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Review

Infectious encephalitis: mimics


and chameleons
Michel Toledano,1 Nicholas W S Davies2

1
Department of Neurology, Abstract unusual presentations (chameleons) of
Mayo Clinic, Rochester,
‘Query encephalitis’ is a common neurological infectious encephalitis.
Minnesota, USA
2
Department of Neurology, consultation in hospitalised patients.
Chelsea and Westminster Identifying the syndrome is only part of the
Hospital, London, UK puzzle. Although historically encephalitis
Infectious encephalitis
has been almost synonymous with infection,
Viruses cause most cases of infectious
Correspondence to encephalitis, but bacteria (especially intra-
Dr Nicholas W S Davies, Chelsea we increasingly recognise parainfectious or
& Westminster Hospital, NHS postinfectious as well as other immune-mediated
cellular organisms such as Rickettsiae),
Trust, London SW10 9NH, UK; ​ causes. We must also distinguish encephalitis
fungi and parasites are also important.
nicholas.​davies@​chelwest.​
from other causes of encephalopathy, including
When evaluating a patient with suspected
nhs.​uk
systemic infection, metabolic derangements,
central nervous system (CNS) infection, it is
Accepted 17 December 2018 toxins, inherited metabolic disorders, hypoxia,
essential to determine why this individual,
trauma and vasculopathies. Here, we review
in this place, has developed this disease at
the most important differential diagnoses
this time2 (box 1). Infectious encephalitis
(mimics) of patients presenting with an
can be sporadic, as with herpes simplex
encephalitic syndrome and highlight some
virus, or can be epidemic, as with many
unusual presentations (chameleons) of infectious
arthropod-borne viruses.1 Age, geography,
encephalitis.
season, immunocompetence and psycho-
social factors define the range of poten-
tial pathogens. All patients with suspected
encephalitis should be tested for HIV, which
Introduction not only predisposes to CNS infection but
‘Query encephalitis’ is a common reason itself can cause meningoencephalitis during
for neurological consultation in hospi- primary infection.3
talised patients. Clinically, infectious The pattern of neurological involve-
encephalitis is characterised by acute ment also provides important clues.
onset of fever, altered mental status, Herpes simplex virus type 1, for example,
focal neurological deficits and gener- preferentially affects the mesial temporal
alised or focal seizures.1 It can be diffi- lobes. Deep grey matter involvement
cult to identify a specific cause, which more commonly results from some flavi-
remains undetermined in up to half of virus infections, such as with Japanese
cases.1 Historically, encephalitis has been encephalitis and West Nile virus. Brain-
almost synonymous with direct infection, stem encephalitis, characterised by cranial
but we now recognise parainfectious or neuropathies, dysautonomia and myoc-
postinfectious causes, as well as non-in- lonus, results from infection with certain
fectious causes. We also have to distin- arthropod-borne viruses, enteroviruses,
guish encephalitis from other causes of listeriosis, brucellosis and tuberculosis.
encephalopathy, including systemic infec- Encephalomyelitis presenting with acute
tion, metabolic derangements, toxins, flaccid paralysis can occur with entero-
inherited metabolic disorders, hypoxia, viruses such as poliovirus and EV-71, as
© Author(s) (or their
trauma, epilepsy, thromboembolic stroke well as flaviviruses.
employer(s)) 2019. No and other vasculopathies. It is essential to Any patient with suspected CNS infec-
commercial re-use. See rights narrow the differential diagnosis, since tion should have a lumbar puncture,
and permissions. Published
by BMJ.
starting treatment promptly can improve unless contraindicated. The cerebral
outcome and avoid unnecessary testing spinal fluid (CSF) profile can confirm
To cite: Toledano M, and treatments. Here we review the most the presence of inflammation and help
Davies NWS. Pract Neurol Epub
ahead of print: [please include important differential diagnoses (mimics) to distinguish between different infec-
Day Month Year]. doi:10.1136/ of patients presenting with an enceph- tious causes. A lymphocytic pleocytosis
practneurol-2018-002114 alitic syndrome and highlight some is typical of viral encephalitis, although

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 1


Review

Box 1  Important questions to ask in patients Box 2  Herpes simplex encephalitis mimics
presenting with encephalitis, modified from Solomon
et al1 Infectious
►► Varicella zoster virus.
►► Current or recent febrile or influenza-like illness. ►► Human herpes virus 6 (in the immunocompromised).
►► Rash. ►► Enterovirus.
►► Sick contacts. ►► West Nile virus.
►► Travel history. ►► Neurosyphilis.
►► Contact with animals/animal bites. ►► Tuberculosis.
►► Exposure to mosquito or tick bites.
Non-infectious
►► Contact with fresh water.
►► Glioma/lymphoma/metastatic malignancy.
►► Consumption of unpasteurised dairy products.
►► Vasculitis.
►► HIV risk factors.
►► Autoimmune limbic encephalitis.
►► Immunocompetence status.
►► Unilateral posterior reversible encephalopathy
►► Altered behaviour or cognition and personality change.
syndrome.
►► Recent vaccination.

polymorphonuclear cells may predominate early in the overlap. For example, autoimmune encephalitis can be
disease. Certain bacterial infections such as listeriosis, triggered by infection but also occurs with malignancy,
brucellosis and tuberculosis also show a lymphocytic and although acute disseminated encephalomyelitis
predominance but these are usually associated with (ADEM) is generally considered to be post-infectious,
higher protein, a low CSF/plasma glucose ratio and an there is not always an identified definitive infectious
elevated CSF lactate.1 The CSF profile of immune-me- trigger.
diated and inflammatory encephalitis also mimics
that of viral encephalitis. An acellular CSF is rare in
infectious encephalitis but can be found early on and Parainfectious and postinfectious encephalopathies
is more common in immunosuppressed patients. CSF ADEM and acute haemorrhagic encephalomyelitis
eosinophilia occurs in coccidioidomycosis and certain ADEM is usually a monophasic, inflammatory demy-
parasitic infections of the CNS. elinating disorder of the CNS. It is more common in
Herpes simplex virus encephalitis is the most children but can occur in all ages.5 It is characterised
common cause of sporadic encephalitis. Most cases by the abrupt onset of neurological symptoms days to
are caused by herpes simplex virus type 1, but around weeks following infection or immunisation.5 Although
10% are caused by type 2.1 The most distinctive there is not always a clearly identified precipitant, most
presenting features are fever, disorientation, aphasia cases have a non-specific flu-like illness preceding the
and behavioural disturbances, and up to a third of onset of neurological symptoms.
patients have convulsive seizures.1 Without a clear history of antecedent infection or
Neuroimaging can be negative acutely, but by 48 vaccination, it can be difficult to distinguish ADEM
hours, over 90% of patients have MR brain imaging from infectious encephalitis on purely syndromic
abnormalities and sensitivity approaches 100% at 3–10 grounds. ADEM is polysymptomatic and multifocal in
days.4 T2-weighted and fluid-attenuated inversion presentation with symptoms and signs evolving over
recovery (FLAIR) images show markedly asymmetric hours to days. Encephalopathy, optic neuritis and
but usually bilateral abnormalities in the limbic system, long tract signs are common. Most patients develop
medial temporal lobes, insular cortices and inferolateral depressed level of consciousness ranging from lethargy
frontal lobes. Restricted diffusion on diffusion-weighted to coma. CSF findings resemble those of viral enceph-
imaging (DWI) may be especially sensitive for early alitis.5 Neuroimaging usually shows bilateral and
changes.1 Although fairly characteristic, neuroimaging asymmetric areas of increased signal in the subcortical
is not 100% specific, and clinicians should be aware of white matter, brainstem, cerebellum, periventricular
important imaging mimics (box 2) (figure 1). white matter and deep grey matter.5 The lesions vary in
CSF herpes simplex virus PCR is both highly sensi- number and size and may enhance with gadolinium.5
tive and specific and usually establishes the diagnosis Acute haemorrhagic encephalomyelitis is considered
but can be negative if obtained acutely.1 Repeated CSF a hyperacute and more fulminant variant of ADEM.
examination 24–72 hours later is usually diagnostic. Like ADEM, it is commonly triggered by infection
or vaccination. Brain imaging usually shows haem-
Neurological conditions that mimic orrhagic lesions in the white matter.6 CSF examina-
infectious encephalitis tion often shows polymorphonuclear cells as well as
We divide the mimics into parainfectious/postinfec- numerous red blood cells (in the absence of a trau-
tious and non-infectious causes, although there is some matic tap).

2 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


Review

Figure 1  A young man presented with subacute cognitive decline, mood disorder and unwitnessed generalised tonic–clonic
seizure. CSF examination showed a pleocytosis. The initial clinical diagnosis was herpes simplex virus encephalitis. Serological tests
confirmed neurosyphilis. Brain imaging shows hyperintensity in left mesial temporal lobe on coronal T2 FLAIR (A) and restricted
diffusion on axial diffusion-weighted imaging (B). FLAIR, fluid-attenuated inversion recovery.

Haemophagocytic lymphohistiocytosis syndrome support the diagnosis but may be available only at
Haemophagocytic lymphohistiocytosis is a syndrome specialty laboratories.7
of excessive inflammation due to abnormal immune
activation, probably caused by a lack of normal down- Influenza-related encephalopathy/encephalitis and acute necrotising
regulation of activated macrophages and lympho- encephalopathy
cytes.7 It can be either familial or sporadic. Systemic Influenza-related encephalitis/encephalopathy is a
infection, rheumatological conditions or malignancy rapidly progressive encephalopathy that develops days
are common triggers in both familial and sporadic after the onset of the first symptoms of influenza.8 Its
cases, and it is commonly associated with immunode- pathophysiology remains unclear, and neither direct
ficiency syndromes. Although it usually affects infants, viral infection of the CNS nor a postinfectious inflam-
it can develop in children and adults of all ages. Clin- matory process appears to cause the condition. CSF
ically, it presents as a febrile illness with multiorgan studies are often normal, although a small number of
dysfunction. Up to a third of patients have neurolog- cases have elevated CSF protein or mild pleocytosis.
ical involvement, including seizures, encephalopathy Similarly, there is only rarely any direct evidence of
and focal deficits.7 viral invasion on CSF and histopathology. The disease
In patients where neurological findings dominate tends to affect children younger than 5 years of age,
the clinical picture, infectious encephalitis is likely. In but there have been isolated cases in adults.8 9
the vast majority of cases, however, neurological symp- Several neuroimaging abnormalities may occur,
toms are preceded by weeks of systemic symptoms. ranging from scattered white matter abnormalities
Cytopenias develop in up to 80% of patients. Serum to diffuse brain oedema, but these changes are not
ferritin is commonly elevated up to and above 10 000 specific. A more distinct imaging pattern is reversible
µg/L. Liver function abnormalities and associated focal swelling and restricted diffusion in the corpus
hypertriglyceridaemia and coagulation abnormalities callosum. This pattern can occur with influenza and
are very common. MR brain scan abnormalities are other infections, as well as in certain metabolic disor-
non-specific and include parameningeal infiltration, ders. It is usually associated with a benign course. This
subdural collections and necrotic changes. Findings clinicoradiological syndrome is termed ‘mild enceph-
consistent with posterior reversible encephalopathy alitis/encephalopathy with reversible splenial lesion’
syndrome are also very common. The CSF protein is (figure 2).10 Another pattern associated with influenza
frequently elevated, and half of cases have a lympho- and other infections manifests as bilateral necrosis of
cytic pleocytosis. Histopathology from bone marrow, the thalami and other regions, including the brainstem,
liver, spleen or lymph nodes may show haemophago- cerebellum and cerebral white matter.8 This syndrome
cytosis. Elevated soluble CD25 (soluble interluekin-2 is termed ‘acute necrotising encephalopathy’ and has
receptor alpha) and reduced natural killer cell function a more severe clinical course and worse prognosis.

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 3


Review

Figure 2  A patient with varicella zoster virus meningoencephalitis presenting with fever, headache and mild encephalopathy, which
resolved with treatment. Brain imaging shows T2 fluid-attenuated inverse recovery hyperintensity in the splenium of the corpus
callosum (A) with associated restriction on corresponding diffusion-weighted imaging (B) and apparent diffusion coefficient MAP (C).
This clinicoradiographical picture has been named mild encephalitis/encephalopathy with reversible splenial lesion.

Familial and recurrent cases of acute necrotising Non-infectious encephalitis


encephalopathy following infection have been linked Autoimmune encephalitis associated with paraneoplastic or neuronal
surface antibodies
to mutations in Ran-binding protein 2.
The term autoimmune encephalitis describes a hetero-
geneous group of neurological disorders associated
Cerebral malaria with antineuronal autoantibodies.12 These can be
Cerebral malaria is a clinical syndrome defined as an subdivided into two major groups based on the loca-
otherwise unexplained encephalopathy in patients tion of the target antigen. The first includes the classic
with malaria parasitaemia. It is almost always asso- paraneoplastic disorders, which are associated with
ciated with Plasmodium falciparum infection. Risk antibodies targeting intracellular antigens (table 1).
factors include young age, pregnancy, HIV seroposi- These antibodies are strongly associated with under-
tivity and splenectomy.11 In adults, cerebral malaria is lying malignancy but are not pathogenic. The second
more common in non-immune individuals than those group is associated with antibodies targeting neuronal
living in endemic areas.11 Cerebral malaria should be surface antigens (table 2). These antibodies are likely
suspected in travellers returning from endemic regions pathogenic and, importantly, patients in this group
who present with unexplained fever, even if they have respond to immunotherapy. Cancer associations are
been taking antimalarial prophylaxis. variable but still relevant, as is the case between ovarian
Clinically, it presents with a prodrome of irregular teratomas and anti-N-methyl-D-aspartate receptor
fevers, malaise, abdominal pain, headache, anorexia, (NMDAR) encephalitis.13 A growing body of litera-
vomiting followed by encephalopathy, seizures and ture suggests that autoimmune encephalitis can occur
coma. In adults, neurological symptoms develop 7 as a parainfectious or postinfectious phenomena, best
days after symptom onset and rapidly evolve to coma. described in cases of anti-NMDAR following HSV
There are often signs of brainstem dysfunction. Retinal encephalitis.13
changes are very common in children and include The clinical spectrum of autoimmune encepha-
macular and extramacular whitening, as well as orange litis is highly variable. There are some well-described
or white discolouration of blood vessels representing syndromes such as anti-NMDAR encephalitis and
areas of parasite sequestration.11 Retinal haemorrhages the limbic encephalitis associated with antibodies
are also very common in children and occur in 15% of to leucine-rich-glioma-inactivated-1, a component
adults.11 CSF is usually normal or near normal. Associ- of the voltage-gated potassium channel complex.
ated haematological and metabolic abnormalities such Note, however, that many patients with autoim-
as hypoglycaemia, anaemia, thrombocytopenia and mune encephalitis do not present with a well-defined
acidosis are common. The diagnosis is made by exam- syndrome.13 The clinical spectrum of phenotypes asso-
ining thick and thin blood films, which may be nega- ciated with known antibodies continues to expand,
tive initially especially in those who have been taking and new antibodies are discovered. In addition, we
antimalarial prophylaxis. increasingly recognise that there are well-described

4 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


Review

Table 1  Antibodies to intracellular antigens


Frequency of Response to
Antibody Oncological association tumour immunotherapy Neurological manifestations
ANNA-1 Small-cell carcinoma. >90% Poor Limbic, cortical encephalitis.
(anti-Hu) Autonomic neuropathies, sensory neuronopathy and other
peripheral neuropathies.
ANNA2 Small-cell carcinoma, breast >60% Poor Brainstem encephalitis (opsoclonus–myoclonus,
(anti-Ri) adenocarcinoma and bladder laryngospasm, trismus and cranial neuropathy) and
cancer. cerebellar degeneration.
ANNA3 Small-cell carcinoma. >60% Poor Limbic and brainstem encephalitis, sensory and sensorimotor
neuropathies and myelopathy.
PCA2 Small-cell carcinoma. >90% Poor Brainstem or limbic encephalitis and cerebellar
degeneration.
Ma1, Ma2 Testicular (Ma2); breast, colon >90% Moderate Ma2 Limbic encephalitis, diencephalitis, brainstem
and testicular (Ma1). encephalitis; Ma1 and Ma2 brainstem encephalitis and
cerebellar degeneration.
CRMP-5 Small-cell carcinoma and >75% Poor Encephalitis.
thymoma. Optic neuritis and retinitis, myelopathy, neuropathy and
Lambert–Eaton myasthenic syndrome.
Amphiphysin Small-cell carcinoma and breast >90% Poor Limbic encephalitis.
adenocarcinoma. Myelopathy, stiff-man syndrome and cerebellar
degeneration.
GAD65 Thymoma; neuroendocrine <10% Moderate Stiff-person syndrome, stiff-person phenomena, brainstem
tumours, breast or colon encephalitis and cerebellar degeneration.
adenocarcinoma.
GFAP None described to date. Good Meningoencephalomyelitis, headache, papillitis and
cerebellar ataxia.
ANNA, antineuronal nuclear antibody; CRMP-5, collapsin response mediator protein-5; GAD65, glutamic acid decarboxylase 65; GFAP, glial fibrillar acidic
protein; PCA, Purkinje cell cytoplasmic antibody.

clinical phenotypes in patients in whom antibodies transient elevations in oligoclonal bands or IgG index
have not yet been identified.11 In general, clinicians but it can also be normal.
should suspect autoimmune encephalitis in patients Detecting a known autoantibody helps to establish
presenting with subacute progressive encephalopathy the diagnosis and determines the need to screen for
and prominent new-onset psychiatric symptoms.13 underlying malignancy. Conversely, failure to detect
New-onset seizures and cryptogenic status epilepticus a known antibody does not rule out autoimmune
can be part of the initial presentation but can also be encephalitis.
the sole presenting symptom.12 Abnormal movements,
including orolingual and limb dyskinesias, dystonia, Bickerstaff’s encephalitis
myoclonus and hyperekplexia occur more frequently Bickerstaff ’s brainstem encephalitis is character-
in autoimmune encephalitis than in infectious enceph- ised by subacute onset of progressive impairment of
alitis. Although autoimmune encephalitis can be consciousness, ataxia and bilateral, relatively symmet-
preceded by a viral prodrome including fevers, fever is rical ophthalmoparesis.15 Bickerstaff ’s encephalitis
not a predominant feature. usually follows an infectious prodrome, has a mono-
MR scan of brain can be normal or show non-spe- phasic course and has a good prognosis. Additional
cific abnormalities; however, it may show findings clinical features include bilateral facial palsies, bulbar
suggesting limbic encephalitis, namely increased signal palsy, hyper-reflexia and pupillary abnormalities.
on T2-weighted FLAIR imaging of the mesial temporal MR scan of brain is usually normal, but a quarter of
lobes.13 In autoimmune limbic encephalitis, there is patients have brainstem abnormalities on T2-weighted
preferential involvement of the amygdala and hippo- and FLAIR imaging. Most patients have an elevated
campus, and bilateral involvement is more symmetrical CSF protein, and half of patients have a mild lympho-
than in herpes simplex virus encephalitis. Restricted cytic pleocytosis.13 15 Finding anti-GQ1b antibodies in
diffusion on DWI and haemorrhagic changes also the serum supports the diagnosis, but this test is nega-
suggest herpes simplex virus encephalitis. EEG can tive in up to 32% of patients.15
show generalised slowing or may identify subclinical The absence of fever at the onset of neurolog-
seizures or non-convulsive status epilepticus. Finding ical symptoms and the relative symmetry of findings
extreme delta brush pattern on EEG strongly suggests usually help distinguish Bickerstaff ’s encephalitis
anti-NMDAR encephalitis.14 CSF can show mild pleo- from infectious rhombencephalitis. Nonetheless, it is
cytosis (usually fewer than 100 cells) sometimes with important to rule out infectious causes.

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 5


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Table 2  Antibodies targetting neuronal cell surface and synaptic proteins


Frequency of Response to
Antibody Oncological association tumour immunotherapy Neurological manifestations
VGKC complex Thymoma, small-cell lung <10% Good Limbic encephalitis, hyponatremia and
LGI1 cancer. faciobrachial dystonic seizures.
CASPR2 Thymoma 40% Good Isaacs syndrome, Morvan’s syndrome and
limbic encephalitis.
NMDAR Ovarian teratomas, Varies with age, Good Psychiatric disturbances, dyskinesias,
testicular germinoma and sex, and ethnicity catatonia, central hypoventilation and
neuroblastoma. autonomic instability, and opsoclonus–
myoclonus.
AMPAR Thymic tumours, lung 70% Good Limbic encephalitis and nystagmus.
carcinoma and breast
adenocarcinoma.
GABA-A receptor Thymoma, small-cell lung 40% Good Status epilepticus, epilepsia partialis
cancer and rectal cancer. continua, psychosis, behavioural
disturbances, orolingual dyskinesias and
chorea.
GABA-B receptor Small-cell lung carcinoma 70% Good Limbic encephalitis and orolingual
and other neuroendocrine dyskinesias.
neoplasia.
mGluR5 receptor Hodgkin’s lymphoma. >90% Good Cerebellar ataxia and limbic encephalitis
(Ophelia syndrome).
GlyR Thymoma, breast cancer and <10% of Moderate Progressive encephalomyelitis with rigidity
Hodgkin’s lymphoma. published cases and myoclonus, oculomotor disturbances,
dysautonomia, hyperekplexia and
respiratory failure.
DPPX None described to date. Moderate Encephalitis, sleep disturbances, myoclonus,
hyperekplexia, dysautonomia and
gastrointestinal dysmotility.
IgLON5 None described to date. Poor Non-REM parasomnias, REM sleep
behaviour disorder, apnoea, stridor and
cognitive decline.
AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Caspr2, contactin-associated protein-like 2; DPPX, dipeptidyl-peptidase-
like protein-6; GABA-A, γ-aminobutyric acid--A; GABA-B, γ-aminobutyric acid-B; GlyR, glycine receptor; LGI1, leucine rich glioma inactivated protein
1; mGluR5, metabotropic glutamate receptor 5.NMDAR, N-methyl-D-aspartate receptor; REM, rapid eye movement; VGKC, voltage gated potassium
channel;

A similar clinical picture can occur with chronic conditions can also rarely cause secondary CNS vascu-
lymphocytic inflammation with pontine perivascular litis; these include systemic lupus erythematosus,
enhancement responsive to steroids (CLIPPERS), a Sjögren’s syndrome, cryoglobulinaemia and rheuma-
recently described inflammatory disorder affecting the toid arthritis.17 Although most patients with these
brainstem. CLIPPERS is associated with a fairly distinc- conditions already have a diagnosis before developing
tive imaging pattern characterised by punctate and neurological symptoms, CNS vasculitis can rarely be
curvilinear gadolinium enhancement ‘peppering’ the the first manifestation of their disease. Serological
pons and adjacent structures including the midbrain, testing, such as antinuclear antibody or antineutrophil
cerebellar peduncles and cerebellum.16 cytoplasmic antibody, can help establish the diagnosis.
MR scan of brain usually shows multiple ischaemic
Vasculitis
infarcts of different ages in the cortex, subcortical
CNS vasculitis usually presents with headache and
subacute progressive encephalopathy. Its classification white matter and deep grey matter. Other features
depends on whether it is confined to the CNS or is include leptomeningeal enhancement, microhaemor-
secondary to an infection or systemic inflammatory rhages and diffuse white matter lesions that suggest
disease.17 Primary CNS vasculitis lacks the symp- small vessel ischaemia.17 Diencephalic and mesen-
toms and signs of systemic involvement that usually cephalic involvement is common in Behçet’s disease,
accompany secondary vasculitis, such as fever, weight an inflammatory vasculitis that usually presents with
loss, oligoarthropathy, ocular inflammation or rash. recurrent oral and urogenital ulcers, uveitis, pathergy,
Inflammatory markers are also usually normal. Most oligoarthropathy and recurrent thrombosis. Isolated
systemic vasculitides can cause secondary CNS vascu- neurological disease is rare and can mimic infectious
litis.17 Other systemic autoimmune or inflammatory brainstem encephalitis.18

6 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


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Angiography showing stenosis or ectasia with varies widely, depending on the population studied,
‘beading’ of intracranial vessels can confirm a vascu- the case definition used or the methods used for
lopathy, but this finding has a sensitivity of only about screening.22 Patients may develop seizures, psychosis
60%.17 Fluorodeoxyglucose-positron emission tomog- and encephalopathy, although they are rare.22 The
raphy (FDG-PET) scanning may be very valuable in pathophysiology is unclear, and it is still unclear
identifying systemic large vessel vasculitis, but it still whether the neuropsychiatric manifestations are
has no clear role in detecting CNS disease.17 Defin- secondary to vasculopathy, coexisting neural auto-
itive diagnosis is made by histopathological analysis, antibodies, infection or toxic-metabolic effects from
but note that a biopsy, particularly ‘blind’ biopsy treatment. Neurological symptoms tend to occur
of the meninges, does not always yield a definitive after systemic manifestations of systemic lupus
diagnosis.17 erythematosus, although sometimes they can be the
Susac’s syndrome or retinocochleocerebral vascu- first manifestation of the disease.22 Neuroimaging
lopathy is an immune-mediated microangiopathy char- can be normal, show non-specific white matter
acterised by subacute encephalopathy, sensorineural abnormalities, leptomeningeal enhancement or find-
deafness, tinnitus and branch-retinal occlusion.19 MR ings consistent with posterior reversible encephalop-
scanning typically shows multiple lesions involving the athy syndrome. Elevated serum antinuclear antibody
central fibres of the corpus callosum, as well as the is sensitive but non-specific. Antibodies to double-
periventricular and subcortical white matter. Retinal stranded DNA or smith nuclear antigen, along with
fluorescein angiography that confirms branch-retinal decreased complement can provide supportive
occlusion can help to establish the diagnosis.19 evidence. Antiphospholipid antibodies, antibodies
to beta-2-glycoprotein and lupus anticoagulant are
Neuromyelitis optica (NMO) spectrum disorder associated with antiphospholipid syndrome, which
NMO spectrum disorder classically presents with occurs in up to 20% of patients with systemic lupus
attacks of bilateral or rapidly sequential optic neuritis erythematosus and is characterised by recurrent isch-
and/or longitudinally extensive myelitis.20 Non-opti- aemic infarction, seizures and cognitive decline.23
cospinal involvement, however, is now well described.
This includes relatively NMO-specific syndromes such Neurosarcoidosis
as intractable nausea and hiccoughs due to area post- Nervous system manifestations of sarcoidosis include
rema involvement, or symptomatic narcolepsy due to cranial neuropathies, myeloradiculopathies including
hypothalamic involvement, but rarely, non-optico- cauda equina syndrome, peripheral neuropathy and
spinal involvement can present with encephalopathy myopathy.24 Some cases present with headache,
and seizures.20 encephalopathy, psychosis and seizures. Neurosar-
Brain lesions seen in NMO spectrum disorder typi- coidosis occurs in approximately 5%–10% of patients
cally occur in aquaporin-4 (AQP-4)-rich sites such as with systemic sarcoidosis but can occur in up to 17%
the area postrema, hypothalamus or periaqueductal of patients without detectable systemic evidence of
brainstem. However, they may also occur in the deep sarcoidosis.24 Although its onset is usually subacute,
white matter where they may have associated cloudy it can rarely present as an acute illness.
enhancement, or an appearance similar to lesions seen Neuroimaging characteristics are protean and
with posterior reversible encephalopathy syndrome.20 non-specific, although leptomeningeal and pachymenin-
Longitudinal extensive corpus callosum lesions are geal enhancement correlates well with disease activity.24
also seen. Leptomeningeal involvement is exceed- Serum ACE has poor sensitivity and specificity. CSF
ingly rare and should prompt reconsideration of the ACE concentration is also insensitive and only moder-
diagnosis. CSF shows primarily a lymphocytic pleocy- ately specific. A CSF CD4/CD8 T cell ratio above 5
tosis, although there may be elevated neutrophil and supports the diagnosis.25 The definitive diagnosis of
eosinophil counts. Detecting autoantibodies to AQP-4 sarcoidosis requires histopathological demonstration of
confirms a diagnosis, although 20%–30% of patients non-necrotising granulomas in affected tissue, but it may
are seronegative.20 A subset of patients with seroneg- be challenging to obtain a suitable sample. FDG-PET
ative NMO spectrum disorder disease has antibodies may identify systemic sarcoidosis and help to identify a
to myelin oligodendrocyte glycoprotein (MOG). potential biopsy site.
MOG-IgG associated encephalomyelitis is now
considered a disease entity in its own right, presenting Syndrome of transient headache and neurological deficits with
with recurrent (although occasionally monophasic) cerebrospinal fluid lymphocytosis (HaNDL)
optic neuritis, myelitis, rhombencephalitis, as well as The syndrome of transient HaNDL is a self-limiting
ADEM-like presentations.21 condition that can mimic encephalitis. As the name
suggests, patients usually present with episodes of
Systemic lupus erythematosus severe migrainous headache, along with transient neuro-
The reported range and prevalence of neuropsychi- logical deficits and lymphocytic pleocytosis.26 The
atric manifestation of systemic lupus erythematosus most frequent neurological deficits are hemiparesis,

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 7


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hemisensory disturbances and aphasia, although there Posterior reversible encephalopathy syndrome
may be visual disturbances and encephalopathy.26 In Posterior reversible encephalopathy syndrome is a
addition to the CSF pleocytosis, there is often a raised heterogeneous clinical syndrome characterised by
CSF opening pressure. Although it is usually mono- acute neurological symptoms arising in the setting of
phasic, many patients have repeated episodes over the blood pressure fluctuations, autoimmune and meta-
duration of the illness, which typically lasts 3 weeks but bolic disorders, infection, eclampsia, transplantation
can last up to 3 months.26 or exposure to immunosuppressant or cytotoxic
drugs.29 The sudden onset of seizures, encephalop-
athy and, less commonly, focal deficits can mimic
Toxic and metabolic encephalopathies encephalitis, especially when the encephalopathy
Septic encephalopathy
arises in the setting of infection (usually systemic
Septic encephalopathy is the most common cause of
but rarely in the CNS). Neuroimaging can be very
infection-associated encephalopathy and develops in
helpful in this regard as posterior reversible enceph-
up to 70% of patients presenting with sepsis.27 Clin- alopathy syndrome has a fairly distinct radiographic
ically, patients with septic encephalopathy develop appearance. Classically, brain imaging shows rela-
confusion and inattention progressing to delirium, tively symmetrical signal abnormality involving the
stupor and coma. There are usually no focal findings, cerebral white matter of both cerebral hemispheres,
and seizures occur less frequently than in patients particularly in the parieto-occipital regions. Other
with encephalitis. Myoclonus and asterixis, typical brain regions are also frequently affected, including
of metabolic encephalopathies, are rare. Neuroim- the fronto-temporal lobes, basal ganglia, brainstem
aging is usually normal, although there may be scat- and cerebellum. Although less common, there may
tered punctate ischaemic changes, presumably due to be gadolinium enhancement and restricted diffusion
in situ thrombosis.27 CSF is usually entirely normal (figure 3). CSF commonly shows an elevated protein
or shows a mild elevation in protein. and sometimes a mild lymphocytic pleocytosis.

Toxic syndromes Mitochondrial encephalomyopathies


Many patients with ingestion/overdose have Mitochondrial diseases have a wide clinical spec-
presenting clinical features suggesting encephalitis, trum. Of the various mitochondrial disorders that
including mental status changes and fever. Identi- can present in adulthood, mitochondrial enceph-
fying a specific toxic syndrome can help to establish alomyopathy with lactic acidosis and stroke-like
a diagnosis, especially when there is no immediately symptoms (MELAS) is the one most likely to mimic
available history of exposure (table 3).28 Serotonin infectious encephalitis. MELAS belongs to a group
syndrome, for example, is characterised by hyper- of mitochondrial diseases caused by point mutations
thermia, flushing, agitation, hypertonia, myoclonus in mitochondrial DNA. Clinically, it presents with
and clonus that is both spontaneous and induced non-ischaemic stroke-like episodes resulting in hemi-
(especially in the legs).28 Neuroleptic malignant paresis, hemianopia, aphasia, encephalopathy and
syndrome, which presents with hyperthermia, cortical blindness.30 Focal and generalised seizures
rigidity, bradykinesia and stupor, is another well-de- also occur.30 Patients commonly have a prior history
scribed toxidrome.28 Withdrawal states, such as those of migraine headaches, vomiting, muscle weakness,
from withdrawal from alcohol and other GABA- psychiatric disturbances, growth failure and hearing
ergic substances can present with tachycardia, hyper- loss, but these may be masked by the more dramatic
thermia, confusion and hallucinations. stroke-like presentation.30 Fever can trigger these

Table 3  Toxic syndromes


Toxic syndrome (causative agents) Vitals Pupils Other findings
Sympathomimetic Hyperthermia, tachycardia, Mydriasis Agitation, paranoia, diaphoresis, tremors
(cocaine, amphetamines and pseudoephedrine) tachypnoea and hypertension. and seizures.
Anticholinergic Hyperthermia, tachycardia, Mydriasis Hypervigilance, agitation, dry flushed
(tricyclic antidepressants, antihistamines and tachypnoea and hypertension. skin and urinary retention.
scopolamine)
Serotonin syndrome Hyperthermia, tachypnoea, Mydriasis Agitation, tremor, diaphoresis, hyper-
(MAOIs, SSRIs, SNRIs, tricyclic antidepressants, tachycardia and hypertension. reflexia, clonus, myoclonus. Findings
triptans, tramadol and dextromethorphan) more prominent in lower extremities.
Neuroleptic syndrome Hyperthermia, tachypnoea, Normal Decreased level of awareness, mutism,
(typical and atypical antipsychotics) tachycardia and hypertension. lead-pipe rigidity and hyporeflexia.
MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressant.

8 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


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Figure 3  A young man presenting with seizures and encephalopathy a week after a viral illness. Blood pressure was labile at
presentation. Brain imaging shows characteristic T2 fluid-attenuated inverse recovery hyperintensities in the cerebellar (A) and
subcortical (B and C) white matter. The lesions in the parasagittal frontal lobes show associated punctate gadolinium enhancement
(C and D). Repeated MR scan of brain 3 weeks later was normal (not shown). The clinicordiological features are in keeping with the
posterior reversible encephalopathy syndrome.

stroke-like events, and its presence may lead clini- Neoplasia


cians to suspect encephalitis. Temporal lobe tumours
Routine neuroimaging during an acute attack Metastatic and primary CNS tumours can rarely present
usually shows hyperintense T2 lesions in the grey and as acute encephalitis.32 Temporal lobe involvement may
subcortical white matter, predominantly affecting suggest herpes simplex virus encephalitis, but the MRI
temporal, parietal and occipital regions.31 The signal changes associated with tumours differ from
lesions cross vascular territories and spare the deep viral encephalitis in that they tend to be unilateral and
white matter. Although they may have associated contiguous, although bilateral involvement can occur
enhancement, there is usually little to no restriction with gliomatosis or lymphomatosis cerebri (figure 4).
observed.31 CSF is usually acellular but may show a Repeating imaging a few days after presentation can also
mild lymphocytic pleocytosis. Certain clues such as be very helpful, as imaging changes in herpes simplex
short stature, myopathy, cardiac abnormalities and virus encephalitis evolve rapidly compared with those
family history of recurrent stroke should raise suspi- associated with neoplasm.
cion.30 Blood and CSF lactate tends to be elevated Intravascular large cell lymphoma
during an acute attack.30 MR spectroscopy showing Intravascular large cell lymphoma is a rare subtype of
a large lactate peak and low ratio of N-acetyl aspar- large cell lymphoma that affects small blood vessels.
tate to creatine is supportive.31 The definitive diag- Virtually any organ can be involved but CNS and cuta-
nosis is through mitochondrial DNA studies. neous involvement is common, particularly in Western

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 9


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Figure 4  A patient presenting with seizures and encephalopathy. Brain imaging shows T2 fluid-attenuated inverse recovery (FLAIR)
hypreintensity in the right mesiotemporal structures (A) with associated cortical restriction on corresponding diffusion-weighted
imaging and apparent diffusion coefficient map (C and D, arrows). An MR scan of brain, repeated 3 weeks later due to persistent
encephalopathy (D), shows significant expansion of the T2 FLAIR signal abnormality in the right cerebral hemisphere. Brain biopsy
was consistent with gliomatosis cerebri.

countries.33 Neurologically, it presents as a rapidly recurrent attacks of headache associated with seizures,
progressive encephalopathy. Constitutional B symp- confusion and focal deficits.34 Neuroimaging shows
toms are very common as are skin manifestations.33 increased T2 signal and swelling of cortical gyri with
Serum lactate dehydrogenase and beta-2-microglob- associated gadolinium enhancement within a previous
ulin are frequently elevated but are non-specific.33 radiation field.34 Both the neurological deficits and
Neuroimaging can be normal or show bilateral but imaging abnormalities usually reverse but permanent
asymmetrical signal change involving subcortical sequelae are possible (figure 5).
white matter and deep grey matter structures. There
may be associated gyriform, perivascular or homog-
Unusual presentations of infectious
enous gadolinium enhancement, as well as restricted
encephalitis (chameleons)
diffusion. Paralytic rabies and viral acute flaccid paralysis
Stroke-like migraine attacks after cranial radiation (SMART) Rabies virus is usually transmitted to humans by bites
SMART is a rare syndrome that occurs years after from animal vectors. There are two clinical forms
successful treatment of CNS neoplasia with thera- of the disease. Encephalitic rabies is by far the most
peutic cranial irradiation. Clinically, it presents with common, and it occurs in 80% of cases35; paralytic

10 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


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Figure 5  a patient with a history gliobastoma multiforme treated with chemoradiation 2 years before, presenting with a 2-day
history of headache, aphasia and right hemiparesis. Brain imaging shows fluid-attenuated inverse recovery imaging hyperinstensity
and swelling (A, arrows) with associated gadolinium enhancement (B) and minimal restriction on corresponding diffusion-weighted
imaging (C) and apparent diffusion coefficient MAP (D). An asterisk marks residual tumour.

rabies occurs in 20% of cases.35 Typically, the onset of piloerection and early bladder dysfunction help differ-
clinical disease is between 20 days and 90 days from entiate it from Guillain-Barré syndrome.
the time of exposure, but there have been documented Other viruses that can present with flaccid paralysis
incubation periods longer than a year. The earliest include poliovirus, other enteroviruses (EV-70, EV-71
neurological manifestations are usually paraesthesia, and EV-68)36 and West Nile virus.37 The presenta-
pain and pruritus near the site of exposure. tion is usually asymmetric and preceded by a viral
►► In encephalitic rabies, this is followed by episodes of prodrome with or without meningismus. The MR scan
hyperexcitability, hallucinations, confusion and dysau- of spine usually shows short segmental and longitu-
tonomia punctuated by periods of lucidity. Hydropho- dinally extensive spinal cord lesions. These preferen-
phia is a distinct clinical feature. Progressive neurological tially involve the grey matter and are associated with
deterioration leads to paralysis, coma and death. haemorrhagic necrosis.36 37
►► In paralytic rabies by contrast, there is early prominent
weakness that initially may affect only the bitten limb Symptomatic CSF HIV viral escape
but invariably progresses to involve other limbs and Patients with HIV on combined antiretroviral therapy
bulbar muscles.35 Sphincter dysfunction, pain, pilo- (cART) can present with neurological symptoms in the
erection and sensory disturbances also occur. Hydro- setting of suppressed peripheral viraemia and normal
phobia is rare. Survival is longer, but patients eventually CD4 counts but ‘discordant’ elevation of CSF HIV RNA.
progress to coma and death. Clinically, paralytic rabies Clinically, these patients tend to present with progressive
may resemble Guillain-Barré syndrome. A history of cognitive decline, behavioural changes, ataxia, apraxia
exposure to an animal bite may not always be clearly and focal deficits.38 Occasionally, they can present
established. Symptoms at the local site, asymmetry, acutely with encephalopathy and seizures. MR scan of

Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114 11


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brain shows fairly symmetrical signal abnormalities in


Box 3  Infectious causes of vasculopathy
the cerebral, brain stem and cerebellar white matter with
or without enhancement.38 CSF can be normal or show ►► Varicella zoster virus.
mildly elevated protein and white blood cell counts. ►► Neurosyphilis.
However, this disorder is characterised by dissociation ►► Tuberculosis.
between CSF and plasma virus concentrations. Those ►► Nocardiosis.
with complete plasma viral suppression have detectable ►► Angioinvasive fungal infections (eg, aspergillosis,
CSF HIV RNA, while in those with low but measureable fusariosis and zygomycosis).
plasma, viral loads have CSF concentrations that is at ►► Cryptococcosis.
least a log order different. Genotypic analysis of the CSF
virus often shows resistance to components of the cART
regimen.38 Optimisation of the cART regimen usually PCR. In patients with negative PCR, finding evidence
results in clinical and radiological improvement. of intrathecal synthesis VZV-specific IgG (measured
with comparison with serum using an antibody index)
Immune reconstitution inflammatory syndrome is diagnostic.41 Box 3 includes other infectious causes of
CNS immune reconstitution inflammatory syndrome vasculopathy.
is defined by a pathological inflammatory response to
either a previously treated (paradoxical) or a previously Atypical presentations of herpes simplex encephalitis
undiagnosed (unmasked) opportunistic infection.39 Immunocompromised patients with herpes simplex virus
Immune reconstitution inflammatory syndrome results encephalitis can present with fewer prodromal symp-
from the restoration of a dysregulated immune response toms and neurological deficits than those with preserved
against pathogen-specific antigens. In the setting of HIV, immune response.42 Absence of CSF pleocytosis is also
it is characterised by paradoxical clinical deterioration more common in the immunosuppressed as is more
following initiation of cART. Although immune recon- widespread brain involvement, including brainstem and
stitution inflammatory syndrome can occur in the setting cerebellum.42 Extratemporal involvement, including
of HIV alone, it more commonly occurs in response of the brainstem, can also occur in HSV encephalitis
to an opportunistic organism such as Mycobacterium secondary to herpes simplex virus type 2.1
tuberculosis, Cryptococcus neoformans or JC virus (the
Conclusion
agent responsible for progressive multifocal leukoen-
There is a broad differential diagnosis for a patient
cephalopathy).39 Paradoxical worsening, manifesting
presenting with possible encephalitis. Infectious causes
altered consciousness, focal deficits, cranial neuropa-
are common, but parainfectious and postinfectious, as
thies and seizures, occurs on average 3–5 weeks after
well as non-infectious causes may also occur. Clinicians
starting treatment but can develop months after treat-
should also consider non-inflammatory encephalopa-
ment.39 Brain imaging varies depending on the under-
thies secondary to systemic infection, toxins and meta-
lying infection, but associated gadolinium enhancement
bolic disorders.
is common.
The histopathological hallmark of immune reconsti- Key points
tution inflammatory syndrome is CD8 T cell predom-
inant inflammatory infiltrate along with evidence of ►► Encephalitis is characterised by acute onset of fever,
underlying infection. CD8 T cell predominant infiltrates altered mental status, focal neurological deficits and
also develop in CD8 encephalitis, a rapidly progressive, generalised or focal seizures.
sometimes fulminant, encephalitic illness that may occur ►► CNS infection is a common cause of encephalitis, but
in HIV seropositive patients on cART. These patients immune-mediated causes are increasingly recognised.
have no evidence of occult CNS infection, although some ►► Non-inflammatory encephalopathies (related to
have shown concurrent CSF viral escape at the time of systemic infection, metabolic disorders or toxins) can
their illness.40 Brain imaging usually shows extensive cause a similar clinical syndrome.
bilateral grey and white matter signal abnormality with ►► Infectious encephalitis sometimes presents subacutely
associated perivascular gadolinium enhancement.40 and without fever, making it more difficult to
recognise.
Varicella zoster virus (VZV) vasculopathy
VZV can cause a vasculopathy affecting both large and
Acknowledgements  Thanks to Dr Christopher Carswell,
small cerebral blood vessels.41 Clinicians should suspect
consultant neurologist, and Dr Anastasia Gontsarova,
VZV vasculopathy in a patient with a recent history of consultant neuroradiologist, Imperial College NHS Trust, for
herpes zoster or varicella infection who presents with sharing figure 1.
stroke or altered mental status. The absence of the Contributors  MT and NWSD contributed equally to the
characteristic rash does not rule out VZV vasculopathy, drafting of this manuscript.
especially in immunocompromised and HIV seropos- Funding  The authors have not declared a specific grant for this
itive patients. The diagnosis is confirmed with VZV research from any funding agency in the public, commercial or

12 Toledano M, Davies NWS. Pract Neurol 2019;0:1–13. doi:10.1136/practneurol-2018-002114


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Competing interests  None declared. glycoprotein antibodies in adults with a neuromyelitis optica
phenotype. Neurology 2012;79:1273–7.
Patient consent for publication  Obtained.
22 Hanly JG. Diagnosis and management of neuropsychiatric
Provenance and peer review  Commissioned. Externally peer
SLE. Nat Rev Rheumatol 2014;10:338–47.
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Liverpool, UK. 23 Roldan JF, Brey RL. Neurologic manifestations of
the antiphospholipid syndrome. Curr Rheumatol Rep
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