ADEM and acute haemorrhagic encephalomyelitis

ADEM is usually a monophasic, inflammatory demyelinating disorder of the CNS. It is more common in children but can occur in all ages.5 It is characterised by the abrupt onset of neurological symptoms days to weeks following infection or immunisation.5 Although there is not always a clearly identified precipitant, most cases have a non-specific flu-like illness preceding the onset of neurological symptoms.

Without a clear history of antecedent infection or vaccination, it can be difficult to distinguish ADEM from infectious encephalitis on purely syndromic grounds. ADEM is polysymptomatic and multifocal in presentation with symptoms and signs evolving over hours to days. Encephalopathy, optic neuritis and long tract signs are common. Most patients develop depressed level of consciousness ranging from lethargy to coma. CSF findings resemble those of viral encephalitis.5 Neuroimaging usually shows bilateral and asymmetric areas of increased signal in the subcortical white matter, brainstem, cerebellum, periventricular white matter and deep grey matter.5 The lesions vary in number and size and may enhance with gadolinium.5

Acute haemorrhagic encephalomyelitis is considered a hyperacute and more fulminant variant of ADEM. Like ADEM, it is commonly triggered by infection or vaccination. Brain imaging usually shows haemorrhagic lesions in the white matter.6 CSF examination often shows polymorphonuclear cells as well as numerous red blood cells (in the absence of a traumatic tap).

Haemophagocytic lymphohistiocytosis syndrome

Haemophagocytic lymphohistiocytosis is a syndrome of excessive inflammation due to abnormal immune activation, probably caused by a lack of normal downregulation of activated macrophages and lymphocytes.7 It can be either familial or sporadic. Systemic infection, rheumatological conditions or malignancy are common triggers in both familial and sporadic cases, and it is commonly associated with immunodeficiency syndromes. Although it usually affects infants, it can develop in children and adults of all ages. Clinically, it presents as a febrile illness with multiorgan dysfunction. Up to a third of patients have neurological involvement, including seizures, encephalopathy and focal deficits.7

In patients where neurological findings dominate the clinical picture, infectious encephalitis is likely. In the vast majority of cases, however, neurological symptoms are preceded by weeks of systemic symptoms. Cytopenias develop in up to 80% of patients. Serum ferritin is commonly elevated up to and above 10 000 µg/L. Liver function abnormalities and associated hypertriglyceridaemia and coagulation abnormalities are very common. MR brain scan abnormalities are non-specific and include parameningeal infiltration, subdural collections and necrotic changes. Findings consistent with posterior reversible encephalopathy syndrome are also very common. The CSF protein is frequently elevated, and half of cases have a lymphocytic pleocytosis. Histopathology from bone marrow, liver, spleen or lymph nodes may show haemophagocytosis. Elevated soluble CD25 (soluble interluekin-2 receptor alpha) and reduced natural killer cell function support the diagnosis but may be available only at specialty laboratories.7

Influenza-related encephalopathy/encephalitis and acute necrotising encephalopathy

Influenza-related encephalitis/encephalopathy is a rapidly progressive encephalopathy that develops days after the onset of the first symptoms of influenza.8 Its pathophysiology remains unclear, and neither direct viral infection of the CNS nor a postinfectious inflammatory process appears to cause the condition. CSF studies are often normal, although a small number of cases have elevated CSF protein or mild pleocytosis. Similarly, there is only rarely any direct evidence of viral invasion on CSF and histopathology. The disease tends to affect children younger than 5 years of age, but there have been isolated cases in adults.8 9

Several neuroimaging abnormalities may occur, ranging from scattered white matter abnormalities to diffuse brain oedema, but these changes are not specific. A more distinct imaging pattern is reversible focal swelling and restricted diffusion in the corpus callosum. This pattern can occur with influenza and other infections, as well as in certain metabolic disorders. It is usually associated with a benign course. This clinicoradiological syndrome is termed ‘mild encephalitis/encephalopathy with reversible splenial lesion’ (figure 2).10 Another pattern associated with influenza and other infections manifests as bilateral necrosis of the thalami and other regions, including the brainstem, cerebellum and cerebral white matter.8 This syndrome is termed ‘acute necrotising encephalopathy’ and has a more severe clinical course and worse prognosis. Familial and recurrent cases of acute necrotising encephalopathy following infection have been linked to mutations in Ran-binding protein 2.

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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.

Cerebral malaria

Cerebral malaria is a clinical syndrome defined as an otherwise unexplained encephalopathy in patients with malaria parasitaemia. It is almost always associated with Plasmodium falciparum infection. Risk factors include young age, pregnancy, HIV seropositivity and splenectomy.11 In adults, cerebral malaria is more common in non-immune individuals than those living in endemic areas.11 Cerebral malaria should be suspected in travellers returning from endemic regions who present with unexplained fever, even if they have been taking antimalarial prophylaxis.

Clinically, it presents with a prodrome of irregular fevers, malaise, abdominal pain, headache, anorexia, vomiting followed by encephalopathy, seizures and coma. In adults, neurological symptoms develop 7 days after symptom onset and rapidly evolve to coma. There are often signs of brainstem dysfunction. Retinal changes are very common in children and include macular and extramacular whitening, as well as orange or white discolouration of blood vessels representing areas of parasite sequestration.11 Retinal haemorrhages are also very common in children and occur in 15% of adults.11 CSF is usually normal or near normal. Associated haematological and metabolic abnormalities such as hypoglycaemia, anaemia, thrombocytopenia and acidosis are common. The diagnosis is made by examining thick and thin blood films, which may be negative initially especially in those who have been taking antimalarial prophylaxis.

Autoimmune encephalitis associated with paraneoplastic or neuronal surface antibodies

The term autoimmune encephalitis describes a heterogeneous group of neurological disorders associated with antineuronal autoantibodies.12 These can be subdivided into two major groups based on the location of the target antigen. The first includes the classic paraneoplastic disorders, which are associated with antibodies targeting intracellular antigens (table 1). These antibodies are strongly associated with underlying malignancy but are not pathogenic. The second group is associated with antibodies targeting neuronal surface antigens (table 2). These antibodies are likely pathogenic and, importantly, patients in this group respond to immunotherapy. Cancer associations are variable but still relevant, as is the case between ovarian teratomas and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.13 A growing body of literature suggests that autoimmune encephalitis can occur as a parainfectious or postinfectious phenomena, best described in cases of anti-NMDAR following HSV encephalitis.13

The clinical spectrum of autoimmune encephalitis is highly variable. There are some well-described syndromes such as anti-NMDAR encephalitis and the limbic encephalitis associated with antibodies to leucine-rich-glioma-inactivated-1, a component of the voltage-gated potassium channel complex. Note, however, that many patients with autoimmune encephalitis do not present with a well-defined syndrome.13 The clinical spectrum of phenotypes associated with known antibodies continues to expand, and new antibodies are discovered. In addition, we increasingly recognise that there are well-described clinical phenotypes in patients in whom antibodies have not yet been identified.11 In general, clinicians should suspect autoimmune encephalitis in patients presenting with subacute progressive encephalopathy and prominent new-onset psychiatric symptoms.13 New-onset seizures and cryptogenic status epilepticus can be part of the initial presentation but can also be the sole presenting symptom.12 Abnormal movements, including orolingual and limb dyskinesias, dystonia, myoclonus and hyperekplexia occur more frequently in autoimmune encephalitis than in infectious encephalitis. Although autoimmune encephalitis can be preceded by a viral prodrome including fevers, fever is not a predominant feature.

MR scan of brain can be normal or show non-specific abnormalities; however, it may show findings suggesting limbic encephalitis, namely increased signal on T2-weighted FLAIR imaging of the mesial temporal lobes.13 In autoimmune limbic encephalitis, there is preferential involvement of the amygdala and hippocampus, and bilateral involvement is more symmetrical than in herpes simplex virus encephalitis. Restricted diffusion on DWI and haemorrhagic changes also suggest herpes simplex virus encephalitis. EEG can show generalised slowing or may identify subclinical seizures or non-convulsive status epilepticus. Finding extreme delta brush pattern on EEG strongly suggests anti-NMDAR encephalitis.14 CSF can show mild pleocytosis (usually fewer than 100 cells) sometimes with transient elevations in oligoclonal bands or IgG index but it can also be normal.

Detecting a known autoantibody helps to establish the diagnosis and determines the need to screen for underlying malignancy. Conversely, failure to detect a known antibody does not rule out autoimmune encephalitis.

Bickerstaff’s encephalitis

Bickerstaff’s brainstem encephalitis is characterised by subacute onset of progressive impairment of consciousness, ataxia and bilateral, relatively symmetrical ophthalmoparesis.15 Bickerstaff’s encephalitis usually follows an infectious prodrome, has a monophasic course and has a good prognosis. Additional clinical features include bilateral facial palsies, bulbar palsy, hyper-reflexia and pupillary abnormalities. MR scan of brain is usually normal, but a quarter of patients have brainstem abnormalities on T2-weighted and FLAIR imaging. Most patients have an elevated CSF protein, and half of patients have a mild lymphocytic pleocytosis.13 15 Finding anti-GQ1b antibodies in the serum supports the diagnosis, but this test is negative in up to 32% of patients.15

The absence of fever at the onset of neurological symptoms and the relative symmetry of findings usually help distinguish Bickerstaff’s encephalitis from infectious rhombencephalitis. Nonetheless, it is important to rule out infectious causes.

A similar clinical picture can occur with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), a recently described inflammatory disorder affecting the brainstem. CLIPPERS is associated with a fairly distinctive imaging pattern characterised by punctate and curvilinear gadolinium enhancement ‘peppering’ the pons and adjacent structures including the midbrain, cerebellar peduncles and cerebellum.16

Vasculitis

CNS vasculitis usually presents with headache and subacute progressive encephalopathy. Its classification depends on whether it is confined to the CNS or is secondary to an infection or systemic inflammatory disease.17 Primary CNS vasculitis lacks the symptoms and signs of systemic involvement that usually accompany secondary vasculitis, such as fever, weight loss, oligoarthropathy, ocular inflammation or rash. Inflammatory markers are also usually normal. Most systemic vasculitides can cause secondary CNS vasculitis.17 Other systemic autoimmune or inflammatory conditions can also rarely cause secondary CNS vasculitis; these include systemic lupus erythematosus, Sjögren’s syndrome, cryoglobulinaemia and rheumatoid arthritis.17 Although most patients with these conditions already have a diagnosis before developing neurological symptoms, CNS vasculitis can rarely be the first manifestation of their disease. Serological testing, such as antinuclear antibody or antineutrophil cytoplasmic antibody, can help establish the diagnosis.

MR scan of brain usually shows multiple ischaemic infarcts of different ages in the cortex, subcortical white matter and deep grey matter. Other features include leptomeningeal enhancement, microhaemorrhages and diffuse white matter lesions that suggest small vessel ischaemia.17 Diencephalic and mesencephalic involvement is common in Behçet’s disease, an inflammatory vasculitis that usually presents with recurrent oral and urogenital ulcers, uveitis, pathergy, oligoarthropathy and recurrent thrombosis. Isolated neurological disease is rare and can mimic infectious brainstem encephalitis.18

Angiography showing stenosis or ectasia with ‘beading’ of intracranial vessels can confirm a vasculopathy, but this finding has a sensitivity of only about 60%.17 Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning may be very valuable in identifying systemic large vessel vasculitis, but it still has no clear role in detecting CNS disease.17 Definitive diagnosis is made by histopathological analysis, but note that a biopsy, particularly ‘blind’ biopsy of the meninges, does not always yield a definitive diagnosis.17

Susac’s syndrome or retinocochleocerebral vasculopathy is an immune-mediated microangiopathy characterised by subacute encephalopathy, sensorineural deafness, tinnitus and branch-retinal occlusion.19 MR scanning typically shows multiple lesions involving the central fibres of the corpus callosum, as well as the periventricular and subcortical white matter. Retinal fluorescein angiography that confirms branch-retinal occlusion can help to establish the diagnosis.19

Neuromyelitis optica (NMO) spectrum disorder

NMO spectrum disorder classically presents with attacks of bilateral or rapidly sequential optic neuritis and/or longitudinally extensive myelitis.20 Non-opticospinal involvement, however, is now well described. This includes relatively NMO-specific syndromes such as intractable nausea and hiccoughs due to area postrema involvement, or symptomatic narcolepsy due to hypothalamic involvement, but rarely, non-opticospinal involvement can present with encephalopathy and seizures.20

Brain lesions seen in NMO spectrum disorder typically occur in aquaporin-4 (AQP-4)-rich sites such as the area postrema, hypothalamus or periaqueductal brainstem. However, they may also occur in the deep white matter where they may have associated cloudy enhancement, or an appearance similar to lesions seen with posterior reversible encephalopathy syndrome.20 Longitudinal extensive corpus callosum lesions are also seen. Leptomeningeal involvement is exceedingly rare and should prompt reconsideration of the diagnosis. CSF shows primarily a lymphocytic pleocytosis, although there may be elevated neutrophil and eosinophil counts. Detecting autoantibodies to AQP-4 confirms a diagnosis, although 20%–30% of patients are seronegative.20 A subset of patients with seronegative NMO spectrum disorder disease has antibodies to myelin oligodendrocyte glycoprotein (MOG). MOG-IgG associated encephalomyelitis is now considered a disease entity in its own right, presenting with recurrent (although occasionally monophasic) optic neuritis, myelitis, rhombencephalitis, as well as ADEM-like presentations.21

Systemic lupus erythematosus

The reported range and prevalence of neuropsychiatric manifestation of systemic lupus erythematosus varies widely, depending on the population studied, the case definition used or the methods used for screening.22 Patients may develop seizures, psychosis and encephalopathy, although they are rare.22 The pathophysiology is unclear, and it is still unclear whether the neuropsychiatric manifestations are secondary to vasculopathy, coexisting neural autoantibodies, infection or toxic-metabolic effects from treatment. Neurological symptoms tend to occur after systemic manifestations of systemic lupus erythematosus, although sometimes they can be the first manifestation of the disease.22 Neuroimaging can be normal, show non-specific white matter abnormalities, leptomeningeal enhancement or findings consistent with posterior reversible encephalopathy syndrome. Elevated serum antinuclear antibody is sensitive but non-specific. Antibodies to double-stranded DNA or smith nuclear antigen, along with decreased complement can provide supportive evidence. Antiphospholipid antibodies, antibodies to beta-2-glycoprotein and lupus anticoagulant are associated with antiphospholipid syndrome, which occurs in up to 20% of patients with systemic lupus erythematosus and is characterised by recurrent ischaemic infarction, seizures and cognitive decline.23

Neurosarcoidosis

Nervous system manifestations of sarcoidosis include cranial neuropathies, myeloradiculopathies including cauda equina syndrome, peripheral neuropathy and myopathy.24 Some cases present with headache, encephalopathy, psychosis and seizures. Neurosarcoidosis occurs in approximately 5%–10% of patients with systemic sarcoidosis but can occur in up to 17% of patients without detectable systemic evidence of sarcoidosis.24 Although its onset is usually subacute, it can rarely present as an acute illness.

Neuroimaging characteristics are protean and non-specific, although leptomeningeal and pachymeningeal enhancement correlates well with disease activity.24 Serum ACE has poor sensitivity and specificity. CSF ACE concentration is also insensitive and only moderately specific. A CSF CD4/CD8 T cell ratio above 5 supports the diagnosis.25 The definitive diagnosis of sarcoidosis requires histopathological demonstration of non-necrotising granulomas in affected tissue, but it may be challenging to obtain a suitable sample. FDG-PET may identify systemic sarcoidosis and help to identify a potential biopsy site.

Syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL)

The syndrome of transient HaNDL is a self-limiting condition that can mimic encephalitis. As the name suggests, patients usually present with episodes of severe migrainous headache, along with transient neurological deficits and lymphocytic pleocytosis.26 The most frequent neurological deficits are hemiparesis, hemisensory disturbances and aphasia, although there may be visual disturbances and encephalopathy.26 In addition to the CSF pleocytosis, there is often a raised CSF opening pressure. Although it is usually monophasic, many patients have repeated episodes over the duration of the illness, which typically lasts 3 weeks but can last up to 3 months.26

Septic encephalopathy

Septic encephalopathy is the most common cause of infection-associated encephalopathy and develops in up to 70% of patients presenting with sepsis.27 Clinically, patients with septic encephalopathy develop confusion and inattention progressing to delirium, stupor and coma. There are usually no focal findings, and seizures occur less frequently than in patients with encephalitis. Myoclonus and asterixis, typical of metabolic encephalopathies, are rare. Neuroimaging is usually normal, although there may be scattered punctate ischaemic changes, presumably due to in situ thrombosis.27 CSF is usually entirely normal or shows a mild elevation in protein.

Toxic syndromes

Many patients with ingestion/overdose have presenting clinical features suggesting encephalitis, including mental status changes and fever. Identifying a specific toxic syndrome can help to establish a diagnosis, especially when there is no immediately available history of exposure (table 3).28 Serotonin syndrome, for example, is characterised by hyperthermia, flushing, agitation, hypertonia, myoclonus and clonus that is both spontaneous and induced (especially in the legs).28 Neuroleptic malignant syndrome, which presents with hyperthermia, rigidity, bradykinesia and stupor, is another well-described toxidrome.28 Withdrawal states, such as those from withdrawal from alcohol and other GABA-ergic substances can present with tachycardia, hyperthermia, confusion and hallucinations.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome is a heterogeneous clinical syndrome characterised by acute neurological symptoms arising in the setting of blood pressure fluctuations, autoimmune and metabolic disorders, infection, eclampsia, transplantation or exposure to immunosuppressant or cytotoxic drugs.29 The sudden onset of seizures, encephalopathy and, less commonly, focal deficits can mimic encephalitis, especially when the encephalopathy arises in the setting of infection (usually systemic but rarely in the CNS). Neuroimaging can be very helpful in this regard as posterior reversible encephalopathy syndrome has a fairly distinct radiographic appearance. Classically, brain imaging shows relatively symmetrical signal abnormality involving the cerebral white matter of both cerebral hemispheres, particularly in the parieto-occipital regions. Other brain regions are also frequently affected, including the fronto-temporal lobes, basal ganglia, brainstem and cerebellum. Although less common, there may be gadolinium enhancement and restricted diffusion (figure 3). CSF commonly shows an elevated protein and sometimes a mild lymphocytic pleocytosis.

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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.

Temporal lobe tumours

Metastatic and primary CNS tumours can rarely present as acute encephalitis.32 Temporal lobe involvement may suggest herpes simplex virus encephalitis, but the MRI signal changes associated with tumours differ from viral encephalitis in that they tend to be unilateral and contiguous, although bilateral involvement can occur with gliomatosis or lymphomatosis cerebri (figure 4). Repeating imaging a few days after presentation can also be very helpful, as imaging changes in herpes simplex virus encephalitis evolve rapidly compared with those associated with neoplasm.

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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.

Intravascular large cell lymphoma

Intravascular large cell lymphoma is a rare subtype of large cell lymphoma that affects small blood vessels. Virtually any organ can be involved but CNS and cutaneous involvement is common, particularly in Western countries.33 Neurologically, it presents as a rapidly progressive encephalopathy. Constitutional B symptoms are very common as are skin manifestations.33 Serum lactate dehydrogenase and beta-2-microglobulin are frequently elevated but are non-specific.33 Neuroimaging can be normal or show bilateral but asymmetrical signal change involving subcortical white matter and deep grey matter structures. There may be associated gyriform, perivascular or homogenous gadolinium enhancement, as well as restricted diffusion.

Stroke-like migraine attacks after cranial radiation (SMART)

SMART is a rare syndrome that occurs years after successful treatment of CNS neoplasia with therapeutic cranial irradiation. Clinically, it presents with recurrent attacks of headache associated with seizures, confusion and focal deficits.34 Neuroimaging shows increased T2 signal and swelling of cortical gyri with associated gadolinium enhancement within a previous radiation field.34 Both the neurological deficits and imaging abnormalities usually reverse but permanent sequelae are possible (figure 5).

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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.