasia
*Confusion
*Status epilepticus
*Drowsiness or stupor from bilateral thalamic dysfunction and obstructive hydrocephalus.
 
//Causes(1)//---
*Systemic venous thrombosis
*Hypercoagulation trigger this symptom.
*Direct cranial trauma
*Neurosurgical procedure
*Antiphospholipid antibody syndrome and genetic forms of hypercoagulability
⇒Factor V Leiden / Protein S and protein C deficiency / Prothrombin mutation / Hyperhomocysteinemia.
*Behçet’s syndrome (infant and children mainly in developing countries)
*Mastoiditis (The first half of the 20th century)
*Acute systemic illnesses and head and neck infections (infant and children)(6)
*Heparin-induced thrombocytopenia
*Autoimmune heparin-induced thrombocytopenia (aHIT), which is not triggered by heparin(7)
*Vaccine-induced immune thrombotic thrombocytopenia (VITT)
 
//The relation of SARS-CoV-2(1)//---
(Adenoviral vector vaccine induced symptom)
Cerebral venous thrombosis
1 case per 100,000 for ChAdOx1 nCoV-19 vaccine [AstraZeneca] 
1 case per 1,000,000 for Ad26.COV2.S vaccine [Johnson & Johnson/Janssen])
Mainly women
Mediated by platelet-activating antibodies to PF4(8)
(SARS-CoV-2 induced symptom)
Less than 1% of patient with severe sysmtom(9), but not thrombocytopenia and anti-PF4 antibodies.
 
//Diagnosis(1)//---
(Method)
CT and MRI with contrast-enhanced venography
Catheter-based angiography
(Criteria)
*A segment of vein or sinus without blood flow(1)(Fig.2)
*Hyperdense region (CT scan)(1)(Fig.1)
*Lack of a normal flow void (T1- and T2-weighted MRI scans)
*Anti-PF4 antibodies detection in HIT, aHIT or VITT clinical cases.
 
//Treatment(1)//---
Short- and long-term anti-coagulant therapy have had inconclusive results(10).
For example, a trial of low-molecular-weight heparin followed by warfarin showed no significant benefit from placebo in clinical severity or death rate(11).
In the 114 children trial, the clinical effect in rivaroxaban after heparin or low-molecular weight heparin was compared to continued treatment with heparin or heparin plus warfarin. On the clinical symptom in systemic, cerebral venous thrombosis and bleeding, no significant clinical benefit was defined(12).
 On the other hand, therapeutic plasma exchange (including intravenous immune globulin) with normal plasma as the replacement (rather than albumin) has also been used successfully in refractory cases(13,14).
 Endovascular treatment of dural sinus thrombosis (thrombectomy rather than thrombolysis) may have favorable result(15,16). However, uncertainty due to technological limitation and diversity for each clinical case is open to debate(17).
 
//Guideline(1)//---
(European Stroke Organization)
*Initiating low-molecular-weight-heparin as soon as possible after diagnosis
*Considering the use of decompressive craniectomy if intracranial pressure is raised.
*Considering the use of anticonvulsant if there have been seizures(18)28
However, glucocorticoids and acetazolamide aren’t recommended for brain swelling.
(American Heart Association―American Stroke Association)
*Providing an algorithm for the use of anti-coagulant therapy, recommending full-dose unfractionated or low-molecular-weight heparin followed by warfarin and acetazolamide.
However, glucocorticoids is not recommended for raised intracranial pressure.
 
(Reference)
(1)
Allan H. Ropper, M.D., and Joshua P. Klein, M.D., Ph.D.
Cerebral Venous Thrombosis
The New England Journal of Medicine 2021; 385:59-64
---
Author Affiliations
From the Department of Neurology, Brigham and Women’s Hospital, Boston.
(2)
Stam  J. 
Thrombosis  of  the  cerebral veins and sinuses.
N Engl J Med 2005; 352: 1791-8.
(3)
Tommaso Baldini, Gian Maria Asioli, Michele Romoli, Mariana Carvalho Dias, Eva C. Schulte, Larissa Hauer, Diana Aguiar De Sousa, Johann Sellner, Andrea Zini
Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis
Enropean Journal of Neurology 11 January 2021
(4)
Coutinho JM, Gerritsma JJ, Zuurbier SM, Stam J.
Isolated cortical vein thrombosis:  systematic  review  of  case  reports and case series.
Stroke 2014; 45: 1836-8.
(5)
Lindgren  E,  Silvis  SM,  Hiltunen  S,  et al.
Acute symptomatic seizures in cerebral venous thrombosis.
Neurology 2020; 95(12): e1706-e1715.
(6)
deVeber G, Andrew M, Adams C, et al.
Cerebral sinovenous thrombosis in children.
N Engl J Med 2001; 345: 417-23.
(7)
Moores  G,  Warkentin  TE,  Farooqi MAM,  Jevtic  SD,  Zeller  MP,  Perera  KS.
Spontaneous heparin-induced thrombo-cytopenia presenting as cerebral venous sinus  thrombosis. 
Neurology:  Clinical Practice.  January  14,  2020 
(https://cp . neurology . org/  content/  early/  2020/  01/  14/  CPJ . 0000000000000805).
(8)
Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S.
Thrombotic  thrombocytopenia  after  ChAdOx1 nCov-19 vaccination.
N Engl J Med 2021; 384: 2092-101.
(9)
Siegler  JE,  Cardona  P,  Arenillas  JF,  et al.
Cerebrovascular events and outcomes in hospitalized patients with COVID-19: the SVIN COVID-19 Multinational Registry.
Int J Stroke 2020 September 30 (Epub ahead of print).
(10)
Einhäupl KM, Villringer A, Meister W, et al.
Heparin treatment in sinus venous thrombosis.
Lancet 1991; 338: 597-600.
(11)
de  Bruijn  SF,  Stam  J. 
Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis.
Stroke 1999; 30: 484-8.
(12)
Connor P, Sánchez van Kammen M, Lensing AWA, et al.
Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).
Blood Adv 2020; 4: 6250-8.
(13)
Schultz  NH,  Sørvoll  IH,  Michelsen AE, et al.
Thrombosis and thrombocytopenia  after  ChAdOx1  nCoV-19  vaccination.
N Engl J Med 2021; 384: 2124-30.
(14)
Greinacher  A,  Selleng  K,  Warkentin TE.
Autoimmune heparin-induced thrombocytopenia.
J Thromb Haemost 2017; 15: 2099-114.
(15)
Siddiqui FM, Dandapat S, Banerjee C, et al.
Mechanical thrombectomy in cerebral  venous  thrombosis:  systematic  review of 185 cases.
Stroke 2015; 46: 1263-8.
(16)
Ilyas A, Chen C-J, Raper DM, et al.
Endovascular mechanical thrombectomy for cerebral venous sinus thrombosis: a systematic review.
J Neurointerv Surg 2017; 9: 1086-92.
(17)
Coutinho  JM,  Zuurbier  SM,  Bousser MG,  et  al. 
Effect  of  endovascular  treatment with medical management vs standard care on severe cerebral venous thrombosis:  the  TO-ACT  randomized  clinical trial.
JAMA Neurol 2020; 77: 966-73.
(18)
Ferro JM, Bousser M-G, Canhão P, et al.
European Stroke Organization guideline for the diagnosis and treatment of cerebral  venous  thrombosis  —  endorsed  by the European Academy of Neurology.
Eur J Neurol 2017; 24: 1203-13.