COVID 19 & THE BRAIN

Volume 11 Issues 4 April, 2021

The infection COVID-19 caused by the SARS-CoV-2 virus was declared as a pandemic on 11 March 2020.The spread via droplet and small airborne particles by even asymptomatic individuals has largely been responsible for the scale of the pandemic. Beyond the common pulmonary manifestations, the virus is capable of multisystem involvement. COVID-19, being a neurotropic infection, also involves the brain. It is in this context that the occurrence of mental illnesses in vulnerable population must be viewed.

Pathophysiology & Inflammatory Responses

On gaining entry into the body, the virus reacts with the immune system in four major ways :

Viral replication in innate immune cells: occurs in the cytoplasm with RNase & replication organelles helping in evading innate response.
Dysregulated immune response: innate cells synthesize & release cytokines, increased levels of which(E.g. IL6, TNFα) correlate with symptom severity.
Cytokine storm: it is responsible for the development of ARDS & MODS- with CNS involvement as one of the manifestations.
Antibody- mediated response: by activation of specific immune responses.

Possible Routes of Neural Spread

Apart from the inflammatory response affecting the brain, the virus can gain direct access to the CNS. Viral binding occurs to ACE-2 receptor on respiratory & GI epithelium following which neural spread is seen through hematogenous route or through the olfactory bulb. Once within neurons transmission is seen in both anterograde & retrograde directions. Further evidence is provided by the involvement of nucleus of solitary fascicle in brainstem which affects respiratory drive.

Neuropsychiatric Manifestations

Among infected individuals, 36.4% were symptomatic with central, peripheral/ musculoskeletal orpsychological manifestations, having an acute or chronic presentation.

Acute Manifestations:

Delirium & confusional states: in elderly, those with comorbidities or premorbid cognitive decline and associated with increased Pulmonary Severity Index (PSI). Present with unique features such as alogia, abulia & rigidity. Prolonged delirium was seen with hypoxia, cytokine storm or use of HCQ.
Dysfunction of olfaction & taste sensation: due to involvement of olfactory lining (ACE2 receptor). It is not only a biomarker for COVID-19 infection but is also an early marker for neurological involvement.
Acute Psychosis: exacerbations have been reported to occur in Schizophrenia patients despite compliance with medication.
Encephalitis & Encephalopathies: seen as drowsiness, behavioral disturbances, catatonic states or movement disorders. Imaging may show B/L hyperintense mesial temporal lobes. It is a consequence of cytokine storm. Individuals with pre-existing cognitive deficits or chronic psychiatric illness are at risk of developing long term sequelae.
Acute cerebrovascular events: ischaemic strokes are more common especially in the context of old age, low platelets & high D-dimer. Via ACE2 receptor, the virus causes hypertension & a hyper-coagulable state. Additionally the SARS-CoV-2 spike protein has a neuro-inflammatory role causing endothelial dysfunction & blood stasis.

Chronic Manifestations

Neuromuscular disorders: such as myopathy, neuropathy, GBS, brainstem encephalitis etc. It can also worsen symptoms of Multiple Sclerosis. Demyelination occurs due to hypoxia, direct injury, inflammation & MHC mediated CMI.
Chronic psychiatric conditions: can worsen pre-existing mood disorders. There is increased depression, anxiety, adjustment disorder, acute stress reaction, somatization & OCD. PTSD tends to have a chronic & complex course. Whether it is a consequence of psychosocial stressors or direct effecton brain is not clear & requires further study. Risk groups include the quarantined, patient’s caregivers, health care workers etc.
Neurodegenerative disorders: basal ganglia involvement seen in mice suggests risk of development of parkinson like features.
Epilepsy: can be of new onset or reactivation due to encephalopathy or cerebral edema. Triggers include psychological stress, poor drug compliance, drug interactions of Remdesivir, Lopinavir etc. with AEDs.

Possible Pathogenesis of these Disorders:

Microglia undergo aggravated activation which is out of proportion to the severity of infection. This along with disruptions of blood brain barrier leads to increased cytokine levels in CNS. Consequent oxidative damage causes disruptions in neurotransmitter signaling. This is in line with the findings of various studies linking pro-inflammatory states and psychiatric disease.

Consideration in Specific Disorders

Psychotic disorders: Disordered tryptophan- kynurenine metabolism (affects serotonin & Glutamatesignaling), in the context of a pro-inflammatory state, leads to disrupted regional dopamine levels as seen in animal models. Antipsychotics tend to also modulate the inflammatory response contributing to clinical response.
Mood Disorders (MDD): Inflammation induced changes in rats lead to disruptions in Serotonin system in the hippocampus via the tryptophan-kynurenine system. Additionally oxidative changes in PFC, striatum& changes in NO-cGMP signaling have been implicated. Some antidepressants, Eg. Fluvoxamine, Ketamine, have anti-inflammatory action leading to added efficacy.
Bipolar disorder: Neuro-inflammation plays a critical role in disease course with associations suggested with manic symptoms in rats. Drugs in BPAD have been found to have both pro- inflammatory (Li, Valproate) & anti-inflammatory role (Aspirin & NSAIDs, CBZ, Lamotrigene, NAC, GSK3 inhibitors).
Anxiety related disorders: Chronic inflammation disrupts Glutamate & GABA systems causing disinhibition of amygdala causing anxiety. Additionally oxidative stress & NMDA-NO-cGMP pathway mediated neuronal toxicity, hippocampal degeneration have been suggested. Agomelatine & SSRIs have shown anti-inflammatory actions.

SARS – CoV-2 – induced Inflammation & Psychiatric Illness

Without immune competent cells, the brain acts as a viral reservoir. Viral infections (Influenza, VZV, HSV, HIV, and HCV) have been linked to increased depression, anxiety & OCD. Maternal influenza has associations with schizophrenia & BPAD.

In the pandemic, a three time increase in prevalence of depression has been reported and psychiatric patients had increased risk for viral illness. A three-way interaction among inflammation, COVID 19 & psychiatric illness and psychotropics has been suggested with immune dysregulation playing a central role. Various psychotropics have been found to exert dual action on psychiatric illness & inflammatory response. Mirtazepine by blocking α2A-adenoreceptor modulates sympathetic stress with potential role in treating ARDS & depression in COVID 19. Similar role suggested for Sildenafil (PDE5 inhibitor) via modulation of cGMP pathway. Antipsychotics were found to Increase pneumonia via anti-inflammatory actions while Flivoxamine, owing to its structural properties reduced viral penetration & replication in host cells.

Conversely drugs used to treat COVID 19, such as antivirals (by direct neuronal injury & oxidative damage) & azithromycin (by interacting with psychotropics) lead to adverse psychiatric outcomes.

Adjunctive Psychotropic Treatments in COVID – 1 9

Various drugs have been suggested such as Agomelatine, Clonidine, Lithium, SSRIs etc.

Psychosocial & Mental Health Issues

The pandemic has created many specific stressors such as confinement, personal & financial losses, limited access to health services etc. The psychological sequelae have been varied such as stress, irritability, anger, frustration, depression, stigma, etc. Therefore patients must be assessed for COVID-19 related stressors, secondary adversities, the psychosocial effects & indicators of vulnerability. Special attention must be given to distress in children & suicidal ideation.

Risk Assessment

This includes evaluating the 3 contributing factors namely- COVID 19, psychiatric illness & psychotropic
medication following which the patients at highest risk are identified. Monitoring such patients for
biomarker levels enables effective adjustment of treatment.