Tuesday, June 19, 2018

Neuroinfluenza: A Review Of Recently Published Studies


Although primarily a self-limiting infection of the respiratory tract, for a small subset of cases - most often among children - influenza can present with a variety of subtle, and sometimes profound, neurological symptoms.
Credit CDC 2018 COCA Call On Severe Influenza

The exact mechanisms behind these neurological manifestations are unknown, as seasonal flu viruses are generally regarded as being non-neurotropic. But some researchers have suggested that these neurological symptoms may be due to neuroinflammation induced by the host's immune response.
That said, we have seen evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others.
In 2009, a PNAS study (link below) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.
Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration
In 2015, after the death of the first imported H5N1 case in Canada, we saw a study (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), where the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.
In a Scientific Reports study on the genetics of the H5N1 clade virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors warned of its neurotropic effects, and that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'
Far less certain are the long-term neurological impacts of severe (or repeated) influenza infections, although we've seen studies suggesting links to Parkinson's, Schizophrenia, and even Alzheimer's  (see Nature Comms: Revisiting The Influenza-Parkinson's Link). 
We last looked this topic in February, in JNeurosci: Another Study On The Neurocognitive Impact Of Influenza Infection, where we saw a study from the Technical University of Braunschweig, which found long-term neurocognitive impairment in mice following infection with specific types (H3N2 & H7N7) of influenza viruses - but not in others (H1N1).
Obviously, not-so-good news if you are a mouse, but how relevant these results are for humans remains an open question. 
Since February several new studies have been published on this topic, and so today a brief review, with links and excerpts.  I'll return with a bit more at the end. 
(Note: Although published in February,  the first study (below) was made available online in 2017).
Neuroinfluenza: evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study)
Paksu, M.S., Aslan, K., Kendirli, T. et al. Childs Nerv Syst (2018) 34: 335. https://doi.org/10.1007/s00381-017-3554-3


Although influenza primarily affects the respiratory system, in some cases, it can cause severe neurological complications. Younger children are especially at risk. Pediatric literature is limited on the diagnosis, treatment, and prognosis of influenza-related neurological complications. The aim of the study was to evaluate children who suffered severe neurological manifestation as a result of seasonal influenza infection.


The medical records of 14 patients from six hospitals in different regions of the country were evaluated. All of the children had a severe neurological manifestations related to laboratory-confirmed influenza infection.


Median age of the patients was 59 months (6 months—15.5 years) and nine (64.3%) were male. Only 4 (28.6%) of the 14 patients had a comorbid disease. Two patients were admitted to hospital with influenza-related late complications, and the remainder had acute complication.
The most frequent complaints at admission were fever, altered mental status, vomiting, and seizure, respectively. Cerebrospinal fluid (CSF) analysis was performed in 11 cases, and pleocytosis was found in only two cases. Neuroradiological imaging was performed in 13 patients. The most frequent affected regions of nervous system were as follows: cerebellum, brainstem, thalamus, basal ganglions, periventricular white matter, and spinal cords. Nine (64.3%) patients suffered epileptic seizures. Two patients had focal seizure, and the rest had generalized seizures. Two patients developed status epilepticus. Most frequent diagnoses of patients were encephalopathy (n = 4), encephalitis (n = 3), and meningitis (n = 3), respectively.
The rate of recovery without sequelae from was found to be 50%. At discharge, three (21.4%) patients had mild symptoms, another three (21.4%) had severe neurological sequelae. One (7.1%) patient died. The clinical findings were more severe and outcome was worse in patients < 5 years old than patients > 5 years old and in patients with comorbid disease than previously healthy group.


Seasonal influenza infection may cause severe neurological complications, especially in children. Healthy children are also at risk such as patients with comorbid conditions. All children who are admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications even if their respiratory complaints are mild or nonexistent.

Our next study comes from the journal Brain Development.

Influenza-associated neurological complications during 2014–2017 in Taiwan
Li-Wen Chen, Chao-Ku Teng, Yi-Shan Tsai, Jieh-Neng Wang, Yi-Fang Tu, Ching-Fen Shen,  Ching-Chuan Liu

Seasonal influenza-associated neurological complications had high mortality and morbidity rates in recent studies. We reported influenza-associated encephalitis/encephalopathy in children during 2014–2017 in Taiwan, focusing on neurological presentations, neuroimaging correlations, and critical care managements.


During January 1st 2014 to June 30th 2017, pediatric patients reported to the Taiwan Centers for Disease Control surveillance system for severe complicated influenza infections in the hospital were retrospectively reviewed. Children with influenza-associated encephalitis/encephalopathy were inspected for clinical presentations, laboratory data, neuroimaging studies, treatment modalities, and neurological outcomes.


Ten children with median age 5.9 years were enrolled for analysis. Influenza-associated encephalitis/encephalopathy appeared in the spring and summer, with a delayed peak comparing with the occurrence of pneumonia and septic shock.
The neurological symptoms developed rapidly within median 1 day after the first fever episode. All patients had consciousness disturbance. Seven patients (70%) had seizures at initial presentation, and six of them had status epilepticus. Anti-viral treatments were applied in all patients, with median door-to-drug time 0.9 h for oseltamivir and 6.0 h for peramivir. Multi-modality treatments also included steroid pulse therapy, immunoglobulin treatment, and target temperature management, with 85.2% of the major treatments administered within 12 h after admission.
Nine of the ten patients recovered without neurological sequelae. Only one patient had epilepsy requiring long-term anticonvulsants and concomitant cognitive decline.


In highly prevalent area, influenza-associated encephalitis/ encephalopathy should be considered irrespective of seasons. Our study suggested the effects of timely surveillance and multi-modality treatments in influenza-associated encephalitis/encephalopathy.

While influenza-related neurological complications are most often reported in children, adults are not necessarily immune, as reported in the following two studies. 
Acute necrotizing encephalopathy in an adult with influenza A infection
Nobuaki Ochi,1 Kento Takahashi,2 Hiromichi Yamane,1 and Nagio Takigawa1


Acute necrotizing encephalopathy following influenza infection is a rapidly progressing disease with high morbidity. Although the neurological disorder is sometimes reported in children, it is very rare in adults.
We herein describe an adult with acute necrotizing encephalopathy captured on a series of brain magnetic resonance images. A 55-year-old man had fever and impaired consciousness. He was diagnosed with influenza A (H1N1). Brain magnetic resonance imaging revealed symmetrical lesions in the cerebellum and basal nucleus, showing typical acute necrotizing encephalopathy. Physicians should know that influenza-associated acute necrotizing encephalopathy can occur even in middle-aged adults.
(Continue . . . )

And finally, this study from the Indian Journal of Critical Care Medicine.
Adult Influenza A (H1N1) Related Encephalitis: A Case Report
Devinder Midha, Arun Kumar, Pratibha Vasudev, Zafar Ahmad Iqbal, and Amit Kumar Mandal

The year 2009–2010 saw H1N1 influenza outbreaks occurring in almost all countries of the world, causing the WHO to declare it a pandemic of an alert level of 6. In India, H1N1 influenza outbreaks were again reported in late 2014 and early 2015. Since then, sporadic cases of H1N1 influenza have been reported.
H1N1 influenza usually presents itself with respiratory tract symptoms. In a minority of patients, abdominal symptoms may occur as well. Acute influenza-associated encephalopathy/encephalitis mostly occurs in the pediatric population, whereas in adults, it is a rare complication. The incidence of neurological complications appears to have increased after the 2009 H1N1 influenza A virus pandemic.
We would like to draw attention to an adult patient case who initially presented with respiratory symptoms but then deteriorated and developed encephalitis, which is rarely reported. As per literature reviewed by Victoria Bangualid and Judith Berger on PubMed, only 21 cases of neurological complications were found in adult influenza A patients, out of whom 8 had encephalopathy.
(Continue . . . )

Despite the mounting evidence, the neurological impacts of influenza are still largely unappreciated by the public, and even by a lot of doctors, and therefore cases likely go under reported.
It may also turn out that some, if not most, of the reported behavioral problems which have been previously (and tentatively) linked to the use of oseltamivir (aka Tamiflu) may have more do to with the neurocognitive effects of influenza infection than from taking the drug. 
But most of all, these studies - along with others, like NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection and Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke - are reminders that influenza is a far more complex, and far more dangerous, virus than most people give it credit for.

Something to seriously consider when you are deciding whether to bother getting that flu shot next fall.