COVID-19
Increasingly recognized sensory symptoms of COVID-19 infection include the sudden onset of anosmia, and, to a lesser extent, dysgeusia (Table 6 ).40 Patients with pre-existing neurological diseases may also have a higher risk for encephalopathy and altered mental status.41 As many as 36.4% patients have neurological symptoms, and these are seen more commonly in patients with severe disease.42 Acute cerebrovascular accidents, altered mental status, and myopathy occurred in approximately one-third of patients. In an observational series of 58 COVID-19 positive patients, Helms et al documented confusion and agitation as the most common neurologic symptoms. Corticospinal tract signs were also evident in nearly two-thirds of patients including increased deep tendon reflexes, ankle clonus and bilateral extensor plantar reflexes.43 One recent case report described acute hemorrhagic necrotizing encephalopathy in a patient with COVID-19 infection.44 Guillain-Barré syndrome has been observed after the onset of COVID-19 in a few patients presenting with lower-limb weakness and paresthesia as well as facial diplegia and ataxia.45 Neurological involvement is present in more severely affected patients, and patients with central neurologic symptoms also had severe lymphopenia, thrombocytopenia and uremia.42 Patients with myopathy have a higher inflammatory response and a higher association with hepatic and renal disease.42
Table 6 Neurological manifestations of SARS-CoV, MERS-CoV and COVID-19.
SARS (only studies with large study population included)
Study Hung et al (2003)N = 1, confirmed casesCase report Lau et al (2004)N = 1, confirmed casesCase report Tsai et al (2004)N = 4, confirmed casesCase reports Tsai et al (2005)N = 664, probableRetrospective study
Clinical features Seizures (4 limb twitching) starting day 5, lasting up to 30 min Seizures (GTCS) started on day 22 • Neurological disturbances - 3 weeks after symptom onset
• Motor predominant peripheral neuropathy (50%)
• Myopathy (25%)
• Myopathy and Neuropathy (25%)
• Mild hyporeflexia (75%)
• Hypesthesia in legs (75%) • Axonopathic polyneuropathy (2) 3-4 weeks after onset
• Myopathy (2)
• Rhabdomyolysis (3)
• Large vessel ischemic stroke (5)
Key findings on investigations CSF:• ↑ glucose
• SARS-CoV RNA detected CSF:• SARS-CoV RNA detected
• Normal cell counts, glucose, opening pressure • Virus not detected in CSF
• ↑ CK
• ↑ Myoglobin
• Nerve conduction studies: ↓ amplitudes of compound muscle action potential (50%)
Key study findings and message Symptoms may be due to direct viral pathogenicity Symptoms likely due to critical illness polyneuropathy and/or myopathy • Symptoms likely due to critical illness polyneuropathy and/or myopathy, cannot exclude direct viral attack
• Strokes due to hypercoagulable state due to virus, medication related, vasculitis, shock
MERS
Study Algahtani et al (2016)N = 2, confirmed casesCase report, review Kim et al (2017)N = 23, confirmed casesRetrospective study
Clinical features • Neuropathy
• Myopathy
• Confusion
• Ataxia, dizziness
• Intracranial hemorrhage • Neurological disturbances – 2-3 weeks after respiratory symptoms
• Myalgia
• Headache
• Confusion
• Hypersomnolence
• Weakness
• Paresthesia
• Hyporeflexia
Key findings on investigations CSF and nerve conduction studies normal
Key study findings and message • Symptoms may be due to critical illness polyneuropathy and/or myopathy
• Hemorrhage secondary to DIC, platelet dysfunction • Symptoms may be due to critical illness polyneuropathy and/or myopathy or toxin or viral induced
COVID-19
Study Mao et al (2020)N = 214, confirmed casesRetrospective study Filatov et al (2020)N = 1, suspectedCase report Bagheri et al (2020)N = 10069, with olfactory dysfunctionCross-sectional Poyiadji et al (2020)N = 1, confirmed casesCase report Helms et al (2020)N = 58, confirmed casesRetrospective study
Clinical features • Neurological symptoms: 36.4%
• CNS symptoms: 24.8%, most common dizziness (16.8%), headache (13.1%)
• PNS symptoms: 8.9%, most common hypogeusia (5.6%) and hyposmia (5.1%).
• Skeletal muscle symptoms: 10.7% Altered mental status • Anosmia/hyposmia (48.23%)
• Sudden onset in 76.24%
• Associated hypogeusia in 83.38%
• Duration: 0-30 days Acute necrotizing encephalopathy • Agitation (69%)
• Corticospinal tract signs (67%)
• Confusion (65%)
• Dysexecutive syndrome (36%)
Key findings on investigations N/A • CT Head: no acute changes
• EEG: bilateral slowing and focal slowing in the left temporal region with sharply countered waves, possible subclinical seizures
• CSF studies: normal N/A • CSF unremarkable (not tested for COVID)
• NCCT Head: symmetric hypoattenuation within the bilateral medial thalami
• CT angiogram, venogram: normal
• MRI Brain: hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions Brain MRI:• Perfusion abnormalities (100% of 11)
• Leptomeningeal enhancement (62% of 13)
• Ischemic stroke (23% of 13)
CSF (N = 7):• Oligoclonal bands (29%)
• Elevated IgG and protein (14%)
• Low albumin (57%)
• Negative RT-PCR in CSF (100%)
EEG (N = 8): Nonspecific
Key study findings and message • Acute CVA (5.7%), impaired consciousness (14.8%), skeletal muscle injury (19.3%) more likely in severe disease (P < 0.05, P < 0.001)
• Patients with CNS symptoms more likely to have lower `lymphocyte and platelet counts and higher BUN (P < 0.05, P < 0.01, P < 0.05)
• Patients with muscle injury more likely to have higher neutrophils, CRP, D-dimer and lower lymphocyte count (P < 0.05, P < 0.001, P < 0.05, P < 0.01)
• Neurologic symptoms may be due to direct viral pathogenicity via hematogenous or retrograde neuronal spread, immunosuppression, or coagulation disorders Can present with encephalopathy acutely or during hospitalization • High correlation between reported olfactory symptoms and regional reporting of COVID-19
• Olfactory symptoms may be due to neuroepithelia injury and damage to olfactory roots. Cytokine storm (known in influenza, other viral infections, more common in pediatrics) Mechanism unknown, may be due to critical illness–related encephalopathy, cytokines, medication-induced or direct viral pathogenicity.
ARDS, acute respiratory distress syndrome; CK, creatine kinase; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; CVA, cerebrovascular accident; EEG, electroencephalogram; GTCS, generalized tonic clonic seizures; MERS-CoV, middle east respiratory syndrome coronavirus; MRI, magnetic resonance imaging; NCCT, noncontrast computed tomography; PNS, peripheral nervous system; SARS-COV, severe acute respiratory syndrome coronavirus.
Patients who underwent magnetic resonance imaging showed leptomeningeal enhancement with bilateral frontotemporal hypoperfusion.43 Electroencephalography showed mostly nonspecific changes with findings consistent with encephalopathy.43 CSF analysis may show oligoclonal bands or elevated IgG levels, however, the significance of these findings is uncertain.
Ocular manifestations of COVID-19 are garnering increasing attention. Animal studies show ACE2 and transmembrane serine protease 2, both established receptors for this virus, are expressed in the conjunctiva, although to a lesser extent than in the kidneys and lungs, and lesser in females.46 A study reported conjunctivitis in as many as 31.6% patients, and more commonly in patients with severe disease.47 It has also been reported as the sole initial presentation.48 SARS CoV-2 has been isolated from conjunctival swabs in patients with ocular symptoms and reportedly detected for as many as 27 days after symptom onset.49 Interestingly, an animal model has also shown that the conjunctival route may lead to systemic infection as well, but viral replication in the conjunctiva and chances of virus release into the bloodstream are very low.50