Therapeutic Approaches to the Neurologic Manifestations of COVID-19

Abstract

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality. In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome. This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences. While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

Keywords: COVID-19; Encephalopathy; Long-COVID; PASC; SARS-CoV-2.

Fig. 1

Neuroimaging case examples of select acute neurologic syndromes. A Acute ischemic stroke. A 66-year-old man presented for fevers, diarrhea, and dyspnea requiring supplemental oxygen due to COVID-19. On hospital day three, he developed new onset atrial fibrillation and later that day an acute left hemiparesis with NIH stroke scale of 15. Angiography demonstrated a proximal right MCA occlusion (arrow). Multiple passes with a stent retriever thrombectomy device with aspiration catheter plus eptifibatide infusion could not establish vessel patency. B Venous sinus thrombosis. A 64-year-old woman with no medical history presented for 3 days of diarrhea and headache. She tested positive for SARS-CoV-2. Chest imaging demonstrated opacities consistent with pneumonia and a large pulmonary embolus involving the left lower lobe, though she did not require supplemental oxygen. CT venography demonstrated acute occlusive venous thrombosis of the right transverse and sigmoid sinuses, right jugular bulb, torcula, posterior half of the straight sinus, and posterior third of the superior sagittal sinus (arrow). MRI demonstrated no infarction and her neurologic exam was unremarkable. Her headache resolved after anticoagulation. C and D Intracerebral hemorrhage secondary to venous infarction. An 18-year-old woman with no medical history presented for one week of diarrhea, mild cough without dyspnea, and two days of headache. She tested positive for SARS-CoV-2 but never required supplemental oxygen. In the emergency department, she demonstrated fluctuating aphasia and at times was mute and could not follow commands. CT demonstrated a left temporal hemorrhage with surrounding hypodensity (C, arrow) and CT angiography (not shown) suggested an overlying thrombosed cortical vein. MRI demonstrated thrombosis of the left vein of Labbe, tentorial, and cortical branch veins (D, arrow) with an associated hemorrhagic venous infarct. The aphasia improved with levetiracetam given in the emergency department, but no seizures were seen on subsequent EEG. Her aphasia gradually resolved after anticoagulation and continuation of levetiracetam. E and F Acute demyelinating encephalomyelitis (ADEM) following SARS-CoV-2 infection. A 47-year-old man with no medical history presented for lower extremity paresthesia, urinary retention, and lower extremity weakness developing over 3 days. He reported fever and cough 7 to 10 days prior and had tested positive for SARS-CoV-2. MRI spine demonstrated cervical and thoracic non-enhancing T2 hyperintensity with spinal cord expansion (E, arrow), and MRI brain demonstrated several small non-enhancing T2 hyperintense white matter lesions (F, arrow). CSF exam showed 201 white blood cells/µL, 201 mg/dL protein, and oligoclonal bands in CSF and serum; no specific pathologic antibodies were identified. He developed complete paralysis of the legs with severe left arm weakness, but he did not require intubation. He received solumedrol 1 g, 0.4 g/kg IVIG, and remdesivir daily for five days. His left arm briefly improved but again worsened when he developed hyponatremia with repeat MRI demonstrating worsened cord edema (not shown). Symptoms improved with hypertonic saline and maintenance of normal serum sodium. Surveillance MRI 12 days after admission demonstrated improved cord swelling but new patchy cervical cord enhancement. Solumedrol 1 g daily was given for three days with normalization of left arm strength and some return of leg movement. He continued to improve and was discharge to rehabilitation on a 12-week taper of prednisone. G Prolonged agitated encephalopathy. A 21-year-old man with no medical history was admitted for hypoxemic respiratory failure requiring mechanical ventilation due to COVID-19. He experienced severe agitation requiring midazolam and hydromorphone with adjunctive ketamine, dexmedetomidine, valproic acid, and scheduled quetiapine for adequate agitation control. An MRI brain was obtained when agitation returned on attempts to wean mechanical ventilation and demonstrated numerous small areas of subtle contrast enhancement (arrow). CSF exam showed 1 white blood cell/µL, 29 mg/dL protein, and was negative for SARS-CoV-2 by RT-PCR. He was diagnosed with encephalopathy and MRI findings were felt to be due to severe systemic inflammation. He was treated with supportive care and gradual reduction of adjunctive sedation agents. He was discharged to rehabilitation and, after 5 months, was living independently and exercising 45 min daily but had not returned to work. H and I Post mRNA vaccination ADEM. A 25-year-old female with no medical history presented with a generalized seizure 4 days after receiving an mRNA COVID-19 booster vaccine. Her neurologic exam was unremarkable following resolution of the seizure. MRI brain demonstrated a left frontal T2 hyperintensity (H, arrow) which enhanced after contrast injection (I, arrow). CSF exam showed 1 white blood cell/µL, elevated IgG synthesis rate of 7.1, elevated IgG index of 1.3, and 12 unique CSF oligoclonal bands. J and K Post mRNA vaccination transverse myelitis. A 65-year-old woman with rectal cancer in remission presented with back pain and saddle anesthesia 7 days after receiving an mRNA COVID-19 vaccine. MRI showed cervical to upper thoracic T2 hyperintensity (J, arrow) with a focus of enhancement at C5 (K, arrow). CSF exam showed 4 white blood cells/µL, protein 51 mg/dL, normal IgG index and synthesis rate, and oligoclonal bands present in serum and CSF. Her symptoms and imaging findings (not shown) completely resolved after two months of oral prednisone therapy. MCA middle cerebral artery, ADEM acute demyelinating encephalomyelitis, CSF cerebrospinal fluid, IVIG intravenous immunoglobulin

Fig. 2

Symptoms of post-acute sequelae of SARS-CoV-2 (PASC). PASC can lead to symptoms involving multiple organ systems and varies by individual patient. Common symptoms include cognitive dysfunction (often called "brain fog" by patients), dizziness, and anosmia. Treatment depends on the systems involved and often involves a multidisciplinary approach