Chronic Kidney Disease: Laboratory Support of Diagnosis and Management

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory virus syndrome-2 (SARS-CoV-2), has been linked to health effects beyond its well-established respiratory manifestations. These include effects on the peripheral nervous system and the central nervous system (CNS).¹ COVID-19 has been reported to result in new neurological conditions and may exacerbate preexisting neurological conditions as well.^2,3

Some neurological signs and symptoms of COVID-19 may precede the onset of symptoms typically observed in the upper respiratory tract. Knowing the wide spectrum of neurological manifestations of COVID-19 can help with diagnosis and isolation of patients early in the course of the disease and may also help inform management of patients with preexisting neurological conditions.

This article will discuss current knowledge of the association of COVID-19 with neurological disease and how the laboratory can help in the diagnosis and management of patients with COVID-19 and neurological complications.

Who Is at Increased Risk for Neurological Symptoms Due to COVID-19?

Overall, studies have shown that 36% to 84% of COVID-19 patients exhibit neurological symptoms at some time during the illness, before or after infection has been definitively diagnosed.^5-8 Neurological symptoms are more common in patients with severe illness; however, they are also observed with mild disease.^5-7 In a recent study of 509 consecutive patients admitted with confirmed COVID-19, approximately 42% of patients had neurological symptoms at COVID-19 onset, 63% at hospitalization, and 82% at any time during their illness.⁷

Individuals at increased risk for neurological symptoms include children and elderly individuals with severe disease; individuals of any age with a history of ischemic or hemorrhagic stroke, dementia, certain autoimmune conditions, and those who are obese or hypertensive; and children who have had multisystem inflammatory syndrome.^5-7

COVID-19 and the Nervous System

A number of mechanisms have been postulated to explain how COVID-19 causes neurological disorders. COVID-19 is known to directly affect the cardiovascular system and coagulation homeostasis, which in turn can have neurological consequences.⁹ Resulting hypoxia or coagulopathy increases the risk of cerebral hypoxia and blood vessel thrombosis.⁹ Systemic inflammatory response from the viral infection is believed to cause hypercoagulability resulting in conditions such as stroke.¹⁰

Other direct and indirect neurological manifestations of COVID-19 are commonly divided into CNS-related and peripheral nervous system–related.

CNS Manifestations

SARS-CoV-2 is believed to directly infect the CNS, and 2 routes of infection have been postulated:

• Virus in the upper respiratory tract can invade olfactory nerve cells in nasal epithelia and subsequently travel to the brain via axonal transmission.⁹
• Virus in the lower respiratory tract can infect monocytes and macrophages in lung capillaries and subsequently travel to the brain via hematogenous transmission. Importantly, brain endothelial cells express ACE-2 receptors targeted by the virus, increasing the possibility of viral-induced vasculitis.¹¹

Common presenting complaints of persons with COVID-19 include headache, nausea/vomiting, dizziness, hypogeusia, hyposmia, and impaired consciousness.¹ These complaints suggest the infection involves the nervous system. Headache, the most common CNS symptom, is seen in approximately 6% to 23% of patients.¹² Acute cerebrovascular disease (eg, stroke) and epilepsy are also manifestations of CNS involvement.¹²

Older individuals who contract COVID-19, especially those with preexisting chronic medical conditions, are at an elevated risk of impaired consciousness or delirium.¹² These patients are more likely to ultimately develop a severe infection, and may present with encephalopathy and confusion.¹² Confusion has been reported in 9% of COVID-19 patients, mostly among those with poor prognosis.¹² Importantly, confusion or impaired consciousness may be a result of intracranial hemorrhages.¹²

Encephalitis/encephalopathy has been associated with COVID-19.¹³ It can be due to the viral infection itself or to a more severe disease as a result of underlying comorbidities.¹³ Typical findings include an EEG showing diffuse and focal slowing with temporal lobe spikes, elevated white blood cells (WBCs) and total protein in cerebrospinal fluid (CSF) with a normal glucose level, and abnormalities on brain magnetic resonance imaging.¹³

Risk factors for encephalopathy include a history of any neurologic condition and chronic kidney disease.³ Encephalopathy has been independently associated with worse functional outcome and higher mortality within 30 days of hospitalization, regardless of respiratory symptom severity.³

Peripheral Nervous System Manifestations

COVID-19 may affect the peripheral nervous system, including the cranial nerves, either by direct invasion of the virus and dissemination into the brain or by secondary effects from inflammation caused by the virus.¹² Examples include hyposmia/anosmia (decreased sense of smell/inability to smell anything), hypogeusia/ageusia (decreased sensitivity to all tastants/complete loss of taste function of the tongue), muscle pain, and Guillain-Barré syndrome.¹²

Loss of smell and taste are the most common peripheral nervous system manifestations of COVID-19 and typically occur suddenly and in the absence of other symptoms generally associated with an upper respiratory tract infection (eg, nasal obstruction or excessive secretions).¹²

COVID-19 and Nervous System Disorders

New-onset Parkinson disease after COVID-19 has been documented.¹⁴ Patients with preexisting Parkinson disease may be at risk of worsening illness; up to 75% of patients with Parkinson disease can experience new or worsening motor and non-motor symptoms after COVID-19.^15,16

Patients with multiple sclerosis are often treated with disease-modifying therapy (DMT), which affects the immune system. One study reported that patients with multiple sclerosis receiving DMT are not at increased risk for contracting symptomatic COVID-19, nor are they at increased risk for severe complications from COVID-19 if infected.¹⁷ On the other hand, patients with multiple sclerosis overall have a higher mortality rate than the general population if they contract COVID-19 (3.2% vs 1.6%), and patients with greater disability have higher mortality.¹⁸

Acute necrotizing encephalopathy (ANE) is a rare progressive neurodegenerative disorder characterized by multiple, symmetric areas of edema and necrosis in the CNS, which is known to be due to the uncontrolled release of cytokines during a febrile disease such as influenza.¹¹ ANE leads to disruption of blood brain barrier without direct viral invasion. ANE has been reported in patients with COVID-19.¹¹

Though rare, Guillain-Barré syndrome has been associated with COVID-19.¹³ Patients present with weakness, with or without sensory loss, which may be preceded by diarrhea.¹³ Patients may also develop the Miller-Fisher variant, autonomic complications, and respiratory failure.¹³ Examination of CSF generally shows elevated protein, no increase in white blood cells, and absence of viral particles.¹³

Neurological Complications and COVID-19 Outcomes

A number of studies have examined the impact of neurological conditions on COVID-19 outcomes. A retrospective study found that preexisting neurological disease in patients hospitalized for COVID-19 did not affect mortality risk; however, the development of a major neurological manifestation during the disease course was an independent predictor of death.¹⁹

Other studies have suggested that a chronic neurological disorder was an independent predictor of death² in patients hospitalized for COVID-19 and that a neurological comorbidity was independently associated with more severe COVID-19.³

Recommendations for COVID-19 Patients With Neurological Conditions

In general, neurological disorders do not predispose patients to COVID-19.⁴ However, as with other infections, patients with neurologic disorders may exhibit worsened symptoms with COVID-19.⁴ In addition, some treatments, particularly immunosuppressive agents, may affect clinical expression of COVID-19.⁴

Professional organizations have published suggestions for the management of patients with neurological conditions during the pandemic:

• National Multiple Sclerosis Society recommends patients continue their disease-modifying multiple sclerosis treatment and not change or stop treatment without discussing risks with their treating neurologist.⁴
• Muscular Dystrophy Association recommends patients with neuromuscular disease contact their physician if they develop any symptoms of COVID-19.⁴
• American Parkinson Disease Association indicates Parkinson disease does not increase susceptibility to COVID-19, but COVID-19 could exacerbate motor symptoms.⁴
• Alzheimer’s Association notes dementia-related behaviors may be exacerbated with COVID-19.⁴
• Guillain-Barré Syndrome/Chronic Inflammatory Demyelinating Polyneuropathy Foundation International has stated these diseases do not increase risk of contracting COVID-19, but chronic immunosuppressive agents can increase susceptibility to any infection.⁴

How the Laboratory Can Help

Quest Diagnostics is committed to assisting healthcare providers during the current COVID-19 pandemic by providing

• Routine testing to establish an understanding of a patient’s baseline health, as well as possible prior undiagnosed SARS-CoV-2 exposure
• Testing in symptomatic individuals to differentiate between suspected active respiratory infections, including COVID-19 and influenza
• Testing for biomarkers and autoantibodies associated with specific neurological conditions (eg, encephalopathies/neuroinflammatory syndromes, Guillain-Barré syndrome, myasthenia gravis)

For more details visit

• QuestDiagnostics.com/COVIDCare/Neuro
• Neurological Complications of COVID Webinar

References

1. Montalvan V, Lee J, Bueso T, et al. Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review. Clin Neurol Neurosurg. 2020;194:105921. doi:10.1016/j.clineuro.2020.105921

2. Garcia-Azorin D, Martínez-Pías E, Trigo J, et al. Neurological comorbidity is a predictor of death in COVID-19 disease: a cohort study on 576 patients. Front Neurol. 2020;11:781. doi:10.3389/fneur.2020.00781

3. Romagnolo A, Balestrino R, Imbalzano G, et al. Neurological comorbidity and severity of COVID-19. J Neurol. 2020:1-8. doi:10.1007/s00415-020-10123-y

4. Butala N, Neurological aspects of coronavirus infectious disease 2019 (COVID-19). Innov Clin Neurosci. 2020;17(4-6):13-15.

5. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. doi:10.1001/jamaneurol.2020.1127

6. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382(23):2268-2270. doi:10.1056/NEJMc2008597

7. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy-associated morbidity in COVID-19 patients. Ann Clin Transl Neurol. 2020;7(11):2221-2230. doi:10.1002/acn3.51210

8. Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020;143(10):3104-3120. doi:10.1093/brain/awaa240

9. Orsini A, Corsi M, Santangelo A, et al. Challenges and management of neurological and psychiatric manifestations in SARS-CoV-2 (COVID-19) patients. Neurol Sci. 2020;41(9):2353-2366. doi:10.1007/s10072-020-04544-w

10. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040. doi:10.1182/blood.2020006000

11. Berger JR. COVID-19 and the nervous system. J Neurovirol. 2020;26(2):143-148. doi:10.1007/s13365-020-00840-5

12. Niazkar HR, Zibaee B, Nasimi A, et al. The neurological manifestations of COVID-19: a review article. Neurol Sci. 2020;41(7):1667-1671. doi:10.1007/s10072-020-04486-3

13. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0

14. Cohen ME, Eichel R, Steiner-Birmanns B, et al. A case of probable Parkinson's disease after SARS-CoV-2 infection. Lancet Neurol. 2020;19(10):804-805. doi:10.1016/S1474-4422(20)30305-7

15. Cilia R, Bonvegna S, Straccia G, et al. Effects of COVID-19 on Parkinson's disease clinical features: a community-based case-control study. Mov Disord. 2020;35(8):1287-1292. doi:10.1002/mds.28170

16. Brown EG, Chahine LM, Goldman SM, et al. The effect of the COVID-19 pandemic on people with Parkinson's disease. J Parkinson's Dis. 2020;10(4):1365-1377. doi:10.3233/JPD-202249

17. Berger JR, Brandstadter R, Bar-Or A. COVID-19 and MS disease-modifying therapies. Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e761. doi:10.1212/NXI.0000000000000761

18. COViMS Registry. The COViMS database public data update. Accessed January 18, 2021. https://www.COViMS.org

19. Salahuddin H,  Afreen  E,  Sheikh IS,  et al.  Neurological  predictors  of  clinical  outcomes in hospitalized patients with   COVID-19. Front Neurol. 2020;11:585944. doi:10.3389/fneur.2020.585944

Models used for illustrative purposes only.

Published date: Jan 2021