Antibody/target
Symptoms (other than seizures/limbic encephalitis)
Associated cancer(s)
VGKC complexa
Personality or behavioral changes, myoclonus (CJD-like picture), neuropathy, and hyponatremia
SCLC, thymoma
NMDA receptor
Psychosis, extrapyramidal disorders (e.g., choreoathetosis), and dysautonomia
Ovarian teratoma
GAD
Stiff person syndrome, ataxia, brainstem encephalitis, parkinsonism, and diabetes (DM-1)
Thymoma
Breast adenocarcinoma
Ma1, Ma2
Brainstem encephalitis
Testicular
ANNA-1 (Hu)
Brainstem encephalitis, autonomic or sensory neuropathy
SCLC
CRMP-5
Dementia, personality change, chorea, ataxia, and neuropathy
SCLC Thymoma
Amphiphysin
Dementia, myelopathy, and neuropathy
SCLC Breast adenocarcinoma
Antibody/target
GABA receptor; Symptoms: encephalopathy; Associated cancer(s)
SCLC, thymoma
Antibody/target
ANNA-2 (Ri); Symptoms: brainstem encephalitis, cerebellar ataxia; Associated cancer(s)
SCLC, breast, gynecological
Antibody/target
AMPA receptor; Symptoms: psychiatric; Associated cancer(s)
multiple solid cancers
One important set of antibodies is directed against the voltage-gated potassium channel (VGKC) complex. This complex was previously implicated in Isaac syndrome (neuromyotonia) which at times was paraneoplastic. These antibodies are associated with non-paraneoplastic autoimmune limbic encephalitis, presenting with seizures, confusion, amnesia, and myoclonus (thus mimicking Creutzfeldt–Jakob disease). There is often associated hyponatremia. Both seizures and MRI abnormalities (T2 hyperintensity, restricted diffusion, or contrast enhancement) are typically in the temporal regions, though generalized seizures may also occur. Variations in presentation may relate to the different antibody targets within the VGKC complex; laboratory results may be reported by the specific target (CASPR2, LGI1, and contactin-2). LGI1-associated disease may present with faciobrachial dystonic seizures (FBDS), characterized by repetitive, brief episodes of facial twitching and ipsilateral arm dystonia, with or without EEG correlation. FBDS may occur before, during, or after the development of cognitive impairment, which can delay diagnosis.
Another important autoimmune epilepsy is related to anti-N-methyl-d-aspartate receptor (NMDA-R) antibodies. This is classically described as a paraneoplastic syndrome associated with ovarian teratoma, though it is often non-paraneoplastic. Typical symptoms include seizures, confusion, catatonia, amnesia, choreoathetosis, and dysautonomia. Anti-NMDA-R antibody titers may correlate to disease severity. The course may be protracted, have relapses, and require hospitalization for weeks or months to control drug-resistant seizures or immunotherapy-resistant symptoms. A recent study suggests that the “extreme delta brush” pattern on EEG may be a unique finding in anti-NMDA-R encephalitis [4].
Management has a four-part approach: first, an aggressive workup including MRI, EEG, CSF, antibody testing, and cancer screening; second, early immunotherapy; third, concomitant AED treatment; and fourth, management of systemic complications. First-line immunotherapy is usually 3–5 days of IV methylprednisolone, IV immunoglobulin, or both. If there is good response, the treatment may be tapered and replaced with mycophenolate or azathioprine. In resistant cases, cyclophosphamide or rituximab may be considered.
Brain Tumors and Epilepsy
Intracranial tumors are a common cause of adult—and childhood-onset epilepsies. In general, the following tumors are more epileptogenic: adult-onset tumors (which tend to be supratentorial, as opposed to pediatric tumors), lower grade tumors, cortical tumors, and tumors closer to sensitive networks, such as hippocampus or motor cortex [5]. Parietal tumors have the strongest association with seizures, followed closely by temporal tumors.
Seizure semiology depends on tumor location, but certain pathologies have stronger association with seizures. Nearly all dysembryoplastic neuroepithelial tumors will cause seizures, followed by gangliogliomas and low-grade astrocytomas; higher grade or fast-growing tumors (such as glioblastoma multiforme [GBM] or primary CNS lymphoma) do not cause seizures as often [6]. A characteristic GBM is shown in Fig. 14.1. Additionally, hypothalamic hamartomas cause gelastic seizures. Regardless of tumor type, a seizure as the initial symptom of tumor presentation may increase the risk of recurrent seizures and refractory seizures, possibly independent of treatment.
Fig. 14.1
Left temporal glioblastoma multiforme, on T2 FLAIR and T1-contrasted MRI
Epileptogenicity may relate to both peritumoral (non-neoplastic) tissue as well as genetic factors. Higher grade tumors may have central necrosis and be electrically silent, whereas surrounding hemosiderin or edematous tissue may be epileptogenic. One example of a genetic correlation is the absence of LGI1 gene product in GBM, due to gene translocation [5]. This is a tumor suppressor gene, but two non-neoplastic epilepsies relate to LGI1: autosomal dominant lateral temporal lobe epilepsy with auditory features caused by LGI1 gene mutation and autoimmune epilepsy related to antibodies against an LGI1 gene product (VGKC complex).
The American Academy of Neurology (AAN) guidelines recommend strongly against AED prophylaxis in brain tumor patients without a history of seizures, since prophylaxis does not prevent the first seizure [7]. AED prophylaxis may be used peri- and post-operatively, but usually only for one week. Once seizures have occurred, AEDs must be chosen carefully due to interactions with chemotherapy and corticosteroids, as well as additive risk of bone marrow suppression. Thus, agents such as levetiracetam and lacosamide may be preferred.
The goal of seizure freedom must be balanced with tumor prognosis; seizure freedom may not be a goal with unresectable tumors. Surgical treatment must be divided into “tumor surgery” (curative) or “epilepsy surgery” (palliative). Poor prognostic factors for seizure control include longer epilepsy duration, lower tumor grade, seizures at time of tumor diagnosis, and incomplete resection. Surgery can be considered even in low-grade tumors with resistant epilepsy, even if stable on imaging. Imaging alone should not guide surgery, since peritumoral tissue can be epileptogenic. Video-EEG, electrocorticography, and functional mapping (e.g., language or motor function) should be used to guide resection.
Malformations of Cortical Development
Classification and understanding of malformations of cortical development (MCDs) continues to evolve. Most definitions are based on genetics, imaging, molecular biology, and pathology [8, 9]. Stem cells not only differentiate into neurons and glia, but they also migrate radially outward from the germinal matrix in the deep forebrain and periventricular regions. They also organize into “cytoarchitectonic” patterns, creating the six layers of neocortex. Any disruption in this process can lead to MCDs (i.e., normal cells in the wrong place, or abnormal cells in the right place).
Many MCDs are named based on descriptive anatomic terms and do not indicate a specific disease or genetic cause per se; in fact, many have overlapping pathology. Some occur in isolation as well as in the context of larger syndromes, such as hemimegalencephaly (HMEG). HMEG is characterized by a triad of intractable partial seizures from infancy, hemiparesis, and developmental delay; imaging readily identifies an enlarged, dysmorphic cerebral hemisphere. HMEG may occur in neurocutaneous syndromes, such as tuberous sclerosis complex (TSC) or neurofibromatosis. Functional hemispherectomy can improve seizure control and quality of life.
Lissencephaly (LIS) and subcortical band heterotopia (SBH) are two distinct phenotypes that may share similar genetic features. LIS is characterized by a “smooth brain” with absent or decreased convolutions (so-called agyria or pachygyria). SBH consists of an extra band of gray matter within the white matter (also known as “double cortex”). The classical form of LIS has a thickened, four-layer cortex and may have associated SBH. The autosomal dominant form of LIS is caused by LIS1 gene mutation and is typically more severe posteriorly, whereas the X-linked form is usually caused by DCX (“doublecortin”) gene mutation and is typically more severe anteriorly. The X-linked inheritance has important implications; males have the more severe phenotype of LIS, whereas females have the milder phenotype of SBH (e.g., mild developmental delay and seizure onset in teenage years).
Polymicrogyria (PMG) is characterized by excessive, small gyri. It may present as bilateral perisylvian polymicrogyria syndrome, consisting of seizures, aphasia, and oromotor dysfunction. Schizencephaly (SCZ) and porencephaly (POR) are both characterized by parenchymal “clefts”; SCZ typically has gray matter along the clefts (which is often PMG), whereas POR has a white matter lining. When SCZ is associated with optic nerve hypoplasia and absence of the septum pellucidum, this is known as septo-optic dysplasia (de Morsier syndrome), and screening for hypopituitarism is important.
Periventricular nodular heterotopia (PVNH) consists of gray matter nodules along the lateral ventricles due to failed neuronal migration (Fig. 14.2), often causing intractable focal seizures. PVNH may be associated with abnormal overlying cortex; there is debate as to whether both the nodule and cortex should be resected. PVHN must be differentiated from the subependymal nodules of TSC (Table 14.2). PVNH can be familial, most often due to the X-linked FLNA (filamin A) gene mutation. Genetic cases are typically female and have bilateral PVNH (presumably the mutation is lethal in males).
Fig. 14.2
Bilateral periventricular nodular heterotopia, as seen on T2-weighted MRI
Table 14.2
Comparison of periventricular lesions in two distinct neurological disorders
Tuberous sclerosis complex (subependymal nodules) | Periventricular nodular heterotopia |
|---|---|
Smaller | Larger |
Less in number | More in number, often bilateral |
Heterogeneous | Homogeneous |
Calcified | Not calcified |
White matter intensity on MRI
Related posts: New-Generation Antiepileptic Drugs
Other Pharmacological Therapies: Investigational Antiepileptic Drugs, Animal Models of Epilepsy, Hormonal Therapy, Immunotherapy
Procedures and Outcomes in Epilepsy Surgery
 Vagus Nerve Stimulation and Other Neuromodulation
 Magnetoencephalography and Magnetic Source Modeling
 Epilepsy Surgery Assessment and Testing
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