Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up

Abstract

Objective: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients.

Methods: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related.

Results: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated.

Conclusion: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

Keywords: COVID-19; Coronavirus; Critical illness; Encephalopathy; Myelitis; SARS-COV-2.

Fig. 1

Flow-chart of patient inclusion and observed neurological complications. Prevalence of prespecified complications observed in 61 prospectively enrolled COVID-19 patients, hospitalized in a tertiary center from April 1 to September 25, 2020. Patients were dichotomized in ICU and non-ICU patients. The observation period was from admission to 3-month after discharge or death. N = number of patients with the specified complication, one patient may have several complications. CNS central nervous system, PNS peripheral nervous system, CIPM critical illness polyneuromyopathy, MP meralgia paresthetica, ICU intensive care unit

Fig. 2

Flow-chart of brain imaging performed during and after admission. Brain imaging overview of 61 prospectively enrolled COVID-19 patients from admission to 3 month after discharge, dichotomized into COVID-19-related scans referring to neuroimaging related to a COVID-19 suspected complication or a complication related to a COVID-19 admission and neuroimaging performed for other reasons (e.g. traumatic injury) or for disease that occurred before COVID-19 (e.g. cerebral hemorrhage with onset before COVID-19). All images were re-evaluated by two board-certified neuroradiologists. # One patient may be scanned multiple times with both CT and MRI and represented in both categorized groups of scanned during and after admission. + This patient was admitted with intracranial hemorrhage and infected with SAR-CoV2 during hospitalization, therefore we categorized this patient’s scan as being unrelated to COVID-19. * See Fig. 3 for images and case history. R right, ICH intracerebral hemorrhage, SAH subarachnoid hemorrhage, CT computed tomography, MRI magnetic resonance imaging

Fig. 3

Brain imaging and histopathology from probable COVID-19 encephalitis and myelitis. A1-A6. A 52-year-old woman was admitted with convulsive seizures and reduced consciousness 19 days after symptom onset with dry cough, fever, a sore throat, headache and myalgias. Three weeks prior to presentation her entire family had experienced flu-like symptoms and a family member was tested positive for SARS-CoV-2. Previous medical history included hypertension, heterozygous Factor V Leiden mutation and chronic tension type headache. Medication before admission included amlodipine and gabapentin. On the morning of admission, the patient had generalized convulsive seizures. On examination, right-sided eye deviation and aphasia were noted. Twenty-four hours after admission, owing to a sudden decrease in consciousness and progressive hypoxemic respiratory failure, the patient was intubated and transferred to the ICU. Chest X-ray revealed a complete white-out of the left lung. Microscopic examination of the bronchoalveolar lavage fluid revealed no microorganisms, and the fluid was negative with broad infectious workup, including negative culture and negative tests for SARS-CoV-2, influenza virus type A and B, adenovirus, metapneumovirus, parainfluenza virus, atypical pneumonia, mycobacteria, pneumocystis, fungi and CMV, except for a positive aspergillus galactomannan antigen. Cytologic examination of the lung biopsy revealed type II pneumocyte hyperplasia and capillary inflammation with macrophages and neutrophils. No hyaline membranes, granulomas, necrosis, fibrosis or vasculitis were observed. There was no microscopic evidence of malignancy or fungi, including immunohistochemical (IHC) staining for fungi. In the alveoli, there were small precipitations of fibrin. The findings were concluded to be unspecific, resembling findings observed in viral infection. Assays for antinuclear antibodies, anti-double-stranded DNA and rheumatoid factor were negative. Lupus anticoagulant and anticardiolipin antibodies were negative. Electroencephalography revealed generalized slowing, with no epileptiform activity. MRI of the brain  with axial T2W (A1) and FLAIR (A2) sequences demonstrated bilateral hyperintense lesions in the right basal ganglia and left thalamus. Axial SWI images (A3) demonstrated hemorrhage, seen as hypointense signal intensity in the right basal ganglia lesion and ventricle system. Microbleeds were seen in the left thalamic lesion (A3) and ring enhancement on the post contrast T1W images (A4). A lumbar puncture was performed. Gram’s staining of the cerebrospinal fluid (CSF) showed no cells or organisms. The white-cell count was 0 per microliter (reference range, < 5), the red-cell count was 0 per microliter (reference range, < 300), the glucose level was 4.4 mmol per liter (2.2–3.9 mmol per liter), and the protein level was 0.3 g per liter (reference value, 0.15–0.50). Cytologic examination of the CSF revealed no malignant cells, and there was no evidence of B- of T-cell lymphoproliferative disorder on flow cytometry. Polymerase-chain-reaction assays of the CSF for herpes simplex virus and VZV were negative, as were mycobacterial smear and culture of the CSF. Culture of the CSF showed no growth. Testing of the CSF for autoantibodies, Lyme disease, syphilis, human herpes virus and SARS-CoV-2 were negative. Whole-body positron-emission tomography and computed tomography (PET-CT), performed after the administration of intravenous 18F-fluorodeoxyglucose (FDG) tracer, revealed no extracranial malignant disease. The differential diagnosis consisted of cerebral abscess or malignant tumor, and the patient was transferred to the neuro-ICU for further evaluation and treatment. To obtain a neuropathological diagnosis, stereotactic biopsy of the cerebral lesions was performed (A5-7). Biopsy specimens from both right and left cerebral hemispheres showed thrombotic occlusion of small vessels by fibrin thrombi. The brain parenchyma showed reactive changes with astrogliosis and microgliosis, axonal swellings, proliferating capillaries and iron deposits (Perl’s stain) as sign of microbleeds. There were sparse diffuse lymphocytic infiltrates consisting of CD3 positive T- lymphocytes. CD20 staining showed no B-lymphocytic infiltrates. There were no granulomas. There was no sign of demyelinating disease when comparing neurofilament immunostaining with myelin stains (LUXPAS and immunostaining for myelin basic protein). Immune staining’s for toxoplasma, herpes 1, cytomegalovirus and JC virus were all negative. There were no fungi or bacteria in special staining’s with PAS, Gomori and Gram.  [Biopsy from the left cerebral hemisphere (A5) with thrombi and reactive changes (PAS staining). Fibrin thrombus in a small vessel (Masson trichrome staining) (A6). Higher magnification showing proliferating capillaries, hemosiderin in macrophages and gliosis (hematoxylin and eosin stain), (A7). Asterix: thrombus.] The team of neuropathologists concluded that the findings in the brain biopsy tissue were consistent with small necrotic lesions/infarctions, likely caused by fibrin thrombi in the vessels. The clinical suspicion of COVID-19 was confirmed by a positive serum test for SARS-CoV-2 showing high titers of neutralizing IgG-antibodies obtained on the 27th day of illness. A diagnosis of COVID-19-associated acute necrotizing encephalitis was made, based on clinical signs, MRI, brain pathology findings and high titers of SARS-CoV-2 IgG and exclusion of other causes following extensive diagnostic work-up. B1-B2. A 28-year-old woman with a previous medical history of hypothyroidism developed a dry cough and myalgia in the beginning of March and was tested SARS-CoV-2 positive 3 days later. COVID-19 symptoms lasted 6 days. Eight days after onset of COVID-19 symptoms, the patient developed lumbar back pain and progressive numbness in both legs with a mid-thoracic sensory level. The patient further developed paresthesia in the right hand, difficulties climbing stairs, and urinary retention with a sense of constant urge. Neurological examination revealed a mild symmetric tetraparesis, hypoesthesia in both legs with a Th5 dermatome sensory level, impaired proprioception in the legs, absent abdominal reflexes and a slightly broad-based gait. Cognitive evaluation and the rest of the exam were unremarkable. Spinal MRI demonstrated on sagittal T1 STIR (B1) and sagittal T2 (B2) hyperintense lesions from C1 to C7 and from Th1 to the conus medullaris, consistent with transverse myelitis. Lumbar puncture showed a lymphocytic pleocytosis of 125 cells/microl, protein levels of 0.59 g/L, with a negative microbiological CSF work-up including herpes simplex virus, varicella zoster virus, cytomegalovirus, enterovirus, and SARS-CoV-2. Blood was negative for HIV and syphilis. Screening for aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies was negative. The patient was treated with high-dose prednisone and plasma exchange and made an uneventful recovery. Eight months later, the patient had a mild degree of Lhermitte’s but no other complaints. C1-C4. A 61-year-old woman with a previous medical history of type 2 diabetes, hypothyroidism and kidney transplant in 2019 due to adult onset polycystic kidney disease and immunosuppression with ciclosporine, developed muscle ache, dry cough, fever and dizziness resulting in a positive SARS-CoV-2 pharyngeal swab test and admission for 6 days. Eleven days after COVID-19 symptom onset, the patient developed headache, progressive confusion, apathy and speech difficulties and was re-admitted. Neurological examination revealed the patient was apractic, apathetic and amnestic. She answered questions with latency and with a mild, non-fluent aphasic speech. Brain MRI demonstrated bilateral hyperintense lesions in the basal ganglia on axial T2 (C1), FLAIR (C2) and DWI (C3), with corresponding hypointense lesions on ADC (C4). Lumbar puncture showed a lymphocytic pleocytosis of 252 cells (E6/L), protein levels of 1.77 g/L. CSF microscopy was unremarkable, and cultures for bacteria and fungi were negative. CSF screening for E.coli., Hemophilus influenzae, listeria, neisseria, streptococcus, enterovirus, Cryptococcus neoformans, syphilis (both intrathecal and peripheral testing), Lyme’s disease, JC virus, 18S-RNA, flow cytometry, and LGI1, NMDA, GABA-B, and CASPR2 antibody screening for autoimmune encephalitis were all negative. HIV and hepatitis B testing, transesophageal echocardiography, whole-body FDG-PET for occult malignancy were also unremarkable. There were a positive PCR and intrathecal antibody titer for EBV, HSV-1, VZV and human herpes virus, but the attending infectious disease and microbiology colleagues considered this to be consistent with a reactive phenomenon owing to chronic immunosuppression. The patient was initially treated with ceftriaxone and acyclovir, but treatment was stopped after a few days when no clear evidence of bacterial or herpes virus encephalitis was found. The patient made a gradual and spontaneous recovery, but cognitive impairment of memory and executive function remained after discharge