A 48-year-old man presents to a medical center in New York City after suddenly developing numbness in his upper left arm, along with weakness, and impairment of positional sensation. He says that for the past 8 hours, he has had severe headaches on the right side of his skull in the back, for which he took ibuprofen. He is right-handed and a nonsmoker.
He notes that he had been diagnosed with SARS-CoV-2 infection about a month earlier, when he went to the same medical center after feeling generally unwell, with fever, low-back pain, and right-sided headache.
At that time, clinicians confirmed COVID-19 via PCR testing. He reports that his symptoms lasted for 12 days, during which he remained quarantined at home, and on day 17, he returned to work.
The symptoms suggest stroke, so the patient is admitted. His blood pressure is elevated, at 178/89 mm Hg; he is afebrile, his oxygen saturation is 98% on room air, his heart rate is 88 bpm, respiratory rate is 17 bpm, and body mass index is 27.4. He remains fully alert and oriented to person, place, and time, and he is behaving appropriately.
Motor testing demonstrates 3/5 strength of all muscle groups of his left upper limb, and cerebellar dysmetria of the left arm; National Institutes of Health Stroke Scale score is 4.
Laboratory tests are ordered at the time of the admission. Complete blood count results are mostly within normal range, including platelet count of 226 × 103/mL and prothrombin time of 12.8 seconds; the one exception is an elevated D-dimer value of 0.77 μg/mL fibrinogen equivalent units.
Other abnormal values are high glucose value of 113 mg/dL, and elevated lipids including triglycerides of 169 mg/dL, cholesterol level of 255 mg/dL, and low-density lipoprotein cholesterol of 166.2 mg/dL.
Thrombophilia work-up shows a minimally high factor 8 activity of 162% (normal range is 50%-149%); lupus anticoagulant is negative, and beta 2 glycoprotein and cardiolipin antibodies are normal.
Clinicians rule out other causes of cerebral venous thrombosis, and order a noncontrast head computed tomography (CT) scan, which reveals a small acute cortical hemorrhage in the right parietal lobe, with a rim of surrounding vasogenic edema.
Serial axial images, starting at the hemorrhage and progressing to the superior sagittal sinus, show a curvilinear structure of increased attenuation that overlies the cortex. Higher-intensity CT signal shows clotted blood within a thrombosed cortical vein. CT angiography of the neck and head is normal, with no vascular malformation, although magnetic resonance imaging of the head confirms the presence of a right parietal lesion.
Magnetic resonance venography identifies a cerebral venous thrombosis — an absent right parietal vein as well as a small filling defect where the vein entered the superior sagittal sinus.
Treatment includes 20 mg of intravenous labetalol, which controls the patient’s blood pressure at 147/87 mm Hg. During his hospitalization, he receives 80 mg of subcutaneous enoxaparin every 12 hours for a total of two doses, as well as two doses of 500 mg of intravenous levetiracetam. The patient maintains neurologic stability throughout the admission, and is discharged.
The patient shows satisfactory progression, with slow improvement of symptoms and signs. After returning to work, he receives occupational therapy, and at 4 and 8 weeks after the stroke, his only remaining deficit is persistent mild numbness of his left pointer finger. He returns for follow-up magnetic resonance imaging, which shows clot maturation and progressive shrinkage of the intracerebral hematoma.
Clinicians presenting this case of a 48-year-old man who develops superficial cerebral venous thrombosis and intracerebral hematoma weeks after recovering from the acute phase of SARS-CoV-2 infection note that it is important to consider the relatively uncommon development of thromboembolic complications, given their potential severity and diverse clinical presentations.
While respiratory symptoms are very common, clinical manifestations of COVID-19 can be dominated by complications caused by systemic inflammation and a hypercoagulable state; when the symptoms involve the central nervous system (CNS), they can result in an altered mental state, hallucinations, and either ischemic or hemorrhagic strokes.
An evaluation of 142 studies found that the rates of reported neurologic manifestations were as follows:
- Olfactory/taste disorders (35.6%)
- Acute cerebral vascular disease (8.1%)
- Altered mental status (7.8%)
- Less common were encephalitis, neuralgia, ataxia, Guillain-Barre syndrome, Miller Fisher syndrome, intracerebral hemorrhage, polyneuritis cranialis, and dystonic posture
Neurological manifestations are thought to occur when SARS-CoV-2 enters the CNS through the olfactory bulb or by thrombosis of the cerebral vasculature, as a result of hypercoagulability, with this viral invasion of the CNS leading to demyelination and inflammation, the case authors explain.
In the presence of SARS-CoV-2, glial cells secrete acute-phase reactants such as interleukins 6, 12p40, and 15; tumor necrosis factor-alpha; chemokine ligand 9; and chemokine ligand 10. In addition, SARS-CoV-2 is believed to use the angiotensin-converting enzyme 2 receptor expressed on glial cells and neurons to permeate CNS cells, resulting in inflammation and causing damage to surrounding structures.
Complications that can occur when diagnosis of neurological manifestations is delayed include progression of thrombosis into the cerebral venous sinuses, intracerebral hemorrhage, and intracranial hypertension. Conversely, most patients diagnosed before complications develop have a favorable prognosis.
Cerebral venous thromboembolism, with or without associated intracerebral hemorrhage, is much less frequent, the team notes, adding that the underlying process that results in hypercoagulability and subsequent stroke in patients with COVID-19 is likely comparable to that of more common systemic coagulopathies, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy.
Regarding coagulation abnormalities and thrombosis in patients with COVID-19, the most typical finding in patients with COVID-19 and coagulopathy was an increased D-dimer concentration, a relatively modest decrease in platelet count, and a prolongation of the prothrombin time.
The authors note that while this combination is suggestive of DIC, the pattern is distinctively different from DIC seen in sepsis, which usually involves more profound thrombocytopenia, and lower D-dimer concentrations than those seen in patients with COVID-19 — which exceeded 0.5 mg/L in 46% of a series of 1,099 COVID-19 patients in China. In fact, most patients with COVID-19 would not be classified as having DIC according to the criteria of the International Society on Thrombosis and Hemostasis.
The clinicians reporting the case stressed the importance of differentiating the cause of intracerebral hemorrhage in COVID-19 patients. For example, one of the better-known neurological complications of acute COVID-19, primary intracranial hemorrhage, is unrelated to venous cerebral thrombosis.
This complication has been reported in patients with prolonged inflammatory syndrome and attributed to COVID-19-related inflammatory endotheliopathy, or in another series, to the anticoagulants used to avoid thrombotic complications of COVID-19.
A less frequent cerebrovascular complication of COVID-19 is cerebral vein thrombosis, with or without associated hemorrhagic venous infarct, which occurred in this patient. The hemorrhagic cases have some features in common, including young age, initial presentation of deep vein thrombosis symptoms, and milder forms of COVID-19 discovered only after the stroke and within less than 2 weeks apart.
The authors note that in this patient, the interval of 26 days before the onset of cerebral vein thrombosis was much longer than any previously reported cases. Furthermore, it raises the possibility that the hypercoagulable state associated with COVID-19 may outlast the active phase of infection.
The four main presentations of cerebral venous thrombosis are isolated intracranial hypertension, focal neurological deficits, diffuse encephalopathy, and cavernous sinus syndrome.
The case authors recommend immediate prophylactic initiation of heparin anticoagulation in all presentations to decreased levels of cytokines, even if, as in this case, there is a presentation with secondary intracerebral hemorrhage.
While acknowledging the recorded success of endovascular thrombolysis, the case authors cite a recent trial that links traditional systemic use of intravenous heparin therapy alone with decreased morbidity, as was seen in his case. Furthermore, the outcome raises the question of whether prophylactic use of antiplatelet or anticoagulant therapy should be considered for patients recovering from milder forms of COVID-19.
The case authors conclude that this case of superficial cerebral venous thrombosis and intracerebral hematoma shows that even mild cases of COVID-19 may be associated with coagulopathy and an increased risk of cerebral thrombosis and hemorrhage. In addition, as clinical management guidelines continue to evolve, care should be taken to provide the most “appropriate and timely individualized anticoagulation therapy” for patients with SARS-CoV-2 infection who present with neurological signs and symptoms.
The case authors reported no conflicts of interest.