Yeditepe University Koşuyolu Hospital Neurology specialist shared important information about neurological problems seen in COVID-19 Coronavirus infection.

Is there neurological involvement in COVID-19 infection?

Since the beginning of the pandemic, studies have now established that more than a third of patients have neurological signs and symptoms. However, this number could be much higher.

In contrast to the typical triad of fever, cough, or respiratory distress, some patients may present to the hospital with specific neurological symptoms such as loss of smell or taste, muscle pain, stroke, or non-specific neurological symptoms such as headache, impaired consciousness, dizziness, or seizures. Moreover, since all clinical data is derived from electronic medical records, mild symptoms, and signs such as taste and smell disturbances can be overlooked.

Detection of neurological signs and symptoms in patients is only possible if these conditions are recognized and investigated. Currently, neurological signs and symptoms are likely to be overlooked. During the COVID-19 coronavirus pandemic, it has become clear that COVID-19 disease should be taken into consideration in order to avoid delayed or incorrect diagnosis of patients with neurological symptoms, to prevent the spread of the disease and not to lose the chance to treat it.

What are the neurological signs and symptoms of COVID-19 infection?

Neurological symptoms fall into 3 categories:

• Central nervous system symptoms: Dizziness, headache, impaired consciousness, stroke, imbalance and seizures, sleep disturbances
• Peripheral nervous system symptoms: Taste disturbance, smell disturbance, visual disturbance, nerve pain, Guillain-Barré syndrome
• Symptoms of skeletal muscle damage: Widespread muscle pain, cramps, generalized weakness

The most common signs and symptoms currently reported are headache (13.1%), dizziness (16.8%), nausea, and vomiting (non-specific). Odor (5.1%) and taste (5.6%) disturbances (specific symptoms) are the most common early neurological manifestations.

Importantly, some neurological involvement may be unknown in patients with impaired consciousness. An encephalopathy (a disease in which the functioning of the brain is affected) is present in a patient who has impaired consciousness or is unconscious during COVID-19 infection. However, coma due to continuous epileptic activity in the brain (non-convulsive status epilepticus) may not be recognized at all. Since this condition is very difficult to improve without anti-epileptic treatment, EEG monitoring is necessary for patients with impaired consciousness to make a timely diagnosis.

How is the COVID-19 virus invading the nervous system?

It is already known that it is common for respiratory viruses to infect the nervous system. Influenza, measles, and flu viruses can all infect the brain or other nervous systems and cause neurological disease. COVID-19 is a new mutant form of the coronavirus, a known pneumonia virus.

COVID-19 can affect neurological systems in different ways:

• The virus can directly invade the nervous system (the ACE2 and DPP4 receptors it uses to enter cells are also found in nerve and muscle cells)
• Inflammatory events caused by the virus can cause secondary damage to neurological systems
• Effects on the respiratory and cardiac systems, in particular, impair blood oxygenation and can cause effects in the brain due to oxygen deprivation
• Virus infection and inflammation can cause blood to clot within blood vessels, leading to infarction in the brain (stroke) or other nerve and muscle tissues
• As with other respiratory viruses, it can enter through the nerve endings (most commonly the olfactory nerves in the nose) and can be transported through the nerve Retrograde neuronal pathway, shingles, and herpes virus are the most common viruses that use this pathway.

In addition, the drugs used to fight the virus can also affect the nervous system and cause neurological signs and symptoms.

Does each COVID-19-positive patient have neurological involvement?

Neurological signs and symptoms are more common in severe cases. Between 46-84% of patients with severe COVID-19 infection show neurological signs and symptoms. It is seen that these problems continue after recovery. However, neurological signs and symptoms can also occur in patients with a mild infections, and the first findings can be neurological in patients with no signs of infection. On the other hand, not all COVID-19 infections cause neurological symptoms.

• Central nervous system signs and symptoms in 24.8% of patients,
• Peripheral nervous system (nervous system outside the brain and spinal cord) signs and symptoms in 8.9% of patients
• Musculoskeletal signs and symptoms were present in 10.7% of patients.

The mean age of patients with neurological involvement is 52.7 years (relatively younger patients) and the male/female ratio is 2/3, meaning that it is more common in women.

The incidence of stroke is about 3-6 times higher than normal in patients with COVID-19. An acute stroke occurs in 6% of patients with serious infections (especially in the elderly, and patients with risk factors such as hypertension, diabetes, chronic lung disease, and obesity).

COVID-19-related coagulopathy (clotting disorder), a condition defined by the American Society of Hematology, is often seen as vein blockages in the legs and lungs and can also cause arterial blockages due to clotting.

At what stage of COVID-19 infection do neurological symptoms appear?

Some patients who do not have typical signs and symptoms of COVID-19, such as fever, cough, anorexia, and diarrhea, may present to the hospital early in COVID-19 infection with only neurological symptoms (average duration 1-2 days). There are 2 publications of patients who presented to the emergency room with a sudden stroke and were later diagnosed with COVID-19 by lung CT. 

There are also reports of patients with fever and headache who were initially admitted to the neurology ward with a diagnosis of COVID-19 excluded due to normal examination, routine blood tests, and lung CT, but a few days later were diagnosed with typical COVID-19 due to the onset of cough, sore throat, low lymphocyte count in blood count and ground glass appearance on lung CT.

For these reasons, during the COVID-19 pandemic, when seeing patients with neurological symptoms, physicians should consider COVID-19 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and prevention of transmission.

How do we know if patients presenting with only neurological findings will have COVID-19?

There is no significant difference in the laboratory findings of patients with severe or mild COVID-19 infection and neurological signs and symptoms. Creatine kinase (CK) levels were significantly higher only in patients with muscle damage. Patients with muscle damage also have higher neutrophil counts, lower lymphocyte counts, and higher CRP, and D-dimer levels. In addition, patients with muscle damage have multiple organ damage, including more liver and kidney abnormalities.

How do those with a neurological disease get affected by COVID-19 infection?

We do not yet know how diseases such as Parkinson's and Alzheimer's will be affected. It seems appropriate to treat these patients like the normal elderly population. However, studies are being carried out rapidly for patients who are taking immunosuppressive drugs for diseases of the immune system, such as Myasthenia Gravis and Multiple Sclerosis (MS), and who may be at higher risk of developing problems. It is even more important to protect this group of patients.

Are there any changes in the medications used for MS and Myasthenia or any treatment discontinuation?

The recommendations by the authorities on this issue are as follows:

• In patients on regular immunosuppressive medications and with documented mild COVID-19 infection, it is usually reasonable to continue treatment.
•  However, discontinuation of treatment should be considered in patients taking medications with high immunosuppressive effects, in patients with risk factors for severe disease (advanced age and presence of other diseases), or patients with worsening signs and symptoms of COVID-19.
• Discontinuation of treatment is recommended in patients on regular immunosuppressive medications, hospitalized with severe or complicated COVID-19 infection
•  Treatment can be restarted after 4 weeks or after signs and symptoms have completely resolved, keeping in mind the risk of relapse.
• Patients with acute attacks are often treated with a short course of high-dose intravenous cortisone (methylprednisolone). High-dose steroids accelerate the recovery of attacks, but usually do not affect the outcome. During the COVID-19 pandemic, cortisone treatment should not be rushed for mild attacks and should be considered for severe attacks.
• Patients in this group who are in good health are advised to avoid routine and non-essential hospital visits during the COVID-19 pandemic and, where possible, follow-up treatment and assessments by online appointment.

Issues to Keep in Mind:

• An acute infection can sometimes temporarily worsen the symptoms and signs of MS and other diseases (pseudo-attack), which should be carefully examined.
• Not all medicines that affect the immune system and are used regularly have the same risk. Immunomodulatory drugs usually work without an increased risk of infection. However, treatment with so-called immunosuppressive drugs, which suppress the number of lymphocytes, may be associated with a higher risk.
• The risk of COVID-19 infection appears lower and milder in children. The risk from treatment will therefore decrease. Treatment should be individualized taking this into account.
• It is recommended that pregnant women follow general health advice during the COVID-19 pandemic, with no specific recommendations.

For most people with MS, the benefits of continuing treatment will outweigh the risks of stopping MS treatment due to concerns about COVID-19.

Do other treatments for neurological diseases also need to change due to COVID-19?

The most frequently asked question is about the administration of vasodilators (intravenous tPA, "Alteplase") in patients with sudden stroke. Several studies have shown that the presence of COVID-19 infection is not a limitation for the administration of tPA therapy for stroke, but it is advisable to follow the guidelines developed on whether the administration should take place in stroke centers or COVID wards or intensive care units, taking into account the presence and severity of the disease.

What is the process for patients with neurological involvement in the future?

In addition to the guidelines prepared by the Ministry of Health of the Republic of Turkey and general guidelines such as other international neurology associations and organizations, the Turkish Neurological Society and its scientific working groups have prepared guidelines and informative documents in the field of neurology in the fight against COVID-19.

It is necessary to provide accurate and effective information about COVID-19 and its neurological symptoms and signs, to support the necessary organizations, to cooperate, to contribute to activities such as surveys, studies, and projects, to evaluate our own data and to create databases that maintain their importance in our country, to pass the process as soon as possible and with minimal damage. This requires the contribution and assistance of the public as well as the contribution of doctors and scientists working in other fields.