REVIEW ARTICLE

Influenza-Associated Neurological Complications

Jenny P. Tsai • Andrew J. Baker

Published online: 9 November 2012

� Springer Science+Business Media New York 2012

Abstract While mostly diagnosed in the pediatric popu-

lation, neurological complications of pandemic influenza A

infection may affect young and previously healthy adults,

and may follow a fulminant, severe, and occasionally fatal

course. We reviewed severe neurological complications

secondary to influenza infection reported in the literature,

in attempt to outline recurrent syndromes that may assist

the clinician in making a timely diagnosis. Vigilance and

awareness of these clinical entities are key in the neurol-

ogist and intensivist’s role in surveillance and early

recognition of pandemic influenza, and in ensuring

improved survival for affected patients.

Keywords Influenza � Influenza vaccine �Encephalopathy � Brain edema � H1N1 � Coma

Introduction

Influenza-associated neurological complications encom-

pass a wide range of clinico-pathological entities. Many

have been reported and are well recognized. Clinical

manifestations may affect any level of the neuraxis, and

present with a large spectrum of severity, ranging from a

mild and progressive course with full symptom resolution

to an aggressive disease rapidly culminating in fatality [6,

13, 39, 44, 56, 93]. While most cases reported pertain to the

pediatric population, a surge in the incidence of severe

diseases in young and otherwise healthy adults is noted

during pandemics. Emergency preparedness is necessary as

the medical community remains on the lookout for a novel

influenza pandemic. The neurologist and neurological

intensivist have a role in epidemic surveillance and,

therefore, should be aware of influenza-associated neuro-

logical complications to correctly and timely substantiate

the diagnosis.

Review of available data in the medical literature on

pandemics of different local and international impact from

the last century shows a recurrent pattern of clinical pre-

sentations. We aim to review these clinical entities and

current theories on their pathophysiology, and to outline a

diagnostic and therapeutic approach to suspected cases of

influenza-associated neurological complications.

Methods

We have conducted a Medline search of the scientific literature

using the MeSH terms ‘‘influenza’’, ‘‘influenza vaccine’’ or

subtypes from recent pandemics (‘‘H1N1’’, ‘‘H5N1’’, ‘‘H3N2’’,

‘‘H2N2’’). These results were matched with different MeSH

terms, such as ‘‘encephalopathy’’, ‘‘meningitis’’, ‘‘myelitis’’,

‘‘Guillain-Barre syndrome’’, ‘‘myositis’’, ‘‘neuritis’’, or

‘‘encephalomyelitis.’’ Limits were placed to identify articles

with abstract or full-text available in English or French. We

reviewed all case reports, laboratory studies and past reviews

pertaining to complications associated with influenza A

infection and vaccination.

J. P. Tsai (&)

Department of Medicine, Division of Neurology,

University of Toronto, Toronto, ON, Canada

e-mail: jennyp.tsai@utoronto.ca

A. J. Baker

Departments of Critical Care and Anesthesia, St. Michael’s

Hospital, University of Toronto, Toronto, ON, Canada

A. J. Baker

Department of Anesthesia and Inter-Departmental Division

of Critical Care, University of Toronto, Toronto, ON, Canada

123

Neurocrit Care (2013) 18:118–130

DOI 10.1007/s12028-012-9796-8

Clinical Presentations Associated with Influenza

Infections

Over the past century, several subtypes of influenza A have

caused pandemics with different impacts worldwide. The

‘‘Spanish flu’’ of 1918–1919 has been the single most fatal

pandemic, caused by an H1N1 subtype of influenza A. An

important epidemiological feature is the relative absence of

influenza-associated neurological complications in the

adult population outside of pandemics [51]. Sporadic cases

have been reported from seasonal influenza, predominantly

affecting the pediatric population [4, 44].

The Early 1900s

Historically, potential severity of a worldwide influenza

pandemic surfaced following two closely occurring epi-

demics circa 1900. In particular, the H1N1 pandemic of

1918–19 has received much attention due to its geo-

graphical spread and high mortality. Two fatal clinical and

pathological entities have been associated with the epi-

demics of the early 1900s: Strumpell-Leichtenstern’s acute

hemorrhagic influenza encephalitis (SLE), and von Eco-

nomo’s encephalitis lethargica (EL) [21, 22, 55, 76].

Von Strumpell and Leichtenstern simultaneously defined

SLE in detail at the end of the 19th century [22]. Clinically, it

mostly affected children, and presented as somnolence, stupor

or coma, with possible seizures and paralysis, over a course of

days to weeks. Outcomes ranged from complete recovery to

varying degrees of psychiatric or motor sequelae [21]. Path-

ologically, it was described as a cortical and basal ganglia

hemorrhagic encephalitis, with pial infiltration and possible

venous sinus thrombosis. Brainstem and cerebellum were

occasionally affected [21, 22]. However, it was uncommon in

the German epidemic of the 1890s, when it was first reported,

and was reported at an even lower incidence in the Spanish flu

of 1918–19 [21, 76]. Nonetheless, it bears similarities with

influenza-associated encephalopathy syndromes subse-

quently reported over the 20th century. [21].

On the other front, much debate surrounded von Eco-

nomo’s EL since the end of the 1918–19 pandemic [55, 59,

76]. While thousands of deaths have been ascribed to EL,

its causal relationship to influenza infection has never been

proven. EL was diagnosed over a wide timeframe: the first

cases over 2 years prior to the influenza pandemic, and the

last, up to 10 years after [21, 76]. It includes three different

clinical subtypes affecting mainly young and previously

healthy adults, with disturbance of sensorium and sleep

patterns, and with or without parkinsonian features [21,

76]. Well-described pathological features showed signifi-

cantly less inflammation when contrasted with SLE.

Initially believed to be secondary to a highly neurotropic

virus, its causal agent has failed to be identified, even after

re-examination of exhumed patient tissues [22, 55, 76]. The

difficulty in establishing an etiology, its fatality and its

disappearance since the 1920s have cast into doubt its

definition and existence over the past decades [22, 59, 76].

Influenza-Associated Complications: Data From

Seasonal Influenza and Recent Epidemics

Since the pandemic of 1918–19, several other epidemics

with smaller repercussion have surged. Virulent strains

isolated include the H1N1, H3N2, and the H5N1 subtypes

[13, 14, 24, 28, 33, 81]. Meanwhile, several clinical syn-

dromes surfaced as recognizable central nervous system

complications of the infection. Most reported cases origi-

nate from Japan and Taiwan, where the annual incidence of

influenza-associated neurological complications are dis-

proportionately elevated compared to other areas of the

world. Much of the experience is drawn from the pediatric

population, up to 5 years of age [33, 46, 67]. While pre-

ponderance for developing these complications are not

exclusive to either East Asians, children, and the elderly,

individuals with pre-existing neurological or neuromuscu-

lar diseases are also at increased risk [4, 28, 39, 63].

Most commonly encountered clinical syndromes can be

classified into five subtypes of influenza-associated

encephalopathy [57, 83]. Other presentations have been

described, such as influenza-associated myopathy, abnor-

mal movements suspicious for extrapyramidal involve-

ment, transverse myelitis, Guillain-Barre syndrome, and

post-infectious acute disseminated encephalomyelitis [52,

77, 85]. Of interest, as pointed out by Drago et al [16].,

viral meningoencephalitis has only infrequently proven

causal association with influenza infection.

Of the above-stated clinical entities, influenza-associated

encephalopathy (IAE) has been most frequently reported to

lead to fatal outcome. IAE is clinically defined as a group of

syndromes with various degrees of cerebral dysfunction closely

following a documented influenza infection, ranging between 1

and 14 days after the first systemic symptoms, with a median of

3 days [4]. Pathologically these syndromes span a large spec-

trum of severity but commonly show no signs of inflammation

on cerebrospinal fluid or tissue examination [28]. Several

subtypes of IAE have been described through case reports and

various reviews in attempt to devise a formal classification of

their clinical and laboratory profiles. In 2007, Mizuguchi et al

[57] reviewed acute encephalopathy syndromes associated

with several viruses, including influenza, and proposed a

classification system by suspected pathophysiology. In 2009,

Takanashi recognized two benign forms of IAE [86]. In 2010,

Akins et al [3]. further described subtypes of acute encepha-

lopathy with malignant cerebral edema. No consensus currently

incorporates all reported influenza-associated encephalopa-

thy syndromes described in the literature. Meanwhile, it is

Neurocrit Care (2013) 18:118–130 119

123

important to recognize that, although these clinical syn-

dromes are most commonly associated with influenza

infection, they are not exclusively the result of influenza

disease: systemic responses to other viral or bacterial

infections may lead to similar clinical presentations [4].

Major syndromes and classifications described are listed in

Table 1. In the present review, we will revisit major IAE

syndromes described in order of severity of illness. Mild

encephalopathy with reversible splenial lesion (MERS) is a

variant of acute encephalopathy with favorable outcomes.

Encephalopathy with malignant brain edema (EMBE), hem-

orrhagic shock and encephalopathy syndrome (HSES) and

acute necrotizing encephalopathy (ANE) are often rapidly

progressive variants with diffuse cerebral dysfunction and

poorer outcomes. Acute encephalopathy with seizure and late

restricted diffusion (AESD) encompasses two variants of IAE

with focal cortical edema often, yet again not exclusively,

associated with influenza infection: acute infantile encepha-

lopathy predominantly affecting the frontal lobes (AIEF) and

hemiconvulsion-hemiplegia syndrome (HHS).

Mild Encephalopathy with Reversible Splenial Lesion

MERS has been described in numerous case reports and

series [3, 20, 25, 87]. It is clinically characterized by a

systemic prodrome of influenza infection with fever,

vomiting, diarrhea, and cough, followed by the onset of

delirium, decreased level of consciousness or seizures

within one to 3 days. Investigations may reveal mild CSF

pleocytosis, diffuse slowing on electroencephalogram

(EEG) and a midline diffusion-restricting lesion in the

splenium of the corpus callosum in an otherwise normal

MRI [20, 88]. The splenial lesion is speculated to be

reflective of intramyelinic edema with fiber layer separa-

tion [25]. Within a month, the patient fully returns to

baseline clinical status with complete resolution of EEG

and MRI findings, independently of treatment attempts. No

therapies have been shown to alter the natural history of the

disease or its symptomatology [20].

In 41 % of reported cases of MERS, no infectious agent

is identified. Among the remaining cases, most commonly

reported pathogens are influenza (A or B strains, 19 %),

followed by mumps, adenovirus, rotavirus, varicella zoster

virus, streptococcal, Staphylococcus aureus, Escherichia

coli O-157, and Legionella pneumophila infections [25,

90]. When compared to other pathogens, influenza-asso-

ciated MERS has a higher incidence of delirium; other

manifestations of altered mental status reported include

frontal lobe dysfunction, mild disturbance in level of

consciousness (35 %) and seizures (33 %) [87].

Table 1 Proposed

classification of influenza-

associated central nervous

system complications

Authors Year of

publication

Proposed classification

Mizuguchi et al. 2007 Acute encephalopathy due to metabolic error

-Classical Reye syndrome

-Reye-like syndrome

Hemorrhagic shock and encephalopathy syndrome

Acute necrotizing encephalopathy

Acute encephalopathy with febrile convulsive status epilepticus

-Acute infantile encephalopathy predominantly affecting

the frontal lobes

-Hemiconvulsion-hemiplegia syndrome

Others

Takanashi et al. 2009 Acute necrotizing encephalopathy

Hemorrhagic shock and encephalopathy syndrome

Clinically mild encephalitis/encephalopathy with a reversible

splenial lesion

Acute encephalopathy syndrome with biphasic seizures

and late reduced diffusion

Akins et al. 2010 Encephalopathy, benign pattern

Encephalopathy, splenial sign

Encephalopathy, PRES pattern

Encephalopathy, ANE pattern

Encephalopathy with malignant brain edema

Post-infectious cerebellitis

Encephalitis lethargica

Post-viral parkinsonism

120 Neurocrit Care (2013) 18:118–130

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Encephalopathy with Malignant Brain Edema

EMBE is also referred to as ‘‘acute brain swelling’’ by

several authors, and Akins et al. have proposed the more

clinically discriminate term EMBE in 2010. Fewer cases

have been reported in the literature when compared to the

other IAE syndromes [3, 39, 79]. While rarer, a feature of

EMBE is the paucity of systemic complications, in clear

contrast with HSES. This distinction raises suspicion that

observed cases of IAE may be manifestations of a common

pathophysiological process in varying degrees of severity.

Meanwhile, a common feature between reported cases

of EMBE is the clinically-correlated lack of radiological

abnormalities with the exception of diffuse brain swelling.

Outcomes are polarized between full neurological recovery

and fatal cerebral herniation [39, 79]. Mainstays of treat-

ment are supportive with careful management of

intracranial pressure. Sakurai et al [79]. reported a case

with complete neurological recovery, following treatment

with oseltamivir, methylprednisolone, intravenous immu-

noglobulins, induced hypothermia, and intravenous anti-

thrombin III.

Hemorrhagic Shock and Encephalopathy Syndrome

HSES is a clinically defined syndrome initially described

by Levin et al. in 1983. It is a severe disease that seems to

exclusively affect the pediatric population. Defining clini-

cal features include shock, coma or seizures, diarrhea,

disseminated intravascular coagulopathy (DIC), drop in

hemoglobin and platelet, elevated liver enzymes, renal

dysfunction, acidosis, and negative blood and cerebrospinal

fluid cultures. ‘‘Definite HSE’’ is defined by satisfaction of

all nine criteria, and ‘‘probable HSES’’ requires the pres-

ence of at least seven of the above with two unknown, or

satisfaction of eight criteria with one unmet criterion [6].

Patients typically present with an acute history of watery or

bloody diarrhea, followed by shock, seizures, and altered

mental status. Disease-defining systemic complications

ensue. A biphasic course of illness is occasionally noted,

with transient improvement in neurological status at

12–24 h, followed by subsequent deterioration and simi-

larly poor outcomes [26].

EEG shows early focal or multifocal spikes with pos-

sible decrease in signal amplitude and diffuse slowing as

early as within the first 72 h, although a minority of

patients may still have normal EEG findings. Subsequent

slowing reflective of encephalopathic state is common [6].

Diffuse cerebral edema with ventricular effacement may be

apparent on CT studies within the first 3 days [57]. MRI

may further delineate areas of prominent hypointensity on

T2-weighted images due to hemosiderin deposition, cor-

relating with pathologic findings of hemorrhagic necrosis

with liquefaction involving the cerebral cortex, basal gan-

glia, and hemispheric white matter [26].

As a clinical syndrome solely defined by specific organ

systems affected, it is conceivable that HSES is also

associated with other pathogens though many known cases

have no identified microbiological etiology [6, 26, 28].

Independently of pathogen, HSES has high mortality and

poor clinical functional outcome on survival. Acute-phase

mortality is estimated at 60 %, and 30 % of survivors have

neurological sequelae [6, 26].

Acute Necrotizing Encephalopathy

ANE is the most commonly reported neurological com-

plication of influenza A infection, affecting both pediatric

and adult populations. The characteristic clinical presen-

tation includes fever and prodrome of upper respiratory

tract infection, followed by rapid and severe decline in

level of consciousness [56]. Seizures may be present at

onset, and are reported to be often refractory to anti-seizure

medications. Neurological symptoms are noted on average

within 1–5 days of systemic symptom onset; progression to

death may occur in as little as 1 day after onset of clinically

apparent infection, in certain fulminant cases reported [44,

56]. A major challenge in the management of a patient with

suspected ANE is the initial ascertainment of the diagnosis.

Differential diagnoses to consider include metabolic or

toxic encephalopathy, infectious, vascular, or neoplastic

pathologies. Certain uncommon viral illnesses may present

similarly, including HHV-6, acute measles encephalitis,

West Nile, Japanese encephalitis, Murray Valley, and

Eastern equine encephalitis viruses, and rabies [53]. It is

equally important to note that ANE is a clinical syndrome

associated with, but not defining, an influenza infection

[56]. However, it remains one of the most severe influenza-

associated neurological complication.

Cerebrospinal fluid in ANE shows mild pleocytosis, but

often is of limited diagnostic value. MRI findings suggestive

of ANE include symmetric, diffusion-restricting lesions in

both thalami, rostral midbrain tegmentum, putamina, peri-

ventricular white matter and cerebellar hemispheres [56].

These area of abnormal MRI signals correspond to macro-

scopically noted hemorrhagic necrosis on autopsy. In limited

angiographic data, decreased flow without stenosis or

thrombosis has been noted in the arterial branches supplying

these areas, notably the thalamoperforating, thalamogenicu-

late and superior cerebellar arteries, and in the deep draining

venous system, notably the internal and great cerebral veins

[56]. Macroscopic pathological examination shows severe

edema and necrosis in the gray matter of the thalamic, teg-

mental and cerebellar dentate nucleus. Similar edema is

diffusely noted in the cerebral and cerebellar white matter.

Microscopic findings show expansion of perivascular space

Neurocrit Care (2013) 18:118–130 121

123

with a small number of extravasated leukocytes and otherwise

no signs of inflammatory infiltrates or vascular necrosis [56,

57, 64]. Therefore, ANE is not an encephalitis but an acute

encephalopathy associated with clear pathologic changes.

Early use of corticosteroids has been suggested to confer

improved survival and cognitive outcomes specifically for

ANE patients without brainstem lesions, likely through

modification of the overwhelming inflammatory response

responsible for blood–brain barrier disruption [69]. It is

unclear whether the absence of benefit from corticosteroids

in patients with brainstem lesions is related to an alternate

pathophysiology or the reflection of an already aggressive

disease course, as many of these patients are at risk for

sudden, neurogenic cardiopulmonary collapse [69]. Alter-

native immunosuppressive therapies such as Cyclosporine

have also been proposed [69].

Despite early steroid therapy, Okumura et al [69].

reported a mortality rate of approximately 30 % in a case

series of influenza-associated ANE, with another 33 % of

patients left with severe cognitive and motor impairment.

While the primary cause of mortality in patients with ANE

is, in most instances, from cardiorespiratory failure, brain

death has been reported in a number of case reports [54].

Acute Encephalopathy with Seizures and Late

Restricted Diffusion

AESD likely represents a syndrome described and known by

various similar titles, such as ‘‘acute encephalopathy with

febrile convulsive status epilepticus’’, ‘‘acute encephalopa-

thy with prolonged febrile seizures and late reduced

diffusion’’, or ‘‘encephalopathy with biphasic clinical

course’’ [57]. AESD is a predominantly pediatric diagnosis,

with a clear and disease-defining biphasic course. It typically

begins with febrile generalized tonic–clonic seizures and

post-ictal decreased level of consciousness over the first

24 h with subsequent normalization in neurological status. It

may be indistinguishable from other febrile convulsive sta-

tus epilepticus in this initial phase. Over 4–6 days following

onset of symptoms, clusters of secondarily generalized sei-

zures recur, with or without fever [86, 88]. Interictal

normalization in mental status only occurs in a minority of

patients at this stage. With resolution of seizures on days

4–18, patients may manifest abnormal neurological signs,

such as choreoathetosis, hand writhing and other stereo-

typical involuntary movements, aphasia, motor apraxia,

cognitive and behavioral abnormalities, or hemiparesis [57].

Investigations reveal normal CSF cell and protein contents.

Serum transaminases may be normal or mildly elevated. Both

hyperglycemia and hypoglycemia may be noted. Importantly,

in the presence of hypoglycemia and diffuse intravascular

coagulopathy, Reye’s syndrome or HSES must be considered

as differential diagnoses portending poorer outcomes. Unlike

in complex febrile seizures, serum interleukin-6 (IL-6) levels

are mild-to-moderately elevated [57]. While initially normal,

MRI performed after 2 days can show hyperintensity on T2-

weighted imaging or diffusion-restriction in the frontal or

fronto-parietal U-fibers and cortex. A ‘‘bright-tree’’ appear-

ance on DWI is characteristic, with frequent sparing of the

peri-Rolandic region [57, 83, 88]. Corresponding affected

cortices are noted to be hyperperfused on single photon-

emission computed tomography [57, 88]. Resolution begins

within one to 4 weeks, as clinically milder cases may show

radiological normalization and more severe cases progress to

atrophy and hypoperfusion of the cortical areas initially

affected [57].

Based on clinical symptoms and signs, Mizuguchi et al

[57, 94]. proposed a further subdivision of AESD into a

predominantly infantile variant with evidence of selective

frontal pathology and another affecting an entire hemi-

sphere. Yamanouchi and Mizuguchi described a pediatric

subset of patients with features of AESD meeting four

characteristics as AIEF [94]. The proposed diagnostic cri-

teria are: (1) acute encephalopathy of infancy or early

childhood following a viral illness; (2) symptoms and signs

of frontal lobe dysfunction; (3) radiological evidence of

selective frontal cortical edema and hyperperfusion followed

by atrophy and hypoperfusion; and (4) the absence of evi-

dence of alternate inflammatory or metabolic disorders [95].

Likewise, HHS may be considered a variant of AESD with

post-ictal hemiparesis, cognitive decline and seizure disor-

der with similar radiographic findings of acute cortical

edema and hyperperfusion, and subsequent atrophy [57].

While HHS is defined as a pediatric condition, Chen et al

[11]. reported a case bearing remarkable similarities in

clinical course, findings and outcomes in a 40-year-old man

with IAE secondary to novel H1N1 influenza A virus.

Outcomes associated with AESD range from normal or

mild cognitive impairment to severe mental retardation,

paralysis, or epilepsy. Mortality rate has been reported at

less than 5 % [57].

The Novel H1N1 Influenza Pandemic of 2009–2010

In April 2009, outbreak of a novel strain of influenza A

(H1N1) virus began in Mexico, followed by cases reported

in the USA and across the world. In a review by the

Writing Committee of the WHO Consultation on Clinical

Aspects of Pandemic (H1N1) 2009 Influenza, by May

2010, the novel H1N1 pandemic accounted for six million

reports cases, 270,000 hospitalizations, and over 12,000

deaths [62]. It is believed that the true incidence of novel

H1N1-related infections in the pediatric population is

underestimated, and likely better approximated at 33 %,

based on serological evidence [8, 62]. Clinically significant

illness in young adults occurred more frequently than with

122 Neurocrit Care (2013) 18:118–130

123

seasonal influenza, with a relative sparing of the population

over 60 years of age, postulated to be due to cross-immu-

nity conferred by the 1957 H1N1 epidemic [8]. Despite a

seemingly low case fatality rate of 0.048 % in the USA and

0.026 % in the UK, 90 % of reported deaths occurred in

individuals less 65 years old, representing a remarkable

contrast from seasonal influenza [56, 72, 96].

In July 2009, Evans et al. [62] published the first report

of H1N1-associated neurological complications, consisting

of four pediatric cases of seizures and encephalopathy with

onset within 5 days of proven systemic influenza illness.

Numerous case reports followed, indicating the novel

H1N1’s association with a wide range of neurological

complications. The Japanese Society of Intensive Care

Medicine and Respiratory Care Medicine’s national regis-

tries recorded that 23 % of children admitted to the Critical

Care Unit had various neurological symptoms [89]. Syn-

dromes reported in different world regions were largely

similar to prior influenza pandemics and seasonal epi-

demics in spectrum and severity: influenza-associated

encephalopathy, seizures, Guillain-Barre syndrome, and

rhabdomyolysis [8, 12, 41, 53, 62, 71, 72, 96]. A case of

ischemic stroke in a 9-month-old infant has also been

reported [30]. Of particular interest is an observed sudden

17-fold increase in pediatric narcolepsy in 2010, following

the pandemic. The etiology of this surge is unclear, but

postulated to be secondary to both genetic and environ-

mental factors [73]. Reye’s syndrome’s remarkable

absence in the literature pertaining to the 2009 H1N1

pandemic may be attributed to its well-recognized associ-

ation with acetylsalicylic acid. Meanwhile, atypical

presentations have been observed. For instance, Fugate

et al. [23] reported a case of acute hemorrhagic leukoen-

cephalitis in a 40-year-old, otherwise healthy man, after

prolonged cardiorespiratory support following H1N1

infection, resulting in severe disability.

First-line treatment options for novel H1N1 are neur-

aminidase inhibitors, most commonly oseltamivir [62]. As

oseltamivir is noted to have limited cerebrospinal fluid

penetration, it likely has limited activity for infections of

the central nervous system [80]. However, it reduces

duration of hospitalization, severity of systemic disease,

and consequent ICU admission or mortality [9]. As most

influenza-associated neurological complications are non-

fatal, but often co-occurring with severe cardiopulmonary

disease or mortality, treatment is recommended [62].

However, oseltamivir-resistant strains exist, frequently

through a neuraminidase-dependent mechanism. The

common point mutation of the viral neuraminidase gene

causing oseltamivir resistance does not simultaneously

confer cross-resistance to zanamivir, which may be used as

a second-line agent [91]. A fatal case of multidrug-resistant

H1N1 virus has also been reported during the 2009

pandemic, with marked increase in the 50 % inhibitory

concentration to oseltamivir, zanamivir, and the new

neuraminidase inhibitor peramivir, leaving the clinician

with few treatment options [91].

Influenza Vaccine-Associated Complications

Inflammatory peripheral and central demyelinating dis-

eases, such as Guillain-Barre syndrome (GBS) and acute

disseminated encephalomyelitis (ADEM), are well-recog-

nized complications of seasonal influenza vaccination,

occurring in both pediatric and adult populations [35, 43,

61]. Neurological complications of lesser severity have

also been reported. Severe vasculitic mononeuritis multi-

plex, Bell’s palsy, optic perineuritis, and giant cell arteritis

have been noted to occur in close temporal association with

influenza vaccine [19, 34, 74, 92].

Safety of seasonal influenza vaccine has also been

studied for various neurological and autoimmune diseases.

No increase in the risk of myasthenia gravis, multiple

sclerosis or systemic autoimmune disease exacerbations

was identified following influenza vaccination [5, 7, 50,

99]. Given the likelihood of poorer prognosis if affected by

respiratory complications of influenza, the vaccine likely

confers protection in these patients often subject to chronic

immunosuppressive therapies. Influenza vaccination has

also been correlated with decreased relative risks of

embolic stroke [65, 84].

Safety Data of the H1N1 Vaccine

Concerns regarding H1N1 vaccines emanated from the

1976–77 season data, when a surge in the incidence of GBS

led to premature cessation of the vaccination campaign in

the USA [18, 71, 78]. GBS affected an estimated rate of 7.2

per million vaccinated individuals, over the first 6 weeks

after receiving the A/NJ/1976 vaccine, versus a risk of 0.79

cases per million unvaccinated people, yielding an attrib-

utable risk of 8.8 per million recipients [18]. Subsequent

in vivo studies have demonstrated the A/NJ/1976 vaccine’s

ability to induce antibodies to epitopes mimicking the

monosialoganglioside GM1, well-known to be involved in

some cases of GBS. However, numerous vaccines used in

past campaigns had similar laboratory behavior, yet dif-

ferent clinical and epidemiological responses [17, 18]. The

etiology of the observed rise in GBS following the 1976

H1N1 vaccination campaign remains unclear. [18].

Over the past decades, numerous large-scale databases

have been established for surveillance of neurological

adverse effects related to the vaccine. These include the

American Vaccine Adverse Event Reporting System and

the Vaccine Surveillance Database, a population-based

computerized encounter code database. They allow rapid

Neurocrit Care (2013) 18:118–130 123

123

analyses of the number of individuals receiving vaccines

and subsequent complications [10, 15, 56, 78]. However,

many adverse effects are reported weeks after vaccination,

which poses a challenge in establishing a certain causal

link between two clinical events [10, 18, 42, 52, 61].

Moreover, most entries are preliminary diagnoses, inevi-

tably including some erroneous data [55]. Para- and post-

infectious GBS have also been increasingly reported as

infectious complications of influenza A virus, further

complicating the vaccine’s risk–benefit analysis [10, 52].

The 2009 H1N1 vaccination campaign reported an attrib-

utable risk of 0.8 cases per million individuals for

developing GBS, similar to that of seasonal influenza

vaccines, and ten-fold less than that recorded in 1976, with

an overall risk profile identical to seasonal influenza vac-

cines [35, 75, 78]. No safety concerns were identified in

vaccinated pregnant patients after the 2009 pandemic [58].

Pathophysiology of Influenza-Associated Complications

Direct tissue invasion has long been the suspected patho-

physiology behind influenza virus’s neurological

complications, and viral genomes have been demonstrated

on sampling of cerebrospinal fluid (CSF), in a small

number of patients. However, subsequent studies failed to

replicate similar results [24, 40, 45]. Shieh et al. reviewed

pathology results of 100 fatal cases of the 2009 H1N1

pandemic, and did not isolate the influenza A virus from

any post-mortem cerebral tissues [82]. This observation is

in contrast to a more frequently observed myotropism in

influenza-associated myositis (IAM), a peripheral nervous

system complication of influenza disease. As viral particles

have more often been identified on tissue sampling, it is

speculated that IAM can indeed be a consequence of direct

infection, unlike IAE [1, 12].

Given associated manifestations often associated with

cytokine dysregulation, including hemophagocytosis in

50 % of the subjects, several authors suggested hypercy-

tokinemia to be a most likely pathophysiological etiology

of clinically observed H1N1-associated encephalopathy

[82, 93].

Pathophysiology of IAE

Increasing evidence suggest hypercytokinemia with sec-

ondary blood–brain barrier disruption and neuronal

apoptosis to be responsible for the observed diffuse cere-

bral dysfunction and pathologies [36, 46, 51, 60, 66].

Furthermore, in one autopsy series, hemophagocytosis was

seen on autopsy of over 50 % of patients with influenza-

related deaths, with or without encephalopathy. As hemo-

phagocytosis is believed to be a cytokine-driven response,

the observation supports the pathophysiological role of a

possible overwhelming and dysregulated inflammatory

state [14, 93]. Oxidative stress and free radical gases also

appear to participate in the pathogenesis of IAE [48, 49].

Fluctuations in inflammatory markers are therefore

important in elucidating IAE’s pathogenesis and studied as

potentially clinically useful markers of disease severity.

Candidate serum markers include interleukin-6 (IL-6),

tumor necrosis factor alpha (TNF-a), soluble TNF recep-

tor-1, interleukin-8 (IL-8), interleukin-1b (IL-1b),

interleukin-10 (IL-10), CD40-ligand (CD40L), matrix

metalloproteinase-9 (MMP-9), and toll-like receptor 3 [29,

31, 36–38, 46, 66] (Table 2). Cerebrospinal fluid nitrite and

nitrate (NOx), reactive oxygen metabolites, and cyto-

chrome c levels have also been considered [31, 32, 48, 49].

Interleukin-6 (IL-6) is known to confer neuroprotection

in physiological states, but serum IL-6 has been noted to be

disproportionately elevated in IAE, correlating with unfa-

vorable outcomes, including severe disability and death [2,

31, 61]. A surge in serum IL-6 can be noted over 12 h prior

to the onset of encephalopathy. The pathophysiological

significance of this rise is unclear. It was proposed that this

observation may be interpreted as evidence of immune

dysregulation in IAE, or that IL-6 overexpression subse-

quently induces or contributes to NMDA-mediated

neurotoxicity, in pathological states [2]. Independently of

its pathophysiologic role, IL-6 level seemed to correlate

reliably with severity of disease.

Elevated serum TNF-a has similarly been demonstrated

[27, 49]. While TNF-a is known to alter blood–brain bar-

rier permeability, it may equally play a role in NMDA-

mediated neurotoxicity [2, 36]. Serum TNF-a levels over

10 pg/mL at presentation, and especially if over 50 pg/mL,

were reported to be associated with poor prognosis [32].

Serum soluble TNF receptor binds TNF-a, and its upreg-

ulation has been invoked as the most sensitive measure in

reflection of TNF-a elevation [36]. Other proinflammatory

cytokines, such as IL-1b and IL-8, were observed to be

elevated, although their significance in IAE remains

unclear [46]. Elevated serum CD40L is similarly noted in

patients with poor outcome in IAE, suggesting platelet

Table 2 Markers of poor outcome on day 1 of acute encephalopathy.

Adapted from Hosoya et al., 2006

Serum marker Upper threshold Sensitivity (%) Specificity (%)

Cytochrome c 45 ng/mL 93 100

AST 58 IU/dL 82 83

sTNF-R1 2,000 pg/mL 79 89

IL-6 60 pg/mL 77 100

TNF-a 15 pg/mL 60 100

AST aspartate aminotransferase, sTNF-R1 soluble tumor necrosis

factor receptor type 1, IL-6 interleukin-6, TNF-a tumor necrosis factor

alpha

124 Neurocrit Care (2013) 18:118–130

123

activation in the early inflammatory response [32]. Mean-

while, overproduction of the anti-inflammatory cytokine

IL-10 is also noted in IAE. Its role as part of the counter-

regulatory response has been correlated with mortality in

sepsis, through possible dysregulation and consequent

immunological anergy. A similar mechanism may be at

play in IAE [46].

Serum MMP-9 and tissue inhibitors of metalloprotein-

ases (TIMP), its regulatory counterparts, play key roles in

mediating blood–brain barrier function, and are known to

be involved in post-thrombolytic cerebral hemorrhage and

post-influenza embolic strokes [37, 60]. Alterations in their

levels are therefore no surprises in IAE, consistent with the

frequent observation of focal or diffuse cerebral edema.

Ichiyama et al. reported IAE patients’ serum MMP-9 levels

and MMP-9/TIMP-1 ratios to be in excess of that observed

in other viral infections such as Ebstein-Barr virus (EBV)

and respiratory syncitial virus [37].

Serum cytochrome c also show a rise in the early phase

of disease and may be the best marker of poor outcome in

IAE [31, 32, 66]. It is estimated to have a sensitivity and

specificity estimated at 93 and 100 %, respectively, for

acute encephalopathy in children [31]. Different cutoffs

were reported at 1000 pg/mL or 45 ng/mL [31, 32]. CSF

cytochrome c has been studied as a marker of apoptosis in

patients with IAE: increase in neuronal cytoplasmic levels

activates caspase-mediated neuronal apoptosis [32]. While

high serum cytochrome c on admission is almost uniformly

associated with fatal outcome, progressive rise in the level

of CSF cytochrome c is closely correlated with high mor-

bidity. As cytochrome c is not transported across the

blood–brain barrier, its rise in CSF is suggestive of

increased intraneuronal expression: it likely plays a direct

role in initiating apoptosis in severe IAE. Its levels corre-

late closely with subsequent degrees of cerebral atrophy

[32, 66].

Role of Host Immunity

Hypercytokinemia implies that the infected host plays a

role in the pathogenesis of influenza-associated neurolog-

ical complications. This theory is supported by two

observations: ethnic predisposition for influenza-associated

neurological complications, and known familial cases of

recurrent influenza-associated ANE [27].

Japan and Taiwan have reported a disproportionate

number of influenza-associated complications over the past

decade. The epidemiological impact of these conditions

have led to a well-established surveillance system in Japan.

The etiology of this preponderance has been questioned,

but remains unclear. However, influenza-associated neu-

rological complications are not exclusive to East Asian

populations, and both sporadic and pandemic cases with

identical natural history have been diagnosed in Caucasian

patients, and reported in the medical literature from various

continents [3, 70, 77].

Genetic predisposition to the development of ANE has

been studied following recurrent presentations, affecting

both mother and child. Gika et al [27]. identified mutations

in Ran-binding protein 2 (RANBP2), a nuclear pore protein

component on chromosome 2q12.1-q13, as susceptibility

alleles for recurrent or familial ANE, termed ANE1. Its

inheritance follows an autosomal dominant pattern with a

penetrance of 40 %, and its clinical behavior differs from

the sporadic variant. Many cases follow a fulminant course,

and it is believed that ANE1 favors involvement of the

claustrum, limbic system, and temporal lobes. The authors

underline that the RANBP2 protein also localizes to

microchondria and microtubules, hence further data is

required to define ANE1 as a nuclear pore disease, despite

its implications in the pathophysiology of infection as well

[27]. Mitochondrial carnitine palmitoyltransferase II (CPT

II) is suspected to be one of such proteins, as certain

compound variants are considered phenotypically normal,

but show significantly decreased metabolic activity during

high fever [97]. Consequent impairments in mitochondrial

fuel utilization in susceptible individuals may contribute to

the development of cerebral edema in IAE [49].

Managing Influenza-Associated Neurological

Complications

As per general clinical management principles, ensuring

patient stability should be the first priority. Thereon,

ascertainment of the diagnosis is key in appropriately

managing influenza-associated neurological complications

(IANC). (Figures 1, 2) Key elements on history are acute

alterations in consciousness following recent influenza

disease, exposure or vaccination, with a clear timeline of

symptom progression, and a detailed review of systems.

Physical examination should be focused on determining the

severity of the alteration in mental status and signs of focal

neurological disease, and broadened to identify evidence of

systemic complications, including signs of thrombocyto-

penia and coagulopathy.

Initial laboratory investigations should include complete

blood count, electrolyte levels, coagulation profile, renal

and hepatic function tests, liver enzyme levels, creatinine

phosphokinase level, bacterial blood cultures, nasopha-

ryngeal swab and lumbar puncture. CSF chemistry profile,

cell count, and microbiological studies including viral PCR

for influenza, adenovirus and enteroviruses, bacterial, and

fungal cultures. Rarer viral infections should be ruled out

based on the patient’s history and exposure. A brain

magnetic resonance study is recommended, including at

Neurocrit Care (2013) 18:118–130 125

123

least basic T1- and T2-weighted sequences and diffusion-

weighted images. A screening brain CT scan should be

performed when the MRI is not readily available. Elec-

troencephalograms findings in IANC are generally non-

specific and of low diagnostic yield, and would only be

recommended in management of suspected non-convulsive

seizures. Following the aforementioned diagnostic inves-

tigations, if suspicion of IANC is high, serum IL-6 and

cytochrome c levels are recommended where available,

mostly for prognostication purposes.

In managing influenza-associated complications of the

central nervous system (CNS), it is important to recognize

that mortality is most frequently a consequence of systemic

illness, while CNS disease portends the highest risk of

disability on survival. Symptomatic treatment of CNS

complications, management of associated cardiopulmo-

nary, metabolic and hematological complications, and

targeted anti-inflammatory therapies and anti-viral thera-

pies are recommended. Close monitoring for expected

complications through serial laboratory studies and a low

threshold for repeat radiological investigations are equally

warranted.

Targeted anti-inflammatory therapies are most likely to

impact or alter the clinical course. Initiation of corticoste-

roid therapy within 24 h of admission has been

demonstrated to confer survival benefit in patients with

ANE and without brainstem disease and has been recom-

mended by the Research Organization for Influenza

Encephalopathy Researchers of Japan since 1999 [69].

Okuruma et al. have demonstrated no significant difference

in outcome between the use of pulsed methylprednisolone

at a dose of 30 mg/kg/day for 3 days or intravenous

dexamethasone at a dose of 0.6 mg/kg/day in four divided

dose over 2–4 days. Despite a limited number of patient

studied, similar outcome was also noted with intravenous

immunoglobulin at a dose of 1–2 mg/kg [68] plasma

exchange directed toward reduction of serum IL-6 levels

have been attempted, for a total of two or three treatments

administered every other day, with reported good outcomes

[47]. Supportive care for CNS complications should also

include intracranial pressure monitoring and management,

where osmotic agents are usually sufficient. Mild hypo-

thermia with target core temperature of 34 �C for 3 days

with subsequent rewarming at a rate of 1 �C per day has

been proposed [98].

Conclusion

Influenza-associated neurological complications have

become increasingly recognized over the past century.

While the incidence remains low in most parts of the world

and is mostly accounted for by the pediatric population,

these clinical entities are not restricted by ethnicity, geo-

graphical area, or patient age, especially during pandemics.

Defining recurrent syndromes instead of individual

Fig. 1 Initial management and investigations in suspected influenza-

associated acute encephalopathy. It is most important to recognize

that a high index of suspicion is primal in ascertaining the diagnosis.

MRI—magnetic resonance imaging; CSF—cerebrospinal fluid;

EEG—electroencephalogram; IAE—influenza-associated encepha-

lopathy; CBC—complete blood count; PCR—polymerase chain

reaction; HSV—herpes simplex virus; VZV—varicella zoster virus;

EBV—Ebstein-Barr virus; HHV-6—human herpesvirus-6

126 Neurocrit Care (2013) 18:118–130

123

neurological symptoms provides the benefit of timely

diagnosis of a potentially aggressive, fatal or disabling

disease, especially when early treatment may decrease

morbidity and mortality. Where clinical presentation dif-

fers from recognized disease patterns, the physician should

seek authorization with substitute decision makers for

biopsy, or autopsy in fatal cases, to ascertain clinical,

microbial, and pathological correlates. Further data is

necessary to expand our understanding and solidify the

international experience with influenza-associated neuro-

logical complications, and may even open the gateway to

better understanding of acute encephalopathies secondary

to dysregulated systemic inflammatory response, of both

infectious and non-infectious etiologies.

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