COVID-19 Neurologic Complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Rinky Agnes Botleroo, M.B.B.S., Wajeeha Aiman, M.D.[2], Parul Pahal, M.B.B.S[3]

Pathophysiology of the Complications in the Nervous System

The spectrum of neurological manifestations have been seen throughout the COVID-19 pandemic. These manifestations range from headache to encephalitis. Here raises a question that how does the SARS-CoV-2 virus reaches the mileu of brain? Severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory Syndrome (MERS-CoV) have caused many neurological manifestations in the previous pandemics of 2003 and 2012, respectively, as the nucleic acid of SARS-CoV and MERS-CoV was found in cerebrospinal fluid and later the nucleic acid was found in autopsy of brain. Genetically, SARS-CoV-2 is 79% identical to SARS-CoV and 50% identical to MERS-CoV. Due to this structural homology of SARS-CoV-2 with SARS-CoV and MERS-CoV it can be proposed that SARS-CoV-2 is neurotropic and uses the same mechanism of pathogenecity as SARS-CoV and MERS-CoV.

The mechanism of SARS-CoV-2 targeting CNS is

1. Direct infection injury to CNS
2. Hematogenous spread to CNS
3. neuronal pathway
4. Immune mediated injury to CNS
5. Hypoxic injury to CNS

Complications in the Central Nervous System

Headache

• Pathophysiology
  • The exact pathogenesis of headache in COVID 19 patients is not fully understood.
  • It is thought that headache is the result of:
    • Cytokine release
      • There is higher concentration on IL-6 and INF-gamma in patients infected with SARS/ CoV2.
      • Cytokines can disrupt blood brain barrier and cause tissue injury and cerebral edema.
    • Direct invasion
    • Metabolic disturbances
    • Inflammation
    • Dehydration
    • Hypoxia

By Fahimeh Shojaei, M.D. / https://en.wikipedia.org/wiki/File:Migraine.jpg

• Natural history
• Sign and symptoms
• Treatment

Cerebrovascular Accident/Stroke

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Acute Encephalitis

• Pathophysiology
  • The pa
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Viral Meningitis

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Epileptic Seizures

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Encephalopathy

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Complications in the Peripheral Nervous system

Guillain-Barre syndrome

• Pathophysiology
  • Guillain–Barre syndrome causes immune-mediated damage to the peripheral nerves that usually follows gastrointestinal or respiratory illnesses. The polyneuropathy in Guillain–Barre syndrome is believed to be due to cross-immunity against epitopes of peripheral nerve components that it shares with the epitopes on the cell surface of bacteria that produces an antecedent infection . Most common antecedent infections are Campylobacter jejuni ,Zika virus and influenza virus.
    
  • The mechanism of Guillain–Barre syndrome in patients infected with COVID-19 is not fully understood yet.
  • COVID-19 stimulates inflammatory cells and produces various inflammatory cytokines and as a result, it initiates immune-mediated processes.'Molecular mimicry' as a mechanism of autoimmune disorder plays an important role in formation of Guillain–Barre syndrome. It is not yet clear whether COVID-19 induces the production of antibodies against specific gangliosides that usually appear with certain forms of Guillain–Barre syndrome.
    In the future further investigations should be conducted about the mechanism of GBS in patients with COVID-19 for better understanding.
• Epidemiology and Demographics
  • Five cases of Guillain-Barre syndrome (GBS) in patients with COVID-19 has been reported in three hospitals in northern Italy from February 28 through March 21, 2020.. Four of these patients had a positive nasopharyngeal swab for SARS-CoV-2 at the onset of the neurologic syndrome, and one had a negative nasopharyngeal swab and negative bronchoalveolar lavage but subsequently he developed a positive serologic test for the virus.
    
  • The first official case of Guillain-Barre syndrome (GBS) associated in patients with COVID-19 in the United States has been reported by neurologists from Allegheny General Hospital in Pittsburgh, Pennsylvania in June,2020..The patient was a 54-year-old man who was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection.The man reported that his wife was tested positive for COVID-19 infection and that his symptoms started soon after her illness. Later he also tested positive for COVID-19.
  • Another case of Guillain–Barre syndrome with COVID-19 has been reported in Iran.

• Sign and symptoms

• Diagnosis
• Treatment

Anosmia

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Acute Myelitis

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Miller Fischer Sydrome

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Polyneuritis Cranialis

• Pathophysiology
• Natural history
• Sign and symptoms
• Diagnosis
• Treatment

Complications due to medication interaction

1. Statin induced myotoxicity

• Myalgia, myopathies, rhabdomyolysis

2. 2nd and 3rd degree atrioventricular block

• Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)

3. Prolong QTc interval

• Chloroquine/Hydroxychloroquine

4. Myelotoxicity

• Ribavirin

5. Prolonged PR interval

• Atazanavir

COVID-19 Experimental Treatments with Interaction Potential

1. Remdesivir (GS‐5734)

Pharmacokinetics and Dosing:

• Adults ≥40 kg: Daily IV dose over 30 min. Day 1: 200 mg, Day 2‐10: 100 mg
• Paed <40 kg: Daily IV dose over 30 min. Day 1: 5 mg/kg, Day 2‐10: 2.5 mg/kg

ClinicalTrials.gov Identifier:

• NCT04302766
• NCT04292899

Interaction Potential:

• Inhibits: CYP3A4, OATP1B1/3, BSEP, MRP4 and NTCP
• Induces: CYP1A2 and CYP2B6
• Unlikely clinically significant (all in vitro data)

2. Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)

Pharmacokinetics and Dosing:

• 400mg/100mg twice daily for 14 days
• Crushing tablet ↓ absorption ≅ 45%133. Use oral liquid (42.4% alcohol and 15.3% propylene glycol)
• Use compatible feeding tubes (PVC or silicone) Avoid metronidazole and disulfiram
• Absorbed in jejunum: NG ok; NJ may ↓ effect

ClinicalTrials.gov Identifier:

• NCT04276688

Chinese Clinical Trials Registry ID:

• ChiCTR2000029539

EU Clinical Trials Register ID:

• 2020‐000936‐23

Interaction Potential:

• Lopinovir extensively metabolised by CYP3A
• Inhibitor of: CYP3A4 (potent), P‐gp, BCPR, OATP1B1
  • can increase concentration of drugs metabolised or substrates of these pathways

• Inducer of: CYP2C9, CYP2C19, glucuronidation

• Can prolong PR interval.
• Rare reports of 2nd and 3rd degree atrioventricular block in patients with underlying risk factors

3. Chloroquine/Hydroxychloroquine

Pharmacokinetics and Dosing:

• 200 mg three times a day for 10 days

ClinicalTrials.gov Identifier:

• NCT04261517

Chinese Clinical Trials Registry ID:

• ChiCTR2000029609

Interaction Potential:

• Metabolised by: CYP2C8, CYP3A4, CYP2D6
• Inhibited by: CYP2D6 and P‐gp
• Can prolong QTc interval, consider ECG monitoring where appropriate

4. Interferon beta

ClinicalTrials.gov Identifier:

• NCT04276688

Interaction Potential:

• Interferons have been reported to reduce CYP450 drug metabolism
• Care with narrow therapeutic index drugs dependent on CYP450 clearance

5. Ribavirin

Pharmacokinetics and Dosing:

• Do not crush – known teratogen.
• Contact hospital pharmacy for solution compounded from capsules or (SAS) product availability

ClinicalTrials.gov Identifier:

• NCT04276688

Interaction Potential:

• Not metabolised by CYP450 unlikely to contribute to CYP interactions.
• Inhibits inosine monophosphate dehydrogenase:
• Can interfere with azathioprine metabolism possibly leading to accumulation of 6‐methylthioinosine monophosphate (6‐MTIMP), which has been associated with myelotoxicity

6. Favipiravir

Chinese Clinical Trials Registry ID:

• ChiCTR2000029600 (favipiravir plus interferon‐α)
• ChiCTR2000029544 (favipiravir plus baloxavir marboxil)

Interaction Potential:

• Metabolised by: Nicotinamide adenine dinucleotide phosphate (NADPH) independent and dependent enzymes.
• Inhibits:
  • CYP2C8 (strong)
  • OAT1, OAT3 (mod)
  • CYP1A2 (weak) , CYP2C9 (weak) , CYP2C19 (weak) , CYP2CD6 (weak) , CYP2E1 (weak) , CYP3A4 (weak)

• Low risk QT prolongation

7. Atazanavir

Pharmacokinetics and Dosing:

• Requires pH <4. Avoid antacids 2 h before and 1 hour after.
• Food ↑ bioavailability
• Absorbed in jejunum: NG ok; NJ may ↓ effect

Interaction Potential:

• Metabolised by: CYP3A4 (extensively)
• Inhibits: CYP3A4, UGT1A1, OATP1B1 (strong), CYP2C8 (weak)
• Absorption depends on low pH; drugs increasing pH will decrease atazanavir concentration
• Dose related prolongation in PR interval.
• Care with drugs increasing QT interval or in patients with pre‐existing risk factors.

8. Nitazoxanide (prodrug) (active metabolite: tizoxanide)

Pharmacokinetics and Dosing:

• May be dispersible or crushed– check brand
• Take with food ‐ increases bioavailability by 50%.

Interaction Potential:

• Nil effects on CYP450 enzymes
• Tizoxanide highly protein bound (>99.9%)
• Will compete for binding sites; monitor drugs highly protein bound with a narrow therapeutic index (such as warfarin)

9. Tocilizumab (IL‐6 monoclonal antibody)

Pharmacokinetics and Dosing:

ClinicalTrials.gov Identifier:

• NCT04310228
• NCT04306705

Interaction Potential:

• Nil significant drug interactions.
• COVID‐19 increases IL‐6 expression. Tocilizumab reduces IL‐6 expression. IL‐6 increases CYP3A4, CYP26C19, CYP2C9, CYP1A2. When tocilizumab is used to treat COVID‐19, the effect on drugs effected by these CYP enzymes is unknown.