The Veterinary Journal 290 (2022) 105928

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The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

Neurosurgery in feline epilepsy, including clinicopathology of feline

epilepsy syndromes
Daisuke Hasegawa a, b, *, Shinichi Kanazono c, James K. Chambers d, Kazuyuki Uchida d
a
Laboratory of Veterinary Radiology, Nippon Veterinary and Life Science University, 1-7-1 Kyounancho, Musashino, Tokyo 180-8602, Japan
b
The Research Center for Animal Life Science, Nippon Veterinary and Life Science University, 1-7-1 Kyounancho, Musashino, Tokyo 180-8602, Japan
c
Neurology and Neurosurgery Service, Veterinary Specialists and Emergency Center, 815 Ishigami, Kawaguchi, Saitama 333-0823, Japan
d
Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Feline epilepsy is treated with antiseizure medications, which achieves fair to good seizure control. However, a
Cat small subset of feline patients with drug-resistant epilepsy requires alternative therapies. Furthermore,
Drug-resistant epilepsy approximately 50 % of cats with epileptic seizures are diagnosed with structural epilepsy with or without hip­
Epilepsy surgery
pocampal abnormality and may respond to surgical intervention. The presence of hippocampal pathology and
Epileptogenic zone
Hippocampus
intracranial tumors is a key point to consider for surgical treatment. This review describes feline epilepsy syn­
Hippocampal sclerosis drome and epilepsy-related pathology, and discusses the indications for and availability of neurosurgery,
Structural epilepsy including lesionectomy, temporal lobectomy with hippocampectomy, and corpus callosotomy, for cats with
Temporal lobe epilepsy different epilepsy types.

Introduction purebred dogs.

Feline epilepsy is classified into idiopathic, structural, and unknown
cause according to the consensus proposal by the International Veteri­
nary Epilepsy Task Force (IVETF; Berendt et al., 2015). While, tradi­
tionally, the presence of idiopathic epilepsy in this species has been
questioned, researchers have demonstrated recently that a considerable
number of cats with recurrent seizures have no identifiable underlying
structural conditions (Barnes et al., 2004; Schriefl et al., 2008; Bailey
and Dewey, 2009; Pakozdy et al., 2010, 2014; Wahle et al., 2014). While
spontaneous genetic epilepsy has not been documented other than in a
closed colony in a research setting called familial spontaneous epileptic
cats (FSEC; Kuwabara et al., 2010). This suggests, at least in part, the
documentation of inheritance may be difficult in the clinical setting of
this species. Additionally, the majority of pet cats are mixed-breed,
rescued, or adopted cats of unknown family lines, in contrast with
A recent epidemiologic study reported the prevalence of epilepsy
(including all types i.e., idiopathic, structural, and unknown cause) in
cats under primary veterinary care in the United Kingdom at 0.04 %,
based on the assessment by first-opinion veterinarians (O’Neill et al.,
2020), while it has been reported in higher prevalence at 1.6–2.4 % in
the referral setting (Schriefl et al., 2008; Pakozdy et al., 2010). In the
referral setting, the percentage of idiopathic and/or epilepsy of un­
known cause (EUC) in cats was reported between 22 % and 54 %, and
that of structural epilepsy was 34–50 % (Schriefl et al., 2008; Pakozdy
et al., 2010; Wahle et al., 2014).
Unfortunately, in contrast to canine epilepsy, there are no estab­
lished diagnostic criteria for feline idiopathic epilepsy (IE) or EUC.
Although a diagnostic approach is generally pursued in a similar manner
as that used in canines, veterinary clinicians often encounter diagnostic
challenges in this species. The relatively high prevalence of structural

Abbreviations: ASM, antiseizure medication; ATL, anterior temporal lobectomy; CC, corpus callosotomy; DRE, drug-resistant epilepsy; ECoG, electrocorticography;
EEG, electroencephalography; EUC, epilepsy of unknown cause; FEPSO, feline complex partial seizures with orofacial involvement; FHN, feline hippocampal ne­
crosis; FSEC, feline spontaneous epileptic cats; GFAP, glial fibrillary acidic protein; GTCS, generalized tonic-clonic seizures; HS, hippocampal sclerosis; IE, idiopathic
epilepsy; IVETF, International Veterinary Epilepsy Task Force; KA, kainic acid; LGI1, Leucine-rich glioma-inactivated protein 1; MRI, magnetic resonance imaging;
MST, multiple subpial transection; NeuN, neuronal nuclei; QOL, quality of life; SAH, selective amygdalo-hippocampectomy; TLE, temporal lobe epilepsy; VGKC,
voltage-gated potassium channel.
* Corresponding author at: Laboratory of Veterinary Radiology, Nippon Veterinary and Life Science University, 1-7-1 Kyounancho, Musashino, Tokyo 180-8602,
Japan.
E-mail address: disk-hsgw@nvlu.ac.jp (D. Hasegawa).

https://doi.org/10.1016/j.tvjl.2022.105928
Accepted 4 November 2022
Available online 5 November 2022
1090-0233/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
D. Hasegawa et al.
epilepsy overall in this species, even in young cats, might partially
contribute to the difficulty of making an accurate antemortem diagnosis
(Barnes et al., 2004; Schriefl et al., 2008; Pakozdy et al., 2010; Qahwash
and Heller, 2018). Among various etiologies underlying feline structural
epilepsy, infectious/inflammatory conditions are well-recognized chal­
lenges in diagnoses. Another diagnostic challenge may arise from some
specific types of ‘epilepsy syndromes’ in this species, such as feline
temporal lobe epilepsy (TLE), hippocampal sclerosis (HS), feline hip­
pocampal necrosis (FHN), and autoimmune limbic encephalitis.
Temporal lobe epilepsy and hippocampal lesions
Human and feline temporal lobe epilepsy
Temporal lobe epilepsy is the most common form of drug-resistant
epilepsy in humans, and 80 % of TLE patients benefit from surgery
(Blümcke et al., 2007). The typical seizure semiology of human TLE is
focal aware or impaired awareness seizures (formerly referred to as
complex partial seizures or psychomotor seizures), originating from
limbic structures, which have autonomic, psychic, sensory, or emotional
aura, orofacial automatism, dyscognition, and some motor signs with or
without secondarily generalization (Wieser, 2004; Beniczky et al., 2022;
Riney et al., 2022).
Temporal lobe epilepsy is one of the most actively investigated areas
in feline epilepsy, with a long history of experimental epilepsy studies
using cats, the FSEC colony (Fig. 1), and documentation of naturally
occurring spontaneous TLE (Kuwabara et al., 2010; Pakozdy et al., 2011,
2013a,b, 2017; Claßen et al., 2016; Kitz et al., 2017; Klang et al., 2018).
Feline complex partial seizures with orofacial involvement (FEPSO)
have been documented as a common seizure semiology in TLE in several
veterinary studies, and a possible link to the underlying etiology and
pathophysiology has been described (Kuwabara et al., 2010; Pakozdy
et al., 2011, 2013a,b, 2015; Kitz et al., 2017).
Hippocampal sclerosis in humans and cats
Histopathologic findings in surgically resected brain tissue from
human TLE patients include HS and malformations, as well as
neoplastic, ischemic, and inflammatory lesions. Hippocampal sclerosis is
the most common imaging and pathologic finding in human TLE, which
consists of selective loss of hippocampal neurons and reactive astro­
gliosis, and is thought to be a key factor for pharmaco-resistance in
human TLE (Blümcke et al., 2007; Wagner et al., 2014). HS in humans is
classified pathologically according to the predominantly affected area of
the hippocampus (Blümcke et al., 2007); typical lesions include severe
neuronal loss in CA1 and moderate loss in other subfields excluding CA2
Fig. 1. Hippocampal seizure recorded by depth electroencephalography (EEG) in a cat with temporal lobe epilepsy (familial spontaneous epileptic cat). (A) Fusion
image of preoperative T2-weighted MRI and post-electrode-implantation CT at the level of hippocampal head. Depth electrode with four electrodes was implanted to
bilateral parahippocampal gyri (① left; ③ right) and hippocampi (② left; ④ right). (B) Intracranial EEG monitoring caught a left hippocampal seizure (channel ②,
which was matched with the electrode number in (A). At the time of these hippocampal discharges, the cat showed head turning to the right.
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The Veterinary Journal 290 (2022) 105928
(type 1, classical type). In atypical cases, severe neuronal loss is
restricted to CA1 (type 2) or the hilar region (type 3).
The pathology of feline TLE has been studied in both experimental
models and spontaneous cases. Cats with experimentally-induced epi­
lepsy have hippocampal neuronal loss, necrosis, and gliosis, and have
been used as models of human TLE (Gastaut et al., 1959; Louis et al.,
1987). Similar pathological changes are observed in spontaneous cases
of feline TLE, which are described as HS or FHN. Both share histo­
pathological similarities with lesions that are observed in the brains of
human patients with TLE and autoimmune limbic encephalitis (Blümcke
et al., 2007; Bien et al., 2007).
A pathologic study in epileptic cats with HS demonstrated that CA3
and CA4 were frequently affected, which is different from the human
classical type (Wagner et al., 2014). Also, unlike in humans, in which
CA2 neuronal cells are spared, CA2 was often affected in cats. These
differences in affected areas between humans and cats may be explained
by the unique projection of mossy fibers in the feline hippocampus
(Hirama et al., 1997). Dentate gyrus granular cell dispersion is observed
in about 50 % of human and feline TLE patients. Immunohistochemistry
for neuronal nuclei (NeuN) can also be used to evaluate neuronal loss
and dispersion of the hippocampal pyramidal cell layer and dentate
gyrus in cats (Fig. 2; Yu et al., 2018). In a case report of hippo­
campectomy in a cat with epilepsy, hippocampal gliosis was confirmed
by immunohistochemistry for glial fibrillary acidic protein (GFAP;
Hasegawa et al., 2021a). In order to elucidate the temporospatial cor­
relation between the histological changes and clinical manifestation of
epilepsy in cats, further studies of surgically resected tissues, guided by
serial MRI and histopathological examination, are necessary.
Feline hippocampal necrosis
Another category of epilepsy syndromes in cats is FHN. Most cats
with seizure semiology consistent with TLE had histopathologically-
confirmed hippocampal necrosis or MRI findings consistent with hip­
pocampal necrosis (Pakozdy et al., 2011; Fig. 3). These hippocampal
findings have been investigated by various researchers, and multiple
etiologies are likely to be attributed to the development of FHN and/or
HS, including presumable toxic or environmental exposures, protozoal
or viral encephalitis, autoimmune limbic encephalitis, neoplasia,
vascular conditions, and a consequence of seizures (Fatzer et al., 2000;
Schmied et al., 2008; Altay et al., 2011; Pakozdy et al., 2011, 2013a,b;
Vanhaesebrouck et al., 2012; Wagner et al., 2014; Fors et al., 2015;
Klang et al., 2018). There is no term ‘hippocampal necrosis’ in human
patients with TLE. Lesions similar to FHN in humans have been
described as bilateral hippocampal edema/swelling, which is usually
observed on MRI in patients with status epilepticus due to autoimmune
D. Hasegawa et al. The Veterinary Journal 290 (2022) 105928

Fig. 2. Immunohistochemistry for neuronal nuclei (NeuN) demonstrates severe

loss of the hippocampal pyramidal cells in a feline temporal lobe epilepsy case
compared to and unaffected control cat. Bar, 50 µm.

or infectious limbic encephalitis (Kumar, et al. 2013; Szots, et al., 2014),

or described as bilateral hippocampal abnormalities including HS,
which results from chronic and/or bilateral TLE (Okujava, et al., 2004;
Miró, et al., 2015).
Although the pathomechanism of HS and FHN in cats is yet to be
elucidated, autoimmunity, ischemia, and toxins have been suggested as
the primary cause (Fatzer et al., 2000; Fors et al., 2015; Klang et al.
2018). Also, hippocampal malformation and space-occupying lesions
such as brain tumors have been reported in cases of FHN, suggesting
their direct or indirect involvement in the pathogenesis. However, it
remains unclear whether neuronal degeneration and necrosis, i.e., HS
and FHN, are the cause or result of the seizure activity, or possibly both
(Wagner et al., 2014; Fors et al., 2015; Klang et al., 2018; de Lahunta
et al., 2021). In a retrospective study of 35 cases consisted of FHN (13 Fig. 3. Magnetic resonance images of feline hippocampal necrosis in a cat with
cases) and HS (22 cases), 26 cases had inflammatory changes, including limbic status epilepticus. Bilateral hippocampi show hyperintensity on fluid-
attenuated inversion recovery (A) and contrast enhancement on T1-weighted
15 cases suggestive of autoimmune limbic encephalitis (Klang et al.,
image following administration of gadolinium (B). Although autoimmune
2018). Also, structural alterations of the dentate gyrus were found in
limbic encephalitis was strongly suspected, antibody measurement and histo­
three cases and neoplastic lesions were found in five cases (two oligo­ pathological examination were not performed in this case. Courtesy of Yasuda
dendrogliomas and three meningiomas). Oligodendroglioma, astrocy­ Animal Hospital, Yokohama, Japan.
toma, meningioma, and lymphoma have been also reported in other
cases of FHN (Vanhaesebrouck et al., 2012; Klang et al., 2015; Scalia
further research into the underlying conditions of autoantibody pro­
et al., 2021).
duction is warranted. A possible association between autoimmune
limbic encephalitis and FHN or HS has been demonstrated recently
Autoimmune limbic encephalitis
(Klang et al., 2018; Hasegawa et al., 2019).
In addition to gliosis and neuronal loss, various degrees of inflam­
A recent study demonstrated an association between acute FEPSO
matory cell infiltration and reactive capillaries are observed in the
and autoantibodies against voltage-gated potassium channel (VGKC)
hippocampus and, occasionally, in the piriform lobe of feline TLE cases
complexes/Leucine-rich glioma-inactivated protein 1 (LGI1), leading to
(Fatzer et al., 2000). Inflammatory cells consist mainly of histiocytes and
the first report of autoimmune limbic encephalitis in cats (Pakozdy et al.,
T cells, and, to a lesser degree, B cells and plasma cells (Klang et al.,
2013a,b). In that study, autoantibodies were positive in five of 14 cats
2014). In such cases, degenerated neuronal cells are immunohis­
with FEPSO. Analysis of sera from cats after immunosuppressive treat­
tochemically positive for IgG (Fig. 4), suggesting an autoimmune etiol­
ment demonstrated that the antibody titer had returned to within the
ogy. These findings are comparable to that of human limbic encephalitis,
reference range. Histological findings in these cats resemble what is
a common condition in human TLE patients with HS (Bien et al., 2007).
observed in VGKC encephalitis in humans and there is growing evidence
Limbic encephalitis is caused by various autoantibodies and could be
to support the presence of autoimmune limbic encephalitis in cats
associated with neoplastic diseases (i.e., paraneoplastic). Autoanti­
(Pakozdy et al., 2013a,b; Klang et al., 2014; Tröscher et al., 2017). This
bodies against LG1, a component of the VGKC complex, have been
discovery opened a new chapter in feline epilepsy and demonstrates that
detected in human and feline TLE cases (Klang et al., 2014).

3
D. Hasegawa et al.
Fig. 4. Immunohistochemistry for feline IgG demonstrates positive immuno­
labeling in degenerated hippocampal pyramidal cells in a cat with hippocampal
necrosis. Bar, 20 µm.
Histopathological examinations of the brains of affected cats have
shown degradation of blood-brain barrier tight junctions and immuno­
globulin leakage selectively in the limbic system, which may explain
why neuronal degeneration is restricted to the limbic system, even
though LGI1 is widely expressed in the brain (Tröscher et al., 2017).
However, inflammatory cells may infiltrate not only the limbic system
but also other areas of the brain, such as the cerebral cortex and white
matter. Perivascular infiltration of CD3-positive T cells is found in
reactive capillaries with transglutaminase 2-positive endothelial cells.
Elevated expression of transglutaminase 2 in the cerebral blood vessels
has been reported in rodent models of experimental autoimmune
encephalomyelitis, suggesting its involvement in cell migration (Pearse
et al., 2021). Recently, the authors have detected autoantibody against
netrin-1 receptor in a case of feline TLE (Hasegawa et al., 2019).
Other structural lesions in feline epilepsy
Besides HS and FHN, neoplastic, inflammatory, and vascular changes
in the brain can be associated with various types of seizures in cats.
Surgical resection may be applicable to treat space-occupying lesions
such as tumors and hematomas, but not likely in inflammatory diseases.
Epileptic seizures can be observed in cats with intracranial neoplasia,
among which meningioma is the most common (Tomek et al., 2006;
Klang et al., 2015; Orgonikova et al., 2021). Histopathologically, fibrous
and transitional meningiomas are the most common types of meningi­
oma in cats, which are classified as grade 1 meningioma in the human
tumor classification (Saito et al., 2021). In fact, most feline meningiomas
are slow-growing and well-demarcated, thus, have favorable prognosis
by surgery (Troxel and Vite, 2003; Cameron et al., 2015). Feline me­
ningioma can develop in the tela choroidea of the third ventricle, which
is located near to the dorsal hippocampi, and has been associated with
epileptic seizure (Klang et al., 2015). Similarly, the choroid plexus of the
lateral ventricle is lying on the hippocampus, and tumors in this region
may induce epileptic seizures. Other neoplastic diseases include gliomas
and lymphomas, although surgical treatment has not been performed in
most cases (Vanhaesebrouck et al., 2012; Tamura et al., 2013; Scalia
et al., 2021). As for vascular changes, focal hemorrhage and
space-occupying hematoma are sporadically seen in the brains of aged
cats in association with meningeal vascular mineralization (Youssef
et al., 2016), which may cause various types of seizures including
epilepsy.
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The Veterinary Journal 290 (2022) 105928
Antiseizure medication and drug-resistant epilepsy in cats
The overall long-term survival is good for many cats with IE/EUC
(Pakozdy et al., 2013a,b, 2014; Finnerty et al., 2014; Wahle et al., 2014;
Barnes, 2018), but a systematic review reported that evidence sup­
porting feline epilepsy treatment is weak to absent, in particular for the
efficacy of antiseizure medications (ASMs; Charalambous et al., 2018).
Recently, survival analysis in cats with EUC reported 34 % with com­
plete remission (seizure-free period of at least one year with ASMs), 37
% of cases with successful control (>50 % seizure reduction), and 29 %
of cases with insufficient seizure control (Szelecsenyi et al., 2017). An
accumulation of further relevant data will aid in guiding the treatment
strategy. Moreover, not only the limited number of available medica­
tions, but also potential challenges inherent in this species with daily
administration of ASMs may preclude successful management in main­
taining the good quality of life (QOL) of cats and caregivers.
A recent systematic review suggested that phenobarbital may be
considered the first choice ASM in feline epileptic management followed
by levetiracetam and imepitoin over diazepam, zonisamide, or pre­
gabalin (Charalambous et al., 2018). Phenobarbital has been reported to
provide the highest response rate (93 %) in seizure control within the
therapeutic serum concentration of 15–45 µg/mL (Finnerty et al., 2014).
However, high prevalence (47 %) of phenobarbital-associated adverse
effects has also been reported (Marsh and Corsini, 2021). These adverse
effects were mainly dose-dependent and, therefore, predictable from
phenobarbital’s known pharmacological properties (Hermans et al.,
2021). Diazepam and potassium bromide are contraindicated in this
species due to potentially lethal adverse events (Bhatti et al., 2015).
While drug-resistant epilepsy (DRE) in humans and dogs has been
well recognized and a prevalence of 22–30 % has been reported (Kwan
et al., 2011; Muñana, 2013; Tang et al., 2017), the prevalence of DRE or
an association between DRE and specific epileptic syndrome has not
been documented in cats. For cats with DRE, medical management,
often with multiple ASMs, could become far more challenging consid­
ering the inherent challenge with daily drug administration. Ancillary
treatment modalities in human DRE include dietary modification, life
cycle change, neuromodulation, and epilepsy surgery. In cats, however,
none have been established in the clinical setting so far, although sur­
gical management has been described recently in the clinical setting, as
well as in a cadaveric study (Hasegawa et al., 2021a, 2021b; Zilli et al.,
2021).
Many aspects of ‘epilepsy syndromes’ in cats overlap, as mentioned
above, thus, further understanding of these findings and the establish­
ment of readily available diagnostic tests differentiating the underlying
etiologies, if any, are warranted. Among these ‘epilepsy syndromes’ in
cats, FHN and limbic encephalitis may be noteworthy with respect to
treatment strategy, especially when cats fail to respond to conventional
ASMs. Currently, feline autoimmune limbic encephalitis is classified as
structural epilepsy (Pakozdy et al., 2017), and the treatment strategy for
this condition may require immunomodulating drugs, as well as con­
ventional ASMs, although a standard treatment protocol has not been
established. While invasive treatment such as surgery may risk exacer­
bating the underlying condition and/or carry a less favorable prognosis
compared to other etiologies such as EUC, a recent study in humans
reported some effect with epilepsy surgery in autoimmune limbic en­
cephalitis (Carreño et al., 2017).
Indications and availability of epilepsy surgery for feline
epilepsy
As described above the cat has been used as an animal model of
human epilepsy, some surgical procedures and efficacies of epilepsy
surgery have been evaluated using the feline model of seizures/epilepsy
in basic experimental studies (Magni et al., 1960; Reichenthal and
Hocherman, 1979, 1983; Hocherman and Reichenthal, 1980; Fukuda
et al., 1987; Oguchi et al., 1988; Okamoto, 1991; Tanaka and Yonemasu,
D. Hasegawa et al. The Veterinary Journal 290 (2022) 105928

Fig. 5. Flowcharts of the proposed strategy for feline epilepsy surgery. First of all, the case is diagnosed with idiopathic/unknown cause epilepsy (A) or structural
epilepsy (B) by neurologic examination, MRI, and CSF analysis. (A) In a case with idiopathic or unknown cause epilepsy, video and EEG analyses must be performed
to detect focal or generalized epilepsy and the seizure-originated cortex. If the cat has primary generalized seizures, corpus callosotomy will be recommended. If the
cat has typical temporal lobe epilepsy, functional neuroimaging and intracranial EEG (i.e., ECoG and/or depth EEG) will be performed and then temporal lobectomy
with amygdalo-hippocampectomy (TL with AH) for unilateral TLE or corpus callosotomy for bilateral TLE will be performed. If seizures originated from other cortex
than the temporal lobe, intracranial EEG should be performed to detect the epileptogenic focus. If the focus is identified in the eloquent area, multiple subpial
transections (MST) should be performed. While, if the focus locates in a non-eloquent area, cortical resection (CR) will be recommended. (B) On the other hand, if the
case is structural epilepsy, the location of the lesion(s) is the first fork. The next step in unilateral limbic or temporal lesion such as hippocampal sclerosis (HS) is TL
with AH via EEG or intracranial EEG. When a focal lesion is located in the unilateral hemisphere other than the temporal lobe, video and EEG analyses are needed to
confirm the agreement between seizure signs and lesional location. If yes, the lesion (or surrounding tissue) will have epileptogenicity, the lesionectomy should be
performed (combined with intraoperative EEG, if possible). If the lesion is not thought to relate to the seizure signs, a lesionectomy will be performed first, followed
by observation for postoperative seizure outcome and reassessment for a possible second surgery for remaining seizures. Additionally, if unilateral HS is present in
addition to the lesion, TL with AH should accompany the lesionectomy. When the lesion(s) distributes bilaterally or diffusely in the brain, for example, lissencephaly,
bilateral polymicrogyria, or unilateral ischemic encephalopathy, EEG should be performed to detect the location of the epileptogenic zone. Although lesionectomy
may be attempted if EEG abnormalities are observed focally, corpus callosotomy is recommended for generalized or multifocal EEG abnormalities. After that, if
seizures remained, a second surgery should be considered. CR, cortical resection; CSF, cerebrospinal fluid; DRE, drug-resistant epilepsy; EEG, electroencephalog­
raphy; EvGTCS, focal seizures evolving into generalized tonic-clonic seizures; FIMG, functional neuroimaging; HA, hippocampal atrophy; HS, hippocampal sclerosis;
MRI, magnetic resonance imaging; MST, multiple subpial transection; TL with AH, temporal lobectomy with amygdalo-hippocampectomy.

5
D. Hasegawa et al.
Fig. 5. (continued).
1994; Hashimoto et al., 1998; Tanaka et al., 2001). In the veterinary
field, feline patients with epileptic seizures caused by intracranial le­
sions, especially meningiomas, have been treated by surgical resection,
which often induces seizure freedom or excellent to good seizure control
(Troxel and Vite, 2003; Forterre et al., 2009; Cameron et al., 2015). For
practical consideration of epilepsy surgery in cats, the authors propose a
surgical strategy at this time as Fig. 5: this algorithm is made by ar­
ranging those in humans (Benbadis et al., 2018) and dogs (Hasegawa
et al., 2022). However, because approximately half of feline epilepsy is
structural, the starting point will be to determine whether the cat has a
structural lesion (structural epilepsy; Fig. 5B) or not (IE/EUC; Fig. 5A),
in contrast to dogs, where the diagnostic workup starts by determining
seizure type. There is a detailed description in the figure legend. This
section introduces some surgical techniques that may be applicable to
the epileptic brain in cats.
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The Veterinary Journal 290 (2022) 105928
Cortical resection, multiple subpial transection, and lesionectomy
As described above, approximately 50 % of cats with epilepsy have
structural lesion(s) in the brain such as HS, necrosis, and tumor. If non-
invasive presurgical evaluations such as ictal movie, MRI, and scalp EEG
suggest an association between the identified structural lesion and sei­
zures (Hasegawa, 2016), that lesion is considered as an epileptogenic
lesion. Additionally, if the lesion(s) is located in the superficial cortex,
which can be approached by conventional craniotomy, the lesion is a
good candidate for resection (i.e., lesionectomy). Ideally, preoperative
or intraoperative electrocorticography (ECoG) monitoring/measure­
ment is recommended to confirm whether the lesion is epileptogenic.
When ECoG reveals epileptiform discharges originating from the lesion,
the surgery could be completed by removing the lesion (lesionectomy).
Some lesions such as glioma or postinjury ulegyria have epileptogenicity
themselves, while others, such as necrosis, hematoma, or meningioma,
are not epileptogenic and the epileptogenicity may exist in the
D. Hasegawa et al. The Veterinary Journal 290 (2022) 105928

surrounding cortex affected by the lesion or in a remote area such as the

hippocampus and/or contralateral cortex. For example, in a cat with
epilepsy secondary to a mass lesion, removing the mass alone is not
sufficient from the viewpoint of epilepsy surgery. ECoG should be
measured on the compressed cortex after removing the mass, and, if
spikes are observed, cortical resection or multiple subpial transection
(MST) should be added (Tran et al., 1997; Mikuni et al., 2006). If a cat
has recurrent seizures following surgical resection of meningioma, the
epileptogenicity still remains in the brain. The procedures of cortical
resection and MST are described in another review for canine epilepsy
surgery of this special issue (Hasegawa, et al., 2022). Lesionectomy and
cortical resection are applied to the lesions such as tumors, cysts, he­
matomas, ulegyria followed by trauma, encephalitis, cerebrovascular
disease, previous surgery, or a non-lesional epileptogenic zone identified
by presurgical or intraoperative ECoG in IE/EUC. When a non-lesional
epileptogenic zone is detected in the eloquent area, MST should be
considered in order to avoid the postoperative dysfunction related to the
eloquent area.

Temporal lobectomy and hippocampectomy for feline TLE

In cats with drug-resistant TLE, regardless of the presence or absence

of a hippocampal lesion, temporal lobectomy including (amygdalo-)
hippocampectomy should be considered, as in human TLE. Anterior
temporal lobectomy (ATL) or selective amygdalo-hippocampectomy
(SAH) is the most common and effective resection surgery for human
mesial TLE, especially in patients with unilateral HS, and results in
seizure freedom in 70–90 % of patients (Téllez-Zenteno et al., 2010;
Engel et al., 2012). This could also provide promising possibility in fe­
line TLE with further investigation. So far, only three studies have
described temporal lobectomy or hippocampectomy in cats. The first
study was an experimental study where amygdalo-hippocampectomy
was performed using the unilateral amygdala kainic acid (KA) model
(Tanaka et al., 2001). In this study, amygdalo-hippocampectomy of the
KA-injected focus was able to inhibit recurrent seizures from the original
focus, but could not suppress the chronic spontaneous seizures origi­
nating from the contralateral hippocampus (the secondary focus). The
second study was a cadaveric study describing hippocampectomy in cats
(Zilli et al., 2021). In this study, the ectosylvian gyrus (temporal cortex)
was removed partially to facilitate entry into the lateral ventricle, and
the middle part of the hippocampus was removed, but the head and tail
remained. The third study was a clinical case with DRE, presumably
caused by congenital temporo-occipital and hippocampal atrophies, that
was identified as the epileptogenic zone by presurgical evaluations
(Hasegawa et al., 2021a). In this case study, focal cortical resection of
part of temporal and occipital cortex and total unilateral hippo­
campectomy (Fig. 6) was performed in two-stages and achieved a
marked seizure reduction (>85 % reduction) without apparent surgical
complications, although the unilateral forebrain signs and bilateral
blindness recognized prior to surgery remained unchanged. Despite the
short-term marked reduction in seizure frequency, this cat had recurrent
seizures originating from the contralateral side, i.e., a secondary
epileptogenic focus, which was also documented in the previously
mentioned experimental study. Therefore, these promising surgical
procedures, feline temporal lobectomy and hippocampectomy, require
further technical improvement, clinical data accumulation, and the
establishment of surgically appropriate timing, i.e., before generating
secondary epileptogenicity, as generally recommended in human ATL
and SAH. There is a case report of a similar approach to the base of
temporal lobe to remove a meningioma in a cat with epileptic seizures
(Forterre et al., 2009).
Corpus callosotomy for generalized seizures
Corpus callosotomy (CC), which bisects the corpus callosum longi­
tudinally and removes the majority of cortical connections between both
Fig. 6. Transverse T2-weighted images of before (A) and 180 days after (B)
hippocampectomy in a cat with drug-resistant epilepsy with the right hippo­
campal and temporal cortical atrophy. Atrophied hippocampus (arrows) and
some of temporal cortex were removed.
hemispheres, has been established as a common palliative surgery for
intractable primary generalized and secondarily generalized (focal to
bilateral tonic-clonic) seizures in human epilepsy (Asadi-Pooya et al.,
2008; Graham et al., 2016). In humans, CC is most effective for drop
attacks such as atonic seizures or myoclonic seizures, and also results in
fair to good outcomes for generalized tonic-clonic seizures (GTCS). In
addition, it is important that CC not only reduces seizures, but also
substantially improves cognition, activity, and QOL. Historically, CC has
been studied in cats in basic experimental studies of CC using kindling,
penicillin, and KA models as cited above. Most of these experimental
studies reported stereotaxic (i.e., blind) CC, which may not be suitable
for clinical use given possible serious complications, some potentially
fatal. We suggest that CC in cats, as well as in humans and dogs, should
be performed with microsurgery. At present, there is only one case
report that performed CC in a cat with DRE (Hasegawa et al., 2021b). In
that report, the cat had a history of many myoclonic seizures and GTCS
daily, as well as non-ambulate deep somnolence, preoperatively.
Although complete CC was not achieved (Fig. 7), after surgery, 76 %
seizure reduction was noted and the cat showed remarkable improve­
ment in awareness and ambulatory function. However, focal motor
seizures were recognized for the first time after surgery, suggesting that
the seizures presumed to be GTCS preoperatively were actually focal to
bilateral tonic-clonic seizures. Corpus callosotomy may be effective in

7
D. Hasegawa et al. The Veterinary Journal 290 (2022) 105928

surgery using cats as laboratory animals may be useful for forecasting

postoperative complications in this species (e.g., Thompson, et al.,
1963a, b). That information, and further investigations, would help
determine the risk associated with surgical procedures and preserve
intact cerebral function as much as possible. When the epileptogenic
zone or lesion is identified in the primary cortex, i.e., the eloquent area,
MST with intraoperative ECoG would be recommended instead of
cortical resection.
In our limited experience of epilepsy surgery, most animals with DRE
had numerous (at intervals from tens of seconds to several minutes)
clinical or subclinical seizures preoperatively, which may disturb
normal brain functions and cause altered consciousness, decreased
neurological responses, and daily activity. Their consciousness, re­
sponses, and activity significantly improved after epilepsy surgery,
particularly associated with decreased seizure activities. The owners of
the animals that underwent epilepsy surgery were satisfied with the
outcomes and QOL after epilepsy surgery (Asada et al., 2021; Hasegawa
et al., 2021a, b). Similarly, in humans with severe DRE such as hemi­
megalencephaly and Rasmussen syndrome, surgical treatment, even
with some sacrifice of neurologic functions, may be preferred to prevent
mental retardation and substantial disability due to severe seizures.
Because our feline (and canine) patients have a certain degree of toler­
ance to brain damage compared to humans (Uemura, 2015), epilepsy
surgery could be considered as a practical and feasible option in veter­
inary medicine with the continuous accumulation of various data and
experience.

Conclusions

Feline epilepsy is generally well controlled with ASM(s). However, a

small number of cats with epilepsy, especially with structural lesions
such as hippocampal abnormalities, are drug resistant. In contrast to
canine epilepsy, TLE exists in the feline epilepsy population and will be a
good candidate for surgical treatment. Although further studies and
accumulation of cases are needed, lesionectomy, cortical resection,
temporal lobectomy with hippocampectomy, and corpus callosotomy
Fig. 7. Midline sagittal T2-weighted images before (A) and after (B) corpus
are available for cats with DRE. In addition, with increasing opportu­
callosotomy in a cat with drug-resistant generalized epilepsy. Total callosotomy
nities to perform epilepsy surgery, pathological and pathophysiological
was attempted, but the genu (arrowhead) remained. Necrotic lesion is observed
in the cingulate gyrus (arrow). data will be accumulated and contribute resolving the mechanism of
DRE and discovering new drugs and surgical techniques in this species.
seizure control and improving QOL for cats with generalized seizures,
which does not require identifying the epileptogenic zone. Because
Conflict of interest statement
neuromodulation devices for vagus nerve stimulation or deep brain
stimulation for cats are size- and/or cost-prohibitive, CC may be a
None of the authors of this paper has a financial or personal rela­
selectable treatment option for feline DRE. However, as with other
tionship with other people or organizations that could inappropriately
procedures, further experience and large-scale studies are needed to
influence or bias the content of the paper.
establish the efficacy of CC in cats. Recently, other techniques such as
stereotactic laser CC or radiosurgical CC have been developed in human
Acknowledgements
medicine (Badger et al., 2020; Tripathi et al., 2021; Vaddiparti et al.,
2021). These advanced and less-invasive CC techniques may be
This article is partially supported by the Grant-in-Aid for Scienctific
considered for veterinary patients in the future.
Research from the Japan Society for the Promotion of Science (grant
number 17H01507) and the Science Research Promotion Fund from the
Complications and expectations of veterinary epilepsy surgery
Promotion and Mutual Aid Corporation for Private School of Japan
(grant number 2022-16). The authors thank Drs. Miyoko Saito, Junya
Complications of epilepsy surgery (both resection and disconnection
Hirashima, Masato Kitagawa, Daisuke Ito, Rikako Asada, Satoshi Miz­
surgeries) in cats have not been studied enough in clinical veterinary
uno, Yoshihiko Yu (he also critically read the manuscript), and Yuji
medicine. Except for our unpublished single feline case that died of
Hamamoto as colleagues of Veterinary Epilepsy Surgery Team.
cerebral hemorrhage and cerebral edema as intraoperative complica­
tions, a very limited number of published papers have not reported
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