Autoimmune epilepsy is a general term for epilepsy mediated
by or associated with antibodies sometimes linked to cancer. Paraneoplastic epilepsy
is a subset of autoimmune epilepsy, always associated with an underlying tumor
or cancer, in which antigens shared by normal neurons and cancer cells are
presented to the immune system resulting in antibody production.3 When
considering a diagnosis of autoimmune epilepsy, a critical detail to keep in
mind is that some antibodies target intracellar antigens, while others target
neural surface antigens. Antibodies to intracellular antigens have a high
association with cancer (≥ 80%) such as ANNA-1 (Anti-Hu), PCA-1 (Anti-Yo),
Anti-Ma1, and Anti-Ma2 (Ta).3,4 Such antibodies are often thought of as an
epiphenomenon of T-cell–mediated neural tissue destruction because the
antibodies are not directly causing the underlying neurologic disease.5 These
syndromes typically do not respond well to immunotherapy.
In contrast, antibodies to neural surface antigens are
thought to directly cause neurologic disease, show a more robust response to
immunotherapy, and have a more variable association with cancer.4-6 For example,
the leucine-rich glioma inactivated 1 (LGI-1) antibody is associated with small
cell lung cancer (SCLC) or thymoma in < 10% of occurrences, but antibodies
to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor
(AMPAR) are associated with thymoma or a lung or breast tumor in approximately
70% of occurrences.3 The N-methyl-D-aspartate glutamate receptor (NMDAR)
antibody is unique in that the association with ovarian teratoma is age
dependent; it is found most often in teenagers and young adults and less
frequently in older adults.
Recommendations for tumor screening are antibody specific
and covered later in this article, although often a specific antibody is not
detected. When no specific antibody is detected, the clinical features and
other test results guide diagnosis of autoimmune epilepsy, and broad cancer
screening is also performed…
Patients with autoimmune epilepsy typically have multifocal
seizures with an unusually high (ie, daily or weekly) seizure frequency at
onset and can also present in nonconvulsive status epilepticus. They often have antiepileptic drug (AED)
resistance at onset5 that may be categorized as new-onset refractory status
epilepticus (NORSE).
Typically, there is no history of epilepsy or seizure risk
factors in the patient’s medical or family history. There can be a personal or
family history of autoimmune disease that is organ or nonorgan specific (eg,
type 1 diabetes, lupus, celiac disease, rheumatoid arthritis, or autoimmune
thyroid disease) or cancer (particularly those strongly associated with
autoimmune disease including SCLC, thymoma, teratoma, or lymphoma).
Seizures of autoimmune epilepsy are most commonly focal temporal
lobe seizures but seizure onset is often seen elsewhere. Flushing or pilomotor
(goosebump) autonomic seizures often occur (especially when there are antibodies
to LGI1, Hu, and Ma). Facial brachial dystonic seizures (FBDS) that affect the
ipsilateral face and arm are a distinct seizure type described more fully later
in this article…
Classically, NMDAR-related epilepsy presents in young women,
although older adults, men, children, and infants have also been affected.
Teratomas are found in about one-third of women over age 18 with this
condition. Approximately 70% of patients have a viral prodrome (ie, headache,
diarrhea, fever, nausea, vomiting, or upper respiratory symptoms) days to weeks
before psychiatric symptom onset (eg, memory impairment, insomnia, catatonia,
depression, anxiety, or psychosis). Seizures are common and occur at any point.
As the disease progresses, patients can develop movement disorders (eg,
orofacial dyskinesias, dystonia, or chorea). These patients can also exhibit
severe autonomic dysfunction (eg, hyperthermia, tachycardia, hypersalivation,
hypertension, urinary incontinence, and erectile dysfunction) followed by
central hypoventilation requiring intubation…
Findings from standard CSF studies that can suggest an
autoimmune diagnosis include lymphocytic pleocytosis, elevated protein, and
elevated oligoclonal bands or IgG index. Clinicians should consider saving
frozen CSF in case further testing is needed after initial test results...
Although positive antibody screening is helpful to confirm a
diagnosis, it is thought that up to half of patients with autoimmune epilepsy
will have negative antibody findings. It
is recommended to use antibody panels rather individual antibody assays and to
test both serum and CSF. It is important to check which antibodies will be
assessed on the panel chosen. Some labs will perform immunofluorescence (IFA)
surveys and enzyme-linked immunosorbent assay (ELISA) but not the gold-standard
confirmatory cell-based assay (CBA). Antibody panels may have confusing titles
such as an autoimmune neurology panel, autoimmune epilepsy panel,
paraneoplastic panel, or some other variation. A clinician should be certain
that the panel chosen includes antibodies for the suspected etiology and screen
for antibodies associated with conditions that present similarly (ie, GQ1B,
ANA, and TPO/thyroglobulin antibodies).
If there is a positive antibody result, cancer screening for
the most common associated cancer type should be done. If antibody testing is
negative, ovarian or testicular ultrasound and thoracic, abdominal/pelvic CT
and full body PET scans are reasonable follow up tests. Repeat imaging every 6
to 12 months for up to 4 years should be considered if an antibody is present
that has a high association with a tumor or if the patient is clinically
considered as being at high risk for malignancy…
Currently, no data from randomized controlled trials is
available. Observational studies and clinical experience suggest that a
response to immunotherapy in epilepsy (RITE) score ≥7 predicts a favorable
response to immunotherapy. First-line
treatment consists of either intravenous methylprednisolone (IVMP) (1 g/day for
3 to 5 days) or intravenous immunoglobulin (IVIg) (0.4g/kg/day for 3-5 days).
If there is no response to the first agent, it is reasonable to try the second.
Plasmapheresis (PLEX) is often reserved for those who have a contraindication
to IVMP or IVIg, have failed those treatments, and have status epilepticus or severe
symptoms. A central venous catheter is
required for PLEX and can be difficult in uncooperative patients, children, and
those with autonomic instability. Weekly IVMP or IVIg may be continued for 4 to
6 weeks (sometimes up to 12 weeks) then followed by increased treatment
intervals over 4 to 6 months. Other protocols suggest using a steroid taper or
monthly infusions. Seizures may respond
(50% reduction or seizure freedom) within 4 weeks but cognitive or psychiatric
symptoms typically recover more slowly. Early treatment has been shown to
predict better outcomes.
If patients worsen or there is no response within 2 weeks of
a first-line therapy, second-line therapies are rituximab (1g IV) given twice 2
weeks apart or cyclophosphamide (750mg/m2 monthly up to 6 months).
If there is a favorable response to treatment, chronic
immunosuppression with mycophenolate mofetil, azathioprine, rituximab or
cyclophosphamide should be considered. Mycophenolate mofetil and azathioprine
are often paired with first-line treatment until they are effective as
monotherapy. Rituxmab is preferred by some groups for treatment of patients
with antibodies to neural cell surface targets, whereas cyclophosphamide is
often used when there are intracellularly targeted antibodies. Appropriate
treatment of an underlying cancer or tumor is also essential to recovery.
Consider withdrawal of immunotherapy after 2 years. Seizure medications should
be used in conjunction with immunotherapy. Recovery can often be gradual and
protracted. Many patients are hospitalized for 3 to 4 months followed by months
of rehabilitation. Relapses of the disease are also possible.
Autoimmune neurology is a fascinating and evolving field,
and this article serves as a guide to the evaluation and treatment of this
challenging disease. The clinical presentation may be complex and testing may
need to be repeated when findings are initially negative or if specific
antibodies are not found. The diagnosis is not based on a single result but the
comprehensive clinical picture. Each antibody has its unique clinical findings,
cancer association, and response to treatment. Early diagnosis and treatment
can drastically alter the course of the disease. Advances in the detection and
identification of causative antibodies and other biomarkers will aid in
diagnosis and prompt treatment of these patients in the future.
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