Autoimmune Encephalitis New horizon of treatable seizures
During the past 2 decades, there has been a dramatic growth in the recognition of autoimmune encephalitis. The most common autoimmune encephalitis syndromes are associated with antibodies against
- Leucine-rich glioma inactivated protein 1 (LGI1),
- N Methyl D Aspartate ( NMDA) Receptor
- Contactin -associated protein like 2 (CASPR2),
- γ-aminobutyric acid (GABA)A or GABAB receptors, and
- Myelin oligodendrocyte glycoprotein (MOG).
Diagnosis can be made when all three of the following criteria have been met 1. Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status or psychiatric symptoms. 2. At least one of the following
- New focal central nervous system findings
- Seizures not explained by a previously known seizure disorder
- CSF pleocytosis (white blood cell count of more than five cells per mm3)
- MRI features suggestive of encephalitis 3. Reasonable exclusion of alternative causes.
- severe autonomic dysfunction (especially hyperhidrosis and cardiovascular instability);
- insomnia;
- peripheral nerve hyperexcitability (often neuromyotonia); and a behavioural syndrome,
- with few seizures but prominent psychiatric impairments including hallucinations, agitation, and delusions occurring at higher rates than in CASPR2 antibody–associated encephalopathy.
- piloerection,
- thermal sensations and
- paroxysmal dizzy spells, and
- the pathognomonic description of Facio brachial dystonic seizures.
1) NMDA RECEPTOR ENCEPHALITIS
Antibodies against the excitatory NMDA receptor preferentially target the NR1 subunit of this heteromeric channel.
NMDA receptor encephalitis presents with a diffuse encephalopathy that predominantly affects females more than males (3:1) and approximately 50% of patients with this condition are younger than 18 years, including some younger than 1 year. Ovarian teratomas are associated commonly in young females while malignant tumours are seen in elderly patients.
PSYCHIATRIC FEATURES
The presentation includes core features of agitation, aggression, hallucinations, delusions, anxiety, mutism, and insomnia, with many patients exhibiting all or many of these features. These features which can often lead to patients initially presenting to psychiatric services and being misdiagnosed.
NEUROLOGIC FEATURES
In particular, patients with this condition can develop seizures and cognitive dysfunction in the early days of their disorder. Adults typically develop a movement disorder after approximately 1 or 2 weeks. This Usually is a highly complex movement disorder, often incorporating elements of chorea, stereotypies, and dystonia in individual patients.
Investigations
The routine MRI is typically and surprisingly normal in most patients with NMDA receptor encephalitis, particularly given the severe clinical presentation. Other patients show typical limbic encephalitis involving medial temporal lobes. However, functional imaging, including imaging of white matter tracts, shows substantial deficits. CSF usually shows lymphocytic pleocytosis, and EEG typically demonstrates slowing.
2) CASPR2 ANTIBODY DISEASE
CASPR2 antibodies are associated with one of the more common forms of autoimmune encephalitis. Patients with CASPR2 antibodies have two broad syndromes affecting the brain:
(A) a limbic-predominant encephalopathy and
(B) Morvan syndrome.
Both affect males far more than females.
A) Limbic -predominant encephalopathy
Patients with a more limbic encephalopathy and CASPR2 antibodies have prominent disorientation, amnesia, seizures, usually no other coexistent antibodies, and low rates of an underlying neoplasm. A variety of movement disorders may be observed in patients with CASPR2 antibodies.
Most commonly these include ataxia, myoclonus, and tremor in addition to the otherwise unusual syndromes of paroxysmal ataxia and orthostatic leg myoclonus.
B) Morvan syndrome
This is characterised by the presence of
CSF and MRI are often normal in patients with CASPR2 antibody disease. EEG will reflect the presence of encephalopathy in most patients. The detection of peripheral nerve hyperexcitability by needle EMG is a specific feature and markedly narrows the differential diagnosis.
CASPR2 antibodies have been reported as frequently positive in disease controls when commercially available kits are used; however, higher titres and their presence in CSF help mitigate this rate of false-positive serum results.
3) LGI 1 ENCEPHALITIS
Patients with LGI1 antibodies are more commonly male than female (2:1), and few patients younger than 50 years present with these antibodies. The median age of onset is approximately 65 years, and some patients present in their nineties. Usually associated with tumours, mostly thymomas and small cell lung carcinomas.
Seizures
The hallmark of LGI1 encephalitis is the nature of the seizures. These patients have among the highest frequencies of seizures in neurology, with some experiencing several hundred per day at their disease nadir. Although these seizures can include common mesial temporal lobe features such as automatisms and epigastric rising sensations, there are more specific patterns, including
Cognition
In addition to seizures, amnesia is another key feature associated with LGI1 encephalitis. Most patients develop dense anterograde amnesia, consistent with bilateral hippocampal involvement, and some retrograde gaps that do not follow a clear temporal gradient. Also, alterations in personality, elated or depressed mood, and heightened emotionality are observed in the acute phase.
Investigations
In patients with LGI1 encephalitis, investigations are often unremarkable. CSF testing typically shows normal white blood cell counts and normal protein levels. MRI can show hippocampal-amygdala hyperintensity on T2-weighted imaging and basal ganglia can be involved too, especially in patients with Facio brachial dystonic seizures. EEG often shows clinical and subclinical seizure activity with mildly slowed background rhythms.
One additional feature of this condition is low serum sodium in approximately one-half of patients, which can be a very helpful clue.
4) GABA-B Receptor and AMPA Receptor Antibodies
GABA-B receptor and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antibodies are typically associated with classic forms of limbic encephalitis: an acute-to-subacute onset of amnesia, seizures, and MRI changes, typically with mesial temporal lobe swelling and T2 hyperintensity on T2- weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences.
5) GABA-A Receptor Antibodies
GABA-A receptor antibody disorders present with a more diffuse, and less limbic centric, encephalitis, consistent with the characteristic multifocal cortical and subcortical lesions observed on T2-weighted MRI sequences.
The MRI appearance of these lesions is very suggestive of the underlying antibody, providing a diagnostic feature with high specificity likely to be available before antibody testing results.
6) Glycine Receptor Antibodies
Patients with antibodies against the glycine receptor develop an encephalopathy typically associated with prominent auditory and tactile startle responses, spasms, stiffness, and myoclonus in addition to brainstem ocular motor and bulbar disturbances, pyramidal signs, and dysautonomia.
This disorder, sometimes termed progressive encephalomyelitis with rigidity and myoclonus, can affect patients from a wide range of ages spanning the very young to the very old and equally affects males and female.
7) DPPX Antibodies
Patients with antibodies to DPPX, a protein expressed in the enteric plexus in addition to the brain, often present with striking gastrointestinal features of diarrhoea, significant weight loss (median of 20 kg [44 lb]), and constipation.
These patients develop an encephalopathy, often with prominent myoclonus, seizures, brainstem features, and tremor, and many show marked improvements after immunotherapies. B-cell lymphoma is a recognised, albeit relatively uncommon, association.
8) MOG Antibodies
Antibodies against MOG were originally recognised in the setting of classic demyelinating features of optic neuritis and myelitis within the neuromyelitis optica spectrum, in addition to acute disseminated encephalomyelitis (ADEM).
Since this observation, it has become recognised that MOG antibodies can also be found in patients with more cortically restricted encephalitis (often termed cerebral cortical encephalitis). ADEM -
is an encephalopathy that particularly affects children, who develop confusion and seizures. It shows white and deep gray matter imaging abnormalities and 50% of patients are now known to be MOG antibody positive.
the more cortical encephalitis-
associated with MOG antibodies is known as unilateral cortical FLAIR hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES) and is characterised by an encephalitis in the context of unilateral or bilateral cortical hyperintensities.
SYNDROMES ASSOCIATED WITH ANTIBODIES TO INTRACELLULAR TARGETS
1)GFAP Antibodies
A commonly detected antibody in routine neurologic practice is directed against GFAP. GFAP antibodies are found in a wide spectrum of conditions encompassing various forms of encephalitis, meningitis, and myelitis.52 One associated radiologic finding is the striking perivascular radial enhancement seen in around one-half of patients.
2)GAD65 Antibodies
Antibodies against GAD65, which are likely nonpathogenic, are another commonly detected antibody. GAD antibodies can help the diagnosis of a variety of neurologic syndromes like stiff person syndrome.
TREATMENT
A)Immunotherapy
Its mainstay of treatment.
1)First-line Immunotherapies
a)High dose corticosteroids
Most patients are initially treated with high-dose corticosteroids, either intravenously or orally. In some forms of autoimmune encephalitis, the response to steroids can be dramatic. Steroids are often combined with either plasma exchange or intravenous immunoglobulin (IVIg); both are considered first-line agents.
b) Intravenous Immunoglobulin
Although the effect of IVIg was superior to that of placebo, both in terms of seizure cessation and improvement in cognition, the magnitude of the effect was relatively disappointing, suggesting that corticosteroids are still the preferred treatment.
c) Plasma Exchange
Plasma exchange is a proven intervention in diseases of the peripheral nervous system, but its value in central nervous system antibody- mediated diseases is perhaps less intuitive.
d) Tumour removal
Although only an option in a small proportion of patients with autoimmune encephalitis, effective tumour removal can help remove a key generator of autoantigen-reactive lymphocytes, hence terminating a potential driver of the condition.
B)Second- and Third-line Immunotherapies
The key second-line immunotherapies are rituximab and cyclophosphamide.
C) Third-line immunotherapies,
including tocilizumab and bortezomib, have also been discussed in the literature, particularly in patients with NMDA receptor and seronegative forms of autoimmune encephalitis In this clinical context, patients who are refractory to first- and second-line therapies may be administered another set of agents.
Of course, this theoretically puts patients at high risk of infection and combinatorial immunotherapy complications.
However, it may be necessary in some of the patients with more refractory autoimmune encephalitis.
