Epilepsy secondary to specific mechanisms

Question 1

Treatment of autoimmune epilepsy

Answer 1

Antiepileptic drugs (AEDs) alone will not suffice as treatment, and a protracted course of multiple immunotherapies may be needed (often over weeks or months).

Question 2

When should autoimmune epilepsy be considered?

Answer 2

Autoimmune epilepsy should be considered early in cases of limbic encephalitis, new-onset refractory epilepsy, or new-onset status epilepticus. Features that favor autoimmune epilepsy include encephalopathy, cognitive decline, personality changes, a movement disorder, or prominent psy- chiatric symptoms (psychosis, catatonia, and agita- tion). Additional “red flags” include autoimmune stigmata (type 1 diabetes mellitus, thyroid disease, celiac disease, and vitamin B12 deficiency) or a history of cancer (or strong cancer risk factors). Stiff person syndrome, type 1 diabetes mellitus, and autoimmune encephalitis can all be associated with anti-glutamic acid decarboxylase (GAD) antibodies.

Question 3

Work-up for autoimmune epilepsies

Answer 3

In any suspected cases, antibody testing and malignancy screening are necessary. Antibodies should be tested in both serum and CSF, though they may be found more consistently in the CSF. Routine CSF studies (cell counts, oligoclonal bands, and IgG index) are usually normal. MRI should be performed with contrast, but this can also be normal. Cancer investigation should include whole-body PET/CT; in select cases, ultrasound, endoscopy, or mammography may be needed.
Antibody testing in the serum and CSF is available both commercially and through private universities. Newer and rarer antibodies may not be available commercially or may not be inclu- ded on the commercial panels. Antibodies can be classified as cellular (“onconeural”) or cell membrane. The cellular antibodies have a stronger association with cancer, though these are thought to represent an epiphenomenon and are not necessarily pathogenic. Cellular antibody-mediated diseases may be poorly responsive to immunotherapy and require an exhaustive search for malignancy. A recent review [3] has an excellent discussion of the most common antibodies, their classifications, and common cancer associations. A brief over- view is given in Table 14.1.

Question 4

VGKC associated epilepsy

Answer 4

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 eizures, confusion, amnesia, and myoclonus (thus mimicking Creutzfeldt–Jakob disease). There is often associated hyponatremia. Both seizures and MRI abnormalities (T2 hyperinten- sity, restricted diffusion, or contrast enhance- ment) are typically in the temporal regions, though generalized seizures may also occur. Variations in presentation may relate to the dif- ferent antibody targets within the VGKC com- plex; laboratory results may be reported by the specific target (CASPR2, LGI1, and contactin-2). LGI1-associated disease may present with faciobrachial dystonic seizures (FBDS), charac- terized 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 cog- nitive impairment, which can delay diagnosis.

Question 5

NMDA-R associated epilepsy

Answer 5

Another important autoimmune epilepsy is related to anti-N-methyl-D-aspartate receptor (NMDA-R) antibodies. This is classically descri- bed as a paraneoplastic syndrome associated with ovarian teratoma, though it is often
non-paraneoplastic. Typical symptoms include seizures, confusion, catatonia, amnesia, choreoa- thetosis, and dysautonomia. Anti-NMDA-R anti- body 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” pat- tern on EEG may be a unique finding in anti-NMDA-R encephalitis

Question 6

Four-pronged approach to treachment of autoimmune epilepsies

Answer 6

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 usu- ally 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.

Question 7

VGKC complex

Answer 7

Question 8

NMDA receptor

Answer 8

Question 9

GAD

Answer 9

Question 10

Ma

Answer 10

Question 11

ANNA-1 (Hu)

Answer 11

Question 12

CRMP-5

Answer 12

Question 13

Amphiphysin

Answer 13

Question 14

GABA receptor

Answer 14

Question 15

ANNA-2 (Ri)

Answer 15

Question 16

AMPA receptor

Answer 16

Question 17

Tumors that tend to be more epileptogenic

Answer 17

In general, the following tumors are more epileptogenic: adult-onset tumors (which tend to be supraten- torial, 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.

Question 18

Which types (pathology) of tumors are associated with seizures

Answer 18

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 presen- tation may increase the risk of recurrent seizures and refractory seizures, possibly independent of treatment.

Question 19

Epileptogenicity related to peritumoral tissue and genetic factors

Answer 19

Epileptogenicity may relate to both peritu- moral (non-neoplastic) tissue as well as genetic factors. Higher grade tumors may have central necrosis and be electrically silent, whereas sur- rounding 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 fea- tures caused by LGI1 gene mutation and autoimmune epilepsy related to antibodies against an LGI1 gene product (VGKC complex).

Question 20

AED prophylaxis in brain tumors

Answer 20

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 corticos- teroids, as well as additive risk of bone marrow suppression. Thus, agents such as levetiracetam and lacosamide may be preferred.

Question 21

Goals of treatment in epilepsy associated with brain tumors

Answer 21

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 incom- plete 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.

Question 22

How are malformations of cortical development defined?

Answer 22

Most definitions are based on genetics, imaging, molecular biology, and pathology [8, 9].

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 iso- lation as well as in the context of larger syn- dromes

Question 23

What is the general mechanism thorugh which malformations of cortical development come into being?

Answer 23

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).

Question 24

Hemimegalencephaly (HMEG)

Answer 24

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.

Question 25

Lissencephaly (LIS) vs subcortical band heterotopia (SBH)

Answer 25

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 inheritanchas important implications; males have the more severe phenotype of LIS, whereas females have the milder phenotype of SBH (e.g., mild devel- opmental delay and seizure onset in teenage years).

Question 26

Polymicrogyria (PMG)

Answer 26

Polymicrogyria (PMG) is characterized by excessive, small gyri. It may present as bilateral perisylvian polymicrogyria syndrome, consisting of seizures, aphasia, and oromotor dysfunction.

Question 27

Schizencephaly (SCZ) vs porencephaly (POR)

Answer 27

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 dys- plasia (de Morsier syndrome), and screening for hypopituitarism is important.

Question 28

Periventricular nodular heterotopia (PVNH)

Answer 28

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 sei- zures. 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).

Question 29

TSC vs PVNH

Answer 29

Question 30

FCD

Answer 30

Focal cortical dysplasias (FCDs) can also cause intractable focal seizures. Typical MRI findings include blurred gray–white junction, thickened cortex (Fig. 14.3), or the transmantle sign (a band of T2 hyperintensity extending radially between the cortex and ventricle). Many FCDs are subtle or not visible on MRI and may be found on functional imaging (PET or interictal SPECT, see Fig. 14.3). FCDs can be classified by pathological severity [10, 11]; more severe pathology has better prognosis, possibly due to being more visible on MRI or due to having better defined resection margins [12]. The mildest type is known as microdysgenesis. The intermediate type (Type I) may or may not be seen on MRI. The most severe type (Type II) can have “balloon cells” on pathology (Type IIb). Type III refers to dual pathology (FCDs associated with other lesions, such as tumors or mesial temporal sclerosis)

Per MB - IIb is the best for resection
I/IIa can have more diffuse disease
EEG signature is low amplitude spiking
You see beta with FCD on intracranial EEG

(https://www.sciencedirect.com/science/article/abs/pii/S0920121117304497)

Question 31

Early vs late post-traumatic seizures

Answer 31

Post-traumatic seizures are classified as early (within the first week) and late (after the first week).

Question 32

What is nearly synonymous with epilepsy in post-traumatic seizures?

Answer 32

A single late unprovoked post-traumatic sei- zure is nearly synonymous with epilepsy, and the terms may be used interchangeably. In one study, the risk of seizure recurrence after a single late seizure was 86% within two years [13]. Therefore, only one late seizure is necessary to diagnose epilepsy and strongly consider AED treatment.

Question 33

Early post-traumatic seizures and the development of epilepsy

Answer 33

Approximately 10% of patients with early post-traumatic seizures develop epilepsy; how- ever, multivariate analysis has shown that this can be explained by factors other than the early sei- zures themselves [14]. Also, early status epilepti- cus may have a higher risk for late seizures.

Head trauma may be classified as mild, moderate, or severe (Table 14.3). The presence of early seizures in combination with moderate or severe head trauma increases the risk of developing epilepsy [15]. Early seizures in mild head trauma do not necessarily increase that risk. In fact, there may be an association between mild head trauma and PNES. In children under five years of age, early seizures after head trauma are more common, but these are less predictive of epilepsy as compared to adults.

Question 34

Grading of head trauma severity

Answer 34

Question 35

Seizure prophylaxis and head trauma

Answer 35

Prophylactic treatment is only recommended in certain situations, and the evidence is strongest for prevention of early seizures in adults; data in children is insufficient. The AAN guidelines recommend phenytoin prophylaxis in adults with severe brain injury, but only for the first week; evidence does not suggest benefit of longer duration of prophylaxis in preventing late sei- zures [17]. Per a Cochrane review, the number needed to treat in preventing early seizures is ten, though maintaining first-week seizure freedom does not reduce mortality, disability, or late sei- zures [18]. There is no evidence for the use of steroids to prevent seizures.

Question 36

Seizure as presenting symptom of stroke; epilepsy risk after stroke in different age groups

Answer 36

Seizure as the presenting symptom of stroke is very common in neonates (about 80%), relatively common in children (about 30%), and rare in adults; epilepsy risk after pediatric stroke can be up to 40%, whereas the risk in adults is less than 5%

Question 37

Early vs late post-stroke seizure

Answer 37

Post-stroke seizures are classified as early (within the first week) or late (after the first week), similar to post-traumatic seizures.

Question 38

Late post-stroke seizures

Answer 38

Even one late unprovoked post-stroke seizure has a high recurrence rate (>50%), and AED treatment should strongly be considered. Therefore, as in head trauma, late post-stroke seizures are nearly synonymous with epilepsy.

Question 39

Predictors of post-stroke epilepsy in adults

Answer 39

Predictors of post-stroke epilepsy in adults include cortical location, presence of hemor- rhage, and stroke severity (based on examination and NIH stroke scale) [19]. The EEG is not consistent in predicting epilepsy after stroke.

Question 40

EEG in stroke (adults)

Answer 40

Lateralized periodic discharges (LPDs, formerly known as periodic lateralized epileptiform dis- charges or PLEDs) are considered a classic finding in stroke and may be predictive of sei- zures, but they are not common, and may only predict early seizures and not necessarily later epilepsy. The most common finding is slow activity (focal or generalized), which is non-specific and not predictive of seizures.

Question 41

Treatment of early post-stroke seizures

Answer 41

A re- cent Cochrane review [20] has not found strong evidence that treating early post-stroke seizures prevents the development of epilepsy, although only one of the studies reviewed met inclusion criteria as a randomized controlled trial designed to address this question.

Question 42

MTS in patients with and without epilepsy

Answer 42

Mesial temporal sclerosis (MTS), also known as hippocampal sclerosis, is one of the most com- mon causes of adult-onset epilepsy, especially refractory epilepsy. However, it has been found in up to 14% of adults without epilepsy [21]

Question 43

MTS semiology and EEG (both MTS and extratemporal onset)

Answer 43

Classic semiology can include abdominal auras (nausea, pressure, butterflies, and epigastric ris- ing), fear, an unpleasant taste or smell, oroali- mentary or (ipsilateral) limb automatisms, and autonomic phenomenon. The typical ictal EEG pattern consists of anterior temporal rhythmic theta or alpha activity, which often exceeds 5 Hz within 30 s of seizure onset [22, 23]. Though many cases may have bilateral temporal onset on scalp (bisynchronous or independent), this does not necessarily rule out surgery. However, since seizures may start elsewhere and spread to the mesial temporal region, a primary extratemporal localization may be the source of seizures, even when semiology and ictal EEG patterns are pre- dominantly temporal

Question 44

MRI findings of MTS

Answer 44

The most common MRI finding in MTS is hippocampal hyperintensity on T2-weighted sequences (e.g., FLAIR). However, this is not very reliable. Hippocampal atrophy is the most specific finding, usually noted on T1-weighted, hin cut imaging (Fig. 14.4) [24]. When com- paring hippocampal volumes, asymmetry of the temporal horns of the lateral ventricle should not be over-interpreted as MTS. Additionally, even if MRI is normal, PET may show temporal hypo- metabolism suggestive of MTS. A recent study found good surgical outcomes after temporal lobectomy in patients with PET-positive, MRI-negative temporal lobe lesions [25], com- parable to the typical MRI-positive MTS patients.

Question 45

Cause of MTS

Answer 45

The cause of MTS is unclear. There may be a relationship between MTS, early complex febrile seizures, and childhood head trauma, but cause and effect remain controversial. Often there is a latent period between the injury and seizure onset, but it is not clear whether the MTS noted on imaging was either not previously present, not apparent since the brain was still developing, or not able to be studied by current imaging techniques.

Question 46

Histopathology of MTS

Answer 46

Histopathology in MTS usually involves neuronal loss and gliosis in the CA1, CA3, and CA4 hippocampal regions, with relative sparing of CA2.

Question 47

Surgical treatment for MTS

Answer 47

Surgical experience has noted two important areas outside the hippocampus that usually require resection to achieve a good sei- zure outcome: the parahippocampal gyrus and the amygdala. Because MTS is so common, and so amenable to surgical resection, new-onset temporal lobe epilepsy at any age warrants evaluation for MTS. Dual pathology (MTS with coexistent neoplasms, MCDs, or vascular lesions) may require resection of both lesions for a good outcome.

Predictors of good postsurgical outcomes include later age at onset, shorter duration of epilepsy, presence of febrile seizures, positive MRI (or positive PET with negative MRI), uni- lateral findings on PET, concordant data (matching of localization based on semiology, EEG, functional imaging, and anatomical imag- ing), and the lack of need for intracranial moni- toring. In a typical case of MTS, the chance of seizure freedom after resection is approximately 60–70%. Surgical options include selective amygdalohippocampectomy, tailored temporal lobectomy (sparing dominant eloquent function), hippocampal laser ablation, and standard anterior temporal lobectomy.

Question 48

Which vascular malformations are most and least associated with epilepsy?

Answer 48

Epilepsy is most strongly associated with arteri- ovenous malformations (AVMs) and cavernous malformations (CMs). Developmental venous anomalies (DVAs) are usually incidental findings and not epileptogenic.

Question 49

What is the epileptogenic tissue in vascular lesions?

Answer 49

In most vascular malformations, the surrounding hemorrhage, gliosis, and encephalomalacia are the epileptogenic tis- sues; the vascular lesions themselves are silent since they do not contain neuronal structures.

Question 50

Goals of surgical management in vascular malformations

Answer 50

Surgical management should have dual goals of seizure freedom and hemorrhage prevention. Electrocorticography-guided resection may have better seizure outcomes, as opposed to pure structural lesion-guided resection, especially in temporal CMs [26]. Stereotactic radiosurgery is also an option in AVMs.

Question 51

AVMs and epilepsy

Answer 51

An AVM is a direct connection between arteries and veins, without capillaries in between. These appear as a small collection of signal void on MRI.

In a recent large population study [27], risk of new-onset seizure over five years in patients with incidental AVMs was 8%, but the risk increased to 23% if the AVM had previously caused hem- orrhage or a focal neurological deficit.

Question 52

CMs and epilepsy

Answer 52

CMs are also known as cavernous angiomas or cavernomas, consisting of small bundles of brittle vascular endothelium (not true vessels) that lead to recurrent bleeding. On MRI, they are heterogeneous, with a core of mixed signal intensity surrounded by a T2 or gradient-echo hypointense rim (presumably hemosiderin). Familial CM syndromes have been reported, usually with autosomal dominant inheritance; some patients also have cutaneous and retinal involvement.

A recent large population study noted that CMs carried a similar risk (4–6%) of new-onset seizure, whether the CM was incidental or symptomatic. There was a suggestion that AVMs (but not CMs) in the temporal lobe were more likely to cause seizures.

Question 53

Venous angiomas and DVAs

Answer 53

Venous angiomas and DVAs rarely cause seizures or hemorrhage and are most often inci- dental. Resection should probably be avoided, as the epileptogenic focus may be unrelated to these lesions. A recent review of fifteen studies (with a combined 714 patients at the time of DVA diagnosis) found that 61% of DVAs were inci- dental findings, 6% were associated with focal neurologic deficits, 6% with symptomatic bleeding, and 4% with seizures; the presenting symptoms were unclear in the remaining 23% [28]. This study also prospectively analyzed an adult DVA population in Scotland, noting that 98% of DVAs (in 93 patients) were incidental.