CNS

Pathology of COVID-19 affects CNS with longer symptom course

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The neurological pathology of COVID-19 becomes more complex as symptoms persist and tends to affect the central nervous system more prominently, according to an expert at the American Neurological Association annual meeting.

“It hasn’t gone away — there are 400 people still dying every day from COVID in the United States,” Avindra Nath, MD, clinical director of intramural research at the National Institute of Neurological Disorders and Stroke at NIH, said during the presentation. “It’s still 10-times more [than the amount of] people [who] die of influenza.”

Tiles spelling out name of novel coronavirus
The neurological pathology of COVID-19 becomes more complex and affects the central nervous system as symptoms persist. Source: Adobe Stock.

All coronaviruses cause neurological complications, Nath explained, each of which possesses different receptors that result in different pathologies. And while clinicians and researchers have become focused on the respiratory effects of COVID-19, the virus affects the CNS and produces longer-lasting health issues.

The long-term devastation of COVID and complications from infection, Nath said, all affect brain function. Although there are many variants to COVID-19, the differences between them are not clear with respect to how each one affects the CNS.

However, Nath noted, it appears that effects of newer strains of the virus tend to linger longer than earlier variants. “The virus may be getting persistent,” he said.

Neurological impacts, according to Nath, can be divided into three categories: acute, subacute and chronic. Acute impacts include loss of smell, stroke, difficulty with respiration and recovery, or sudden death during sleep. Subacute affects include inflammatory syndromes such as encephalomyelitis, hemorrhagic encephalopathy and multisystem inflammatory syndrome, while chronic affects are defined by what is known as long COVID.

With respect to long COVID, Nath said there is no consensus on a definition — the diagnosis was coined by patients themselves. However, he offered two broad categories based on symptom course: one in which the severity of symptoms increases and does not resolve as time goes on, and another in which symptoms are initially mild, then decrease sharply or disappear over days or weeks, with new symptoms suddenly appearing and increasing. The latter, he added, is challenging to address due to the intermittent healthy middle gap, in which patient and doctor are left to determine whether the two episodes are related.

Patients dealing with long COVID can be easily divided into four subcategories between those who suffer from respiratory, cognition, autonomic or neuralgic pain issues.

The main pathogenetic factor at issue, Nath said, is whether COVID can enter the brain through nasal mucosa. While studies have shown that a small amount of the virus was found in very few individuals at autopsy, the fact that it is rarely detected may demonstrate that direct invasion of the virus likely does not explain neurological pathology.

“I think we need to look at all neuronal injury, vascular injury, biomarkers. We need to start immunotherapies,” Nath said to conclude his presentation. “And at the same time, study disease pathophysiology together.”

Systemic Treatment for Brain Metastases from HER2-Positive Breast Cancer.

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Two thirds of patients achieved a partial response; half experienced grade 3 or 4 adverse effects.

As new targeted agents have improved outcomes in HER2-positive breast cancer, studies have suggested that survivors might have a longer time to be at risk for developing brain metastases. Radiation therapy is the mainstay for treatment of breast-cancer brain metastases, but it causes adverse effects, and whole-brain radiotherapy (WBRT) impairs cognitive function. Alternatively, systemic therapy seems to have relatively little penetration into the central nervous system (CNS), and evidence of it producing a CNS antitumor effect is lacking. However, recent studies have shown that the oral tyrosine kinase inhibitor lapatinib — administered as monotherapy or in combination with capecitabine — might be an effective treatment. To determine whether this approach could delay radiation therapy, French investigators conducted an industry-funded, single-arm, open-label, phase II (LANDSCAPE) trial of lapatinib and capecitabine involving 44 evaluable patients with HER2-positive breast cancer who had not received whole brain radiotherapy (WBRT).

Treatment was administered in 21-day cycles: patients received oral lapatinib (1250 mg) daily and oral capecitabine (2 gm/m2) on days 1 to 14. Clinical assessments of toxicity and neurological effects were conducted every 3 weeks. Patients underwent computed tomography and magnetic resonance imaging studies to detect CNS lesions every 6 weeks. More than 90% of patients had received prior trastuzumab, 57% had neurological signs and symptoms at enrollment, and 84% had extra-CNS sites of disease, most commonly in bone, liver, and lung. The primary end point of the study was the rate of objective CNS response, defined as a 50% volumetric reduction in CNS lesions without progression of symptoms, extra-CNS disease, or use of steroids.

At median follow-up of 21.2 months, 66% of patients achieved objective CNS responses, all of which were partial responses. Patients were equally likely to attain CNS response whether previously treated with trastuzumab or not. Median time to CNS progression was 5.5 months, and median time to radiotherapy was 8.3 months. The majority of patients (78%) had CNS as the first site of disease progression. Nearly 50% of patients had at least one grade 3 or 4 adverse event, most commonly diarrhea or hand-foot syndrome.

Comment: Brain metastases remain a significant therapeutic challenge, and patients who have a relatively long survival after WBRT might experience some of the well-described cognitive and functional deficits. The LANDSCAPE trial offers patients with HER2-positive brain metastases the potential to delay radiation therapy. However, the combination of lapatinib and capecitabine has the potential to produce substantial adverse effects, which can also negatively affect quality of life.

Source: Journal Watch Oncology and Hematology