Autoimmune encephalopathies

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Introduction
Neurologists are often consulted to evaluate patients with subacute encephalopathy, defined as the onset of
cognitive and behavioral disturbances over days or weeks. Toxic/metabolic encephalopathy and infectious
causes of meningoencephalitis must be foremost in the differential diagnosis. Once these are excluded, an
autoimmune process may be suspected on the basis of clinical presentation, brain MRI, electrodiagnostic studies
and serological tests of the serum and CSF. Specifically, the presence of certain serum or CSF autoantibodies
and elevated CSF protein with normal cell count (or a mild lymphocytic pleocytosis only) should raise the
possibility of an autoimmune/inflammatory disorder.
Accurate and prompt diagnosis of autoimmune encephalopathy is important since effective treatment may be
available, and permanent impairment will result if the encephalopathy is left untreated. It is particularly important
to differentiate these disorders from rapidly progressive dementia due to prionopathy or other degenerative
conditions. Treatable autoimmune encephalopathies are probably more common than appreciated. Various
autoimmune and inflammatory conditions may be considered in the differential diagnosis of a progressive
dementia or subacute encephalopathy as listed in Table 1. Some forms of autoimmune encephalopathy,
including Morvan syndrome, paraneoplastic limbic encephalitis (PLE), and non-paraneoplastic autoimmune limbic
encephalitis have recognizable characteristic clinical and serological features. In the absence of distinctive
diagnostic features, a clinical response to steroids may be the only evidence of an autoimmune cause and can
define the syndrome as steroid-responsive encephalopathy (SRE). Features of some of these syndromes are
compared and summarized in Table 2.
Paraneoplastic Limbic Encephalitis
Paraneoplastic limbic encephalitis (PLE) is characterized by the triad of short-term memory impairment, temporal
lobe seizures and psychiatric symptoms (commonly depression, psychosis or change in personality). For a
recent review and discussion of the diagnostic criteria, see Tuzun and Dalmau, 2007. 1 As with most
paraneoplastic syndromes, there is a female predominance. Two thirds of patients have overt seizures (usually
complex partial temporal lobe seizures) which may be difficult to control, and nearly all patients will show
abnormalities on electroencephalography. 2 Sometimes, patients present initially with unexplained seizure rather
than cognitive complaints. In others, brief complex partial seizures may be subtle and unrecognized, and the
behavioral and cognitive presentation can mimic a rapidly progressive dementia. The differential diagnosis
includes primary psychiatric illness, viral encephalitis, Creutzfeld-Jakob disease (CJD), vasculitis, and non-
paraneoplastic autoimmune encephalopathies (Table 2). 3
Certain additional clinical features should increase the suspicion of a paraneoplastic cause. The presence of
other progressive neurological symptoms (especially sensory neuropathy or gastrointestinal dysmotility) could be
explained by a coexisting paraneoplastic syndrome. Other systemic symptoms (loss of smell and taste,
unexplained weight loss, night sweats) or laboratory findings (elevated sedimentation rate, hyponatremia) may
signify the presence of occult cancer.
The pathology of PLE is focused in the anteromedial temporal cortex, hippocampus, and amygdala although
adjacent limbic structures (hypothalamus and insular cortex) may be involved, and the process may be quite
asymettrical. 2 MRI typically shows non-enhancing signal changes in the mesial temporal lobes. Positron
emission tomography of the brain may show hypermetabolism in the same region. 4, 5 Later in the disease course,
marked hippocampal atrophy often develops, associated with permanent cognitive impairment and epilepsy. The
electroencephalogram is abnormal and often shows epileptiform activity in the mesial temporal lobes as well as
diffuse slowing. 2 Cerebrospinal fluid examination is important to rule out infectious causes (especially herpes
simplex encephalitis) that may have a similar clinical and radiographic presentation.
A variety of autoantibody markers are associated with PLE including ANNA-1 and anti-Ma2 (see Table 3). New
antibody markers are likely to be described in the future (e.g. antibodies against hippocampal “neuropil” and
NMDA receptors as described below 5, 6 ). The autoantibody findings are very useful in directing the search for
occult malignancy, but up to 30% of patients with PLE and cancer have negative antibody studies. 2 In those
cases, a search for malignancy must be conducted according to the patient’s individual cancer risk factors. The
most common tumors associated with PLE are small-cell lung carcinoma (SCLC), 2, 7, 8 testicular cancer, 9, 10
thymoma, 11, 12 and breast cancer. Since the syndrome usually occurs prior to the cancer diagnosis, these patients
present to neurologists rather than oncologists. In most instances, the cancer is limited in stage and can be
difficult to detect even when suspected. In cases of occult SCLC, imaging the chest with FDG-PET scan appears
to be more sensitive than computed tomography alone. 13
PLE may stabilize or partially improve following treatment of the cancer or treatment with immunomodulatory
therapies, but most patients are left with residual memory impairment and seizures. High dose steroids
sometimes produce a meaningful response. Hence, a response to steroids does not rule out a paraneoplastic
disorder.
Autoimmune limbic encephalitis with potassium channel antibodies
Antibodies reactive with neuronal voltage-gated potassium channels (VGKC) were initially identified in patients
with Isaacs syndrome, an acquired disorder of neuromuscular hyperexcitability characterized
electromyographically by high-frequency neuromyotonic discharges. 14 Isaacs syndrome is now better named
autoimmune neuromyotonia. VGKC antibodies are also found in patients that have Morvan syndrome, a
combination of neuromytonia and encephalopathy (see below). More recently, VGKC antibodies were described
in several individual patients with encephalopathy who did not have neuromuscular hyperexcitability, 15-17 and two
larger case series have defined this entity as a distinct clinical syndrome. 3, 18 The clinical and radiological findings
at presentation in these patients are indistinguishable from those of paraneoplastic limbic encephalitis, consisting
of subacute cognitive impairment with behavioral changes and temporal lobe seizures, high T2 and FLAIR signal
in the mesial temporal lobes and temporal lobe EEG abnormalities. Unique features of this disorder are the
frequent association with hyponatremia, a strong male predominance, and often dramatic response to treatment
with high dose steroids or plasma exchange (Table 2).
Patients with limbic encephalitis associated with lung cancer or thymoma may have VGKC antibodies, so the
presence of VGKC antibodies does not preclude the need to search for occult cancer. However, when limbic
encephalitis is associated with very high levels of VGKC antibodies, no other paraneoplastic neurological
symptoms, and no other paraneoplastic autoantibodies, most cases are not paraneoplastic. 3, 18
Further studies are needed to prove that limbic encephalitis is caused by VGKC antibodies. It is possible that
these antibodies are a marker of autoimmunity but not directly involved in the pathogenesis of the disorder. The
reported response to plasma exchange implicates a direct role of the antibodies. 18 The commercial assay used to
detect VGKC antibodies utilizes radiolabelled alpha-dendrotoxin (which binds to Kv1.1, 1.2 and 1.6 subtypes of
voltage-gated potassium channels). Sera from limbic encephalitis patients binds to Kv1.1 subunits more
prominently than neuromyotonia sera, suggesting an association between Kv1.1 specificity and limbic
manifestations. In contrast,neuromyotonia sera bind more strongly to Kv1.2 subunits than to Kv1.1 or Kv1.6 19
The rapid response to steroids in many patients suggests that inflammation may also play an important role. The
imaging characteristics are consistent with inflammation and disruption of the blood-brain barrier similar to that
seen in PLE or Herpes Simplex encephalitis. The pathological findings in autoimmune limbic encephalitis and
PLE are similar and non-specific. Brain biopsy often shows perivascular lymphocyte infiltration, microglial
activation (nodules) and gliosis.
In addition to well-recognized paraneoplastic antibodies and VGKC antibodies, other neurological autoantibodies
may be associated with limbic encephalitis. Ances et al. reported seven patients with antibodies reactive against
synaptic areas in the hippocampus (neuropil antibodies). 5 Patients with these antibodies had inflammatory CSF
findings (like PLE) but were often responsive to treatment (similar to those with VGKC antibodies). About half the
patients had systemic tumors (teratoma or thymoma) but these differed from the tumors commonly associated
with PLE.
Paraneoplastic encephalitis with NMDA receptor antibodies
6
This disorder has been recognized relatively recently and predominantly affects young women. The presentation
is a complex subacute syndrome with a flu-like prodrome followed by psychosis (behavioral changes with
delusions and hallucinations), often leading to a psychiatric evaluation for schizophrenia. Central hypoventilation,
unresponsiveness resembling catatonia, and dyskinesias then develop. The latter can take the form of orofacial
movements, head and neck dystonia or complex movements of the extremities. Seizures and autonomic
instability (dramatic fluctuations of heart rate, blood pressure and temperature) can occur. Brain MRI is often
normal, but a minority of patients can show some findings of limbic encephalitis. The EEG shows diffuse delta-
theta slowing. Cerebrospinal fluid analysis shows lymphocytic pleocytosis and increased protein concentration.
Many cases have been associated with cystic pelvic tumors (such as ovarian teratoma) that may be initially
overlooked.
Untreated patients require intubation for ventilatory support and intensive care and may eventually die of
complications. Prompt identification of the disorder followed by tumor removal and immunotherapy seems to
result in gradually recover over weeks. Diagnosis of this disorder has been facilitated by the recent
demonstration of serum and CSF antibodies to NMDA glutamate receptor. These antibodies target extracellular
epitopes contained in NR1/NR2 heteromers of the NMDAR. 6 This receptor type is predominantly concentrated in
the hippocampus and forebrain.
NMDA receptor antibodies have also been reported in some patients with CNS manifestations of systemic lupus
erythematosus, but the significance of this finding is unknown. 20
Morvan syndrome
In rare instances, a subacute encephalopathy is associated with neuromuscular hyperexcitability. The French
physician Augustin Marie Morvan first used the term “la chorée fibrillaire” in 1870 to describe a syndrome
characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium. 21 The
current use of the term “Morvan syndrome” describes the association of acquired neuromyotonia (involuntary
rippling, twitching  and stiffness of muscles), myokymia, severe insomnia, hyperhidrosis and encephalopathy. 22-24
The typical cognitive presentation of Morvan syndrome includes confusion, hallucinations and fluctuating
cognition. Needle electromyography (EMG) typically reveals spontaneous muscle fiber activity with
fasciculations, multiplets, myokymia and neuromyotonic discharges.
The precise pathophysiology of Morvan syndrome has not been established, but it is almost certainly an
autoimmune disorder. It may be associated clinically with myasthenia gravis and with certain neoplasms
(particularly thymoma and small-cell lung carcinoma). 23, 24 Voltage-gated potassium channel (VGKC) antibodies
are found in most, if not all, patients with this syndrome. 24, 25 Symptoms may improve with immunomodulating
therapy (e.g., steroids, azathioprine, cyclophosphamide or plasmapheresis).
The classic diagnosis of Morvan syndrome should be reserved for patients in whom at least 4 cardinal features
develop: myokymia or neuromyotonia, dysautonomia (typically with hyperhidrosis, hypersalivation, labile
hypertension), severe insomnia, and fluctuating encephalopathy with vivid hallucinations. Unlike limbic
encephalitis, the head MRI in Morvan syndrome is usually normal. Electrographic seizures and mesial temporal
lobe structural abnormalities, which are typical of PLE, are not present in Morvan syndrome. The majority of
patients are male and the age of onset is younger than PLE. The diagnosis can be confirmed by demonstrating
myokymia and neuromyotonia by EMG, absence of normal sleep architecture on polysomnography, and serum
VGKC antibodies. In addition to limbic encephalitis, various forms of degenerative dementia might be considered
in the differential diagnosis; fatal familial insomnia (because of the complete insomnia), CJD (because of the
cognitive presentation) and Lewy body dementia (because of the fluctuating symptoms, hallucinations and sleep
disturbance). The key distinguishing clinical feature to recognize in Morvan syndrome is the spontaneous
neuromuscular and autonomic hyperactivity.
Steroid-responsive encephalopathy
Non-paraneoplastic forms of autoimmune encephalopathy are currently recognized by various terminologies,
including non-vasculitic autoimmune inflammatory meningo-encephalitis, 26 steroid-responsive encephalopathy,
and Hashimoto encephalopathy. 27, 28 Steroid-responsive encephalopathy associated with autoimmune thyroiditis
(SREAT), often referred to as “Hashimoto’s encephalopathy”, was initially described by Lord Brain. 29 The name
reflects the presence of thyroid autoimmunity, often without clinical or biochemical evidence of thyroid
dysfunction, in these patients. Patients may have serum antibodies against either thyroperoxidase (TPO) or
thyroglobulin (formerly known as thyroid microsomal antibodies). The titer of the thyroid antibodies does not
correlate with severity or any clinical features. While overt thyroid dysfunction is uncommon at the time of
neurological presentation, many patients will develop hypothyroidism sometime later in the clinical course.
Evidence of thyroid autoimmunity, however, is non-specific and quite common among all patients with
autoimmune neurological disorders. A direct causal relationship between thyroid antibodies and encephalopathy
is unlikely. 30 Anti-thyroid antibodies may also be found in CSF of patients with SREAT. 31 Again, however,the
presence and level of the CSF antibodies does not appear to correlate with clinical features of the disease. The
brain MRI is often normal.
The typical presentation of SREAT is a subacute cognitive disorder with fluctuating symptoms (which may present
as stroke-like events), tremor, myoclonus, and neuropsychiatric features. Patients are predominantly women, and
there is a wide age range in reported cases likely reflecting the demographics of autoimmune thyroiditis. Non-
specific CSF evidence of inflammation (high protein) is common and similar to other forms of autoimmune
encephalopathy. When abnormal, MRI may show changes in subcortical white matter or in the meninges. 30, 32
These MRI changes may resolve with successful treatment. Ultimately, there are no specific clinical, laboratory or
neuroimaging findings for this entity. The differential diagnosis includes CJD (because of the myoclonus and
cognitive features), CNS vasculitis (because of the stroke-like events), primary psychiatric disease and
paraneoplastic encephalitis. The presence of thyroid antibodies does not obviate the need to consider these
alternate diagnoses.
Patients typically improve with corticosteroid therapy but may relapse. 30, 33 It is still unclear whether steroid
responsiveness should be a necessary criteria to make this diagnosis. Treatment with intravenous
immunoglobulin, azathioprine or other immunosuppressants may work for refractory cases. There have also
been a few reported cases of response to plasma exchange. 34
When all antibody tests (thyroid, VGKC and paraneoplastic) are negative, the empiric use of steroids in patients
with unexplained encephalopathy remains controversial. We have often advocated a short trial of high dose
intravenous steroids (1 gram methylprednisolone daily for 5 days) when there is no evidence of infection or
metabolic disturbance and the rapidity of onset is inconsistent with a degenerative disorder. For the diagnosis of
steroid-responsive encephalopathy, the clinical response should be unequivocal and persist for a week or more
beyond the time of treatment.
Encephalitis Lethargica
Encephalitis lethargica (EL) was first described by von Economo in 1917, shortly after the start of the 1916 to
1927 influenza epidemic. The patients, mostly children, characteristically presented with headache and malaise,
lethargy, insomnia, and ophthalmoplegia. Some recovered, but others either died or developed an insidious
neurodegenerative disorder characterized by Parkinsonism, oculogyric crises, chorea, myoclonus, mutism,
catatonia or behavioral problems. Although linked to the influenza epidemic, the neurological features of EL
occurred at a considerable latency after flu symptoms, and the virus was not found in postmortem brain tissue.
Sporadically, cases of post-infectious encephalitis with features of EL have continued to occur, but there have
been no further epidemics. The characteristic features in contemporary cases of EL are sleep disorder, lethargy,
Parkinsonism (or chorea) and neuropsychiatric disorders (e.g. mutism, anxiety, depression, obsessive/compulsive
behavior). 35 The patients range between 2 and 69 years of age; the majority are children or teenagers. Some
patients have a monophasic illness with spontaneous recovery, but others have persistent problems with
movement disorders and neuropsychiatric impairment (especially psychomotor slowing and sleep disturbances).
This latter group may resemble a rapidly progressive dementia, and the associated movement disorder may
suggest a diagnosis of CJD or Lewy body dementia. Features that help differentiate EL from the other subacute
neuropsychiatric disorders are childhood onset, chorea, ophthalmoparesis and prominent sleep disorder.
In recent years, an autoimmune basis for EL has been proposed,possibly as a post-viral or post-streptococal
phenomenon. About half of patients have a history of upper respiratory infection, and many have raised levels of
anti-streptolysin-O antibodies. Brain MRI may show T2 signal hyperintensity, predominantly in the deep grey
matter (basal ganglia). CSF analysis can show increased protein, oligoclonal bands or increased intrathecal IgG
synthesis. Pathologically, plasma cell infltrates can be found in the brain. EL probably represents part of a
spectrum of post-streptococcal neurological disorders (mostly involving children) that also includes Sydenham
chorea, pediatric autoimmune neurolopsychiatric disorders associate with streptococcal infections (PANDAS),
and post-infectious tic disorders.
Many patients with EL (like those with other post-streptococcal neurological disorders) are reported to have
antibodies against basal ganglia, but the significance of these antibodies is still unclear. 36
Autoantibodies and idiopathic epilepsy
Seizures are a prominent feature of many of the autoimmune encephalitides described here. Recent studies
have suggested that autoantibodies may be associated with some forms of idiopathic intractable epilepsy (without
the other features of limbic dysfunction). In particular, VGKC antibodies may be detected in a small subset of
patients with recent onset seizures. 37 These patients may represent a “forme fruste” of autoimmune limbic
encephalitis. A different clinical group of patients with chronic intractable epilepsy and normal brain imaging may
have antibodies against glutamic acid decarboxylase (GAD-65). 37, 38 Again, these patients have seizures but do
not have other behavioural features of autoimmune encephalopathy. It is still unclear whether immunological
treatment is warranted in epilepsy patients who harbor these neurological autoantibodies.
Summary
Autoimmune encephalopathy is becoming increasingly recognized as a potential cause of progressive cognitive
deterioration. The evaluation of cases of rapid onset encephalopathy and dementia should include spinal fluid
evaluation, MRI brain imaging and EEG. Several treatable syndromes have characteristic clinical features, and
antibody studies help confirm a diagnosis of autoimmune encephalopathy in some cases.
Table 1. Autoimmune and inflammatory causes of progressive dementia
Paraneoplastic Limbic Encephalitis
small-cell lung carcinoma
testicular cancer
thymoma
other tumors (breast, lymphoma, non-small cell lung)
Non-paraneoplastic Limbic Encephalitis
with VGKC antibodies
Morvan syndrome
Steroid-responsive encephalopathy (SRE)
with anti-thyroid antibodies (Hashimoto encephalopathy)
Post-infectious autoimmune encephalopathy
“Encephalitis lethargica”
“Cognitive” presentation of multiple sclerosis
Inflammatory vasculopathies (occasionally present as progressive dementia)
CNS vasculitis
Retinocochleocerebral (Susac’s) syndrome
Lupus cerebritis
Sjögren’s syndrome
Antiphospholipid antibody syndrome
Table 2. Clinical features of autoimmune encephalopathies*
Paraneoplastic LE LE with VGKC
antibody Morvan syndrome SREAT
# of reported cases > 100 ~ 40 ~ 15 ~ 80
Onset (years) 50 – 75 44 – 79 37 – 76 12 – 84
Gender M:F 1 : 1.2 3 : 1 9 : 1 1 : 4
Memory loss +++ +++ ++ ++
Seizures 65% 67% No** 50%
Hallucinations Occasional Occasional +++ Uncommon
Insomnia No No +++ +/-
Hyperhidrosis No with seizures ++ No
Myokymia   No No ++ No
Tremor No No No ++
VGKC Antibody + +++ +++ No
Thyroid antibody 20% 20% ND 100%
High CSF protein 80% 40% 50% 80%
Hyponatremia 25% 80% ND Uncommon
MRI  Increased signal in
mesial temporal lobes Increased signal in
mesial temporal lobes Normal Normal (60%) or non-
specific WM changes
EEG Slowing and
epileptiform
discharges Slowing and
epileptiform
discharges Normal or mild
slowing Slowing and
epileptiform
discharges
Response to steroids Partial response in
some pts ++ + +++
* Data represent a summary of English-language literature and the author’s experience
** Patients may have spells of confusion or autonomic hyperactivity without EEG correlate
ND = no data available
Table 3: Autoantibodies in autoimmune encephalopathies
Clinical Presentation Antibody Interpretation
PLE ANNA-1 (anti-Hu) Highly predictive of SCLC
PLE CRMP-5 (anti-CV2) Highly predictive of SCLC or thymoma
PLE N-type VGCC Suggestive of lung cancer or breast cancer
PLE Anti-Ma2 Highly predictive of testicular cancer (men)
PLE or LE VGKC About 20% have SCLC or thymoma
Morvan syndrome VGKC About 20% have SCLC or thymoma
PLE NMDA receptor Association with teratoma
SREAT thyroperoxidase (TPO) or thyroglobulin Predictive of ongoing or future thyroiditis
Encephalitis lethargica Basal ganglia
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