The World Health Organization (WHO) monitors the spread of diseases globally and maintains a list of diseases with epidemic or pandemic potential. Currently listed diseases include Chikungunya, cholera, Crimean-Congo hemorrhagic fever, Ebola virus disease, Hendra virus infection, influenza, Lassa fever, Marburg virus disease, Neisseria meningitis, MERS-CoV, monkeypox, Nipah virus infection, novel coronavirus (COVID-19), plague, Rift Valley fever, SARS, smallpox, tularemia, yellow fever, and Zika virus disease. The associated pathogens are increasingly important on the global stage. The majority of these diseases have neurological manifestations. Those with less frequent neurological manifestations may also have important consequences. This is highlighted now in particular through the ongoing COVID-19 pandemic and reinforces that pathogens with the potential to spread rapidly and widely, in spite of concerted global efforts, may affect the nervous system. We searched the scientific literature, dating from 1934 to August 2020, to compile data on the cause, epidemiology, clinical presentation, neuroimaging features, and treatment of each of the diseases of epidemic or pandemic potential as viewed through a neurologist's lens. We included articles with an abstract or full text in English in this topical and scoping review. Diseases with epidemic and pandemic potential can be spread directly from human to human, animal to human, via mosquitoes or other insects, or via environmental contamination. Manifestations include central neurologic conditions (meningitis, encephalitis, intraparenchymal hemorrhage, seizures), peripheral and cranial nerve syndromes (sensory neuropathy, sensorineural hearing loss, ophthalmoplegia), post-infectious syndromes (acute inflammatory polyneuropathy), and congenital syndromes (fetal microcephaly), among others. Some diseases have not been well-characterized from a neurological standpoint, but all have at least scattered case reports of neurological features. Some of the diseases have curative treatments available while in other cases, supportive care remains the only management option. Regardless of the pathogen, prompt, and aggressive measures to control the spread of these agents are the most important factors in lowering the overall morbidity and mortality they can cause.

Neurologic Manifestations of the World Health Organization's List of Pandemic and Epidemic Diseases

Influenza is a widespread respiratory infection, accompanied by damage to the lower respiratory tract of a person, and can lead to severe complications, up to a fatal outcome. Currently existing therapeutic agents and vaccines do not provide fully effective protection against influenza viruses. The development and creation of drugs based on the mechanism of RNA interference in the context of this problem is a promising direction. The aim of this study is to select and experimentally substantiate cellular target genes for miRNAs whose knockdown suppresses viral reproduction. A549 cells (human lung adenocarcinoma) were transfected with small interfering RNAs. After 4 hours, the transfected cells were infected with the influenza virus pri MOI = 0.1; 0.01 and 0.001. The virus-containing liquid was sampled within three days from the moment of transfection and the intensity of the dynamics of viral reproduction was assessed by the CPD titration method. The use of all small interfering RNAs at MOI = 0.1 resulted in a significantly significant decrease in the viral titer relative to non-specific control. Similar results were obtained at MOI = 0.01 and 0.001. The most effective siRNA ISSINUP98, since when using it, at MOI = 0.1, the viral titer values decreased by 1.7 lg TCD50/ml and by 3 lg TCD50/ml at MOI = 0.01 on the third day. The results showed that miRNAs directed to human cellular genes FLT4, Nup98 and Nup205, whose derivatives play an important role in the life cycle of the influenza virus, effectively reduce its reproduction in vitro. Thus, the studied genes and their products are potential targets for the development of anti-influenza drugs.

Creation of a model for studying the antiviral effect of small interfering RNAs in vitro

Objectives. To evaluate the effect of cellular genes FLT4, Nup98, and Nup205 on the reproduction of the influenza A virus in A549 human lung cancer cell line.Methods. The work was carried out using the equipment of the center for collective use of the I.I. Mechnikov Research Institute of Vaccines and Sera (Russia). The virus-containing fluid was collected within three days from the moment of transfection and infection and the intensity of viral reproduction was assessed by viral titration and hemagglutination reaction. The viral RNA concentration was determined by real-time reverse-transcription polymerase chain reaction (RT-PCR). To calculate statistically significant differences between groups, the nonparametric Mann–Whitney test was used.Results. In cells treated with small interfering RNAs (siRNAs) targeted at FLT4, Nup98, and Nup205 genes, a significant decrease in their expression and indicators of viral reproduction (virus titer, hemagglutinating activity, viral RNA concentration) was observed at a multiplicity of infection (MOI) = 0.1. Additionally, it was found that a decrease in the expression of target genes using siRNA does not lead to a significant decrease in cell survival. The viral titer in cells treated with siRNA FLT4.2, Nup98.1, and Nup205 on the first day was lower by an average of 1.0 lg, and on the second and third days, by 2.2–2.3 lg, compared to cells treated with nonspecific siRNA. During real-time RT-PCR, a significant decrease in the concentration of viral RNA was observed with siRNA Nup98.1 (up to 190 times) and Nup205 (up to 30 times) on the first day, 26 and 29 times on the second day, and 6 and 30 times on the third day, respectively. For FLT4.2 siRNA, the number of viral RNA copies decreased by 23, 18, and 16 times on the first, second, and third days. Similar results were obtained when determining the hemagglutinating activity of the virus. The hemagglutinating activity on the third day most strongly decreased in cells treated with siRNA Nup205 and FLT4.2 (16 times). In cells treated with siRNA FLT4.1, Nup98.1, and Nup98.2, hemagglutinating activity decreased by 8 times.Conclusions. In the present study, three cellular genes (FLT4, Nup98, and Nup205) were identified—the decrease in the expression of which effectively suppresses viral reproduction— and the original siRNA sequences were obtained. The results obtained are important for creating therapeutic and prophylactic medication, whose action is based on the RNA interference mechanism.

Knockdown of FLT4, Nup98, and Nup205 cellular genes as a suppressor for the viral activity of Influenza A/WSN/33 (H1N1) in A549 cell culture

Mild encephalopathy/encephalitis with a reversible splenial lesion (MERS) and longitudinally extensive transverse myelitis (LETM) are neuroinflammatory conditions related to the brain and spinal cord, respectively. Most cases of MERS and LETM are related to a secondary autoimmune process in response to an initial insult (i.e., infection, immunization, etc.). The case of an 18-year-old female who developed a three-day history of fever, quadriplegia, cough, and mild encephalopathy is reported here. The patient tested positive for influenza B by nasopharyngeal swab with polymerase chain reaction (PCR). Initial magnetic resonance imaging (MRI) revealed the presence of a diffusion-restricted non-enhancing lesion confined to the splenium of the corpus callosum (MERS type I) and longitudinally extensive non-enhancing T2 hyperintensities from C1 to C5. The patient was managed with a five-day course of 1,000 mg of intravenous methylprednisolone (IVMP). Additionally, five days of therapeutic plasmapheresis (PLEX) was completed. The patient showed significant improvement with medical management and physical therapy. At the one-year follow-up, her motor symptoms had resolved and endorsed only mild paresthesia in the upper extremities. A repeat MRI revealed a reversal of the splenium lesion and moderate improvement in T2 hyperintensities of the cervical cord. Assessing neuroinvasion of the influenza virus is difficult, and diagnostic challenges arise in determining primary infectious versus autoimmune-mediated neuroinflammation. A review of the literature on influenza infection with radiographic findings of MERS and LETM is included.

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Mild Encephalopathy/Encephalitis With a Reversible Splenial Lesion (MERS) and Longitudinally Extensive Transverse Myelitis (LETM) in Influenza B: Neurotropic Mechanisms and Diagnostic Challenges

A 32-year-old male presented to the emergency department (ED) with a productive cough for 4 days and confusion for 2 days prior to presentation. He was febrile, tachycardic, and hypotensive. Initially, labs and influenza A/B PCR were performed. An elevated WBC of 17.3 and a lactate level of 3.1 were noted. He was given a bolus of normal saline and broad spectrum antibiotics, ceftriaxone and azithromycin. The patient was then subsequently found to be positive for influenza A via rapid antigen testing of the nares. On hospital day 2, the patient’s mental status and respiratory distress worsened requiring intubation with mechanical ventilation. CT of the head without contrast revealed symmetric areas of hypoattenuation in the frontoparietal deep white matter. Lumbar puncture showed a slight elevation in WBCs and mild lymphocytic pleocytosis. Brain MRI without contrast revealed symmetric hyperintense T2 FLAIR signaling in the periventricular white matter and the splenium of the corpus callosum. He was found to have encephalitis secondary to influenza A and was started on a course of oseltamivir at higher doses of 150 mg BID for 2 weeks. On hospital day 10, after nine days of intubation, the patient received a tracheostomy due to failure to extubate and no improvement in mental status. He remained ventilator-dependent with little improvement in mental status; the patient was transferred to a long-term acute care hospital (LTACH) facility for further specialized care. He did not show any neurologic recovery or improvement in the three months after initial presentation of symptoms. In the fifth month after the initial symptoms, there was no recovery of preinsult neurologic function. The family had a palliative care meeting to discuss the plan and goals of care. It was decided by close family members that “compassionate extubation” would be done due to ongoing stress on the patient’s body physically and neurologically. This case illustrates the importance of prompt identification and treatment of influenza in the prevention of rapidly progressive sequelae.

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Hanadi Abou Dargham

Papers

Acute Influenza Encephalitis/Encephalopathy Associated with Influenza A in an Incompetent Adult.