VIEWS & REVIEWS

Radwa A.B. Badawy,

MBBCh, PhD
Alan Lai, B Eng, PhD
Simon J. Vogrin, BAppSci
Mark J. Cook, FRACP,
PhD

Correspondence to
Dr. Badawy:
badawyr@unimelb.edu.au

Subcortical epilepsy?

ABSTRACT

In the past, the cortex has for the most part been considered to be the site of seizure origin in the
different forms of epilepsy. Findings from histopathologic, electrophysiologic, and brain imaging
studies now provide ample evidence demonstrating that like normal cerebral function, epileptic
seizures involve widespread network interactions between cortical and subcortical structures.
These studies show that different forms of generalized and focal epileptiform discharges and
seizures engage various subcortical structures in varying ways. This interaction has been the subject of many reviews and is not the focus of the current work. The aim of this review is to examine
the evidence suggesting the possibility for some of the subcortical structures to initiate seizures
independently and the clinical implications of this. Neurology 2013;80:19011907
GLOSSARY
DBS 5 deep brain stimulation; GSW 5 generalized spike-wave discharges; VNS 5 vagus nerve stimulation.

In the late 19th century, Hughlings Jackson proposed his concept on the origins of epilepsy.1 In
his proposal, he regarded epileptic seizures as being due to a neuronal discharge. This moved the
site of origin of epileptic seizures to the cerebral cortex, included focal seizures as part of the
epilepsy spectrum, and discarded the idea of epilepsy being due to a peripheral reflex mechanism. For a long time after that, epilepsy was considered to be mostly cortical in origin, with
little attention to other structures. Even with the development of the centrencephalic concept
proposed by Penfield and Jasper2 in 1954, which drew attention to the complex integration of
several systems (including the thalamus and brainstem) for the facilitation and spread of epileptic
activity, a cortical basis for epilepsy remained the predominant theme. This was mainly due to
the controversy about the relative importance of subcortical structures in animal and human
literature. The last few decades have changed this and there is now ample animal and human
neuropathologic, imaging, and electrophysiologic evidence to suggest a more complex cortical
subcortical interaction as the basis of the epileptic process.3 It is also plausible that any lesion
with inherently epileptogenic neurons anywhere in the CNS might produce epileptic seizures if
functional connections are retained. The purpose of the present review is to examine the evidence supporting a subcortical role in the initiation of seizures. It is not our intention to
de-emphasize the role of the cortex. We mainly aim to consider the evidence suggesting the
possibility of subcortical epilepsy as a clinical entity.
SUBCORTICAL EPILEPSY: A CLINICAL ENTITY? Thalamus.

Supplemental data at
www.neurology.org

Evidence supporting 3 Hz spike-and-wave seizure initiation in the thalamus has been suggested in early human intracranial recordings2,4,5 and it is welldocumented (based on animal models of absence epilepsy) that cortex and thalamus as well as their connecting
pathways (figure 1) are necessary for generating generalized spike-wave discharges (GSW) and typical absence
seizures.68 Networks that involve the thalamic reticular nucleus and T-currents of the thalamic relay cells are
similar to those thought to be responsible for generating sleep spindles,9 which involves a complex interaction
of excitatory and inhibitory firing of thalamic reticular, thalamic relay, and neocortical pyramidal neurons. A
disturbance within this interaction is thought to result in the generation of the rhythmic burst firing underlying
From the Department of Clinical Neurosciences (R.A.B.B., S.J.V., M.J.C.), St Vincents Hospital, Sydney; Departments of Medicine (R.A.B.B.,
S.J.V., M.J.C.) and Electrical and Electronic Engineering (R.A.B.B.), The University of Melbourne, Melbourne; and Bionics Institute (A.L.B.E.),
East Melbourne, Victoria, Australia.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
2013 American Academy of Neurology

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Figure 1

Thalamocortical circuits

Thalamocortical connections thought to be involved in generation of generalized spike-wave

discharges.

spike-wave complexes.911 Further support comes

from PET studies12 and changes in water diffusion
and volume reduction in the thalamus and caudate on
diffusion tensor and volumetric MRI.13 There is also
strong evidence for more extensive subcortical
involvement in GSW and absence seizures on combined EEG and functional MRI studies. These studies demonstrate that during GSW and absence
seizures there is prominent activation in the thalamus
and cerebellum in addition to the signal activation
changes seen in primary cortical areas (reviewed in
reference 14). Conversely, there is evidence of deactivation in the caudate and posterior brainstem including the reticular formation alongside of cortical
association areas (reviewed in reference 14). This suggests that thalamic and cerebellar activation is associated with GSW and absence seizures correlate to a
widespread brain hyperexcitability.
There are also reports suggesting thalamic epileptogenicity in patients with other forms of epilepsy.
Features suggestive of generalized epilepsy following
unilateral stereotaxic thalamotomy were found in 4
patients with parkinsonism (among 1,500 procedures).15 Although clinical symptoms were sometimes
atypical, all 4 patients had an EEG at some point
demonstrating bilaterally synchronous spike-andwave discharges. In addition, with neuroimaging
techniques becoming available for more patients, thalamic lesions are being found in several patients with
focal or multifocal motor seizures,16 rotatory seizures,17 and infantile spasms.18 While this lesion could
be a coincidental finding in those particular patients,
this is unlikely to be the case in children with the
syndrome of epilepsy with continuous spike-wave
during slow-wave sleep, in whom evidence of perinatal thalamic injury is not an uncommon finding.1820
More recently, several patients with clinical histories
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compatible with idiopathic generalized epilepsy and

who had unilateral thalamic lesions associated with
GSW on EEG have been reported.19,21,22 Three of
those patients had intractable seizures19,22 and one
patient had a history of absence attacks in childhood
in whom absence status with GSW developed after a
left-sided thalamic ischemic insult.21 Unilateral thalamic lesions associated with both GSW (figure 2) as
well as persistent lateralized epileptiform discharges
ipsilateral to the lesion on EEG were found in 4 other
patients.23 Two of those patients had a long history of
intractable epilepsy, while the other 2 presented with
recent onset seizures. There was a strong temporal
relation between the emergence of the thalamic lesion
and occurrence of GSW and focal discharges in those
latter patients. While the coexistence of thalamic
lesions can be explained as a downstream effect of
seizures in longstanding epilepsy (see before), and
the GSW can be due to secondary bilateral synchrony24 in patients who also had cortical (frontal)
lesions, the temporal relation between the thalamic
lesion and GSW suggests a thalamic role for the initiation of the epileptic process in these patients. The
lesion may have altered the integrity of the thalamocortico-thalamic circuits, generating abnormal rhythmic oscillations recruiting the contralateral cortex
through the corpus callosum.21 A less likely theoretical possibility is that the lesions were only activating
an otherwise silent genetically determined GSW pattern. Another possibility is that the presence of such
lesions may be simply the factor of imbalance in
tightly interconnected thalamocortical circuits. In this
case, irrespective of the size or nature of the lesion, it
would disrupt the equilibrium of the thalamocortical
circuits and thus lead to seizures. Nevertheless, these
reports suggest that patients with an electroclinical
picture consistent with idiopathic generalized epilepsy
especially if refractory or atypical may indeed be
driven by an underlying structural thalamic abnormality. Clearly this requires further investigation,
and warrants consideration of MRI of patients with
this clinical presentation.
Hypothalamus. Hypothalamic hamartomas are developmental malformations that occur in the region of
the tuber cinereum and inferior hypothalamus. This
syndrome is the best example of subcortical pathology
causing epilepsy. The hallmark feature of the syndrome
is frequent, brief, stereotyped episodes of ictal laughter,
or gelastic seizures, which often begin in infancy or
early childhood.25 This is usually followed by other
seizure types and cognitive and behavioral problems,
all of which are refractory to antiepileptic drug therapy.26 Though many of these patients have surface and
intracranial EEG evidence suggestive of focal seizure
onset in the temporal (figure 2) or frontal lobes,

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Figure 2

EEG abnormalities in subcortical epilepsies

Examples of scalp and intracranial EEG abnormalities that may be seen with epilepsy arising from the different subcortical structures based on case reports.

cortical resections have been ineffective in reducing

seizure frequency.27,28 Several studies have shown that
the gelastic seizures originate within the hamartoma
itself.29,30 This is supported by the observation that
small neurons within the hypothalamic hamartoma
exhibit spontaneous firing31 and evidence of low-voltage fast activity confined to the hamartoma during
periods of ictal laughter on stereo-EEG.29 In addition,
ictal SPECT studies consistently show well-localized
hyperperfusion in the region of the hamartoma25,28
and in one patient in whom a depth electrode was
implanted into the hamartoma, electrical stimulation
reproduced gelastic seizures 3 times. Furthermore,
there are many reports that surgical resection of the
hamartoma leads to complete resolution of seizures
with normalization of the EEG and improvement of
behavioral abnormalities.3234 All this confirms a hypothalamic (subcortical) basis in this patient population.
Cerebellum. Despite being described as early as
1871,35 to this day, the issue of whether seizures
can arise in the cerebellum remains controversial.

The seizures were described as tetanus-like because

of opisthotonic posturing without loss of awareness.
Similar case reports of patients with cerebellar tumors
and tonic seizures were later reported36; however, to
this day, many believe that these episodes do not
represent epileptic seizures at all. Rather, they may
be the result of transient, reversible brainstem compression that interrupts corticobulbar pathways and
causes temporary decerebrate rigidity.36,37 This is supported by the fact that early experimental stimulation
of the cerebellum had never been found to produce a
typical epileptic seizure. Several investigators, however, have produced characteristic slow postural and
adaptive movements by stimulating the roof nuclei,
white matter, and cortical surface of the cerebellum.38,39 More recently, electrical stimulation of the
cerebellum has also been shown to cause generalized
seizures in animal models40 and influence the EEG
and clinical manifestations of generalized seizures in
patients with medically intractable epilepsy.41
Stronger evidence comes from a growing number
of reports of newborn infants with a dysplastic lesion
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within the cerebellum presenting with very frequent

and brief daily seizures characterized by unilateral
facial (hemifacial) spasm and eye blinking, stereotyped extremity movements, postural arching, and
intermittent altered (though predominantly retained)
consciousness.4244 Those seizures sometimes became
secondarily generalized and were refractory to antiepileptic medications. Interictal and ictal scalp EEG
recordings were either normal42 or demonstrated
bilateral electrical abnormalities.43 Ictal and interictal
SPECT revealed a focal perfusion abnormality in the
region of the cerebellar mass and intraoperative EEG
recordings revealed focal seizure discharges that arose
in the region of the cerebellar mass (figure 2) and
influenced electrographic activity in both cerebral
hemispheres. Resection of this mass led to complete
resolution of those patients seizures with normalization of the scalp EEG readings and neuropathologic
findings were consistent with ganglioglioma.
There are also several reported infants with hemifacial spasm and similar imaging findings and histopathology,4549 though the clinical findings in these cases were
not attributed to an epileptic phenomenon.
Many of the cases presenting with hemifacial seizures
were found to have dysplastic neuronal lesions of the
floor of the fourth ventricle and in most cases, the hemifacial spasm occurred on the side of the face ipsilateral to
the tumor, suggesting an infranuclear effect of the
tumor. This together with the recording of rhythmic
theta or beta activity in the dysplastic lesions using a
depth electrode inserted during surgery50 and rhythmic
theta waves using a strip electrode on the tumor during
eyelid twitching corresponding to electromyography51
led some authors to propose that the hemifacial seizures
are mediated via the facial nerve nucleus.50 This hypothesis of cranial nerve origin, however, cannot explain the
secondary generalization of some of these seizures.43 In
addition, cases presenting with other forms of seizures
have been reported as well. One describes a 9-year-old
child who presented with medically refractory secondary
generalized epilepsy associated with recurrent headaches
since 6 months of age. The child also had moderate
intellectual impairment and autism. A brain MRI
showed a small superior cerebellar arachnoid cyst. Interictal EEG did not provide any localizing information,
while intraoperative electrocorticography demonstrated
epileptic activity from the cerebellar tissue adjacent to
the cyst. Fenestration of the cyst resulted in dramatic
seizure control postoperatively.52 There are also 2
reports of progressive myoclonus in infants with cerebellar gangliogliomas. The first presented with progressive
myoclonic jerking of both proximal lower extremities.
Her brain MRI showed an ill-defined mass involving
cerebellar vermis and the right middle cerebellar peduncle. 11C-methionine PET showed no abnormalities, but
18
F-fluorodeoxyglucose PET revealed a well-defined
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hypermetabolic focus. Depth electrodes inserted deep

into the mass recorded focal slow waves associated with
the clinical myoclonus. Following the removal of the
tumor, the myoclonus was completely resolved with
no neurologic deficit.53 The second presented with intermittent, nonrhythmic jerking of the distal lower extremities and less frequently by trunk and arm jerking. The
jerking was present only while awake and occurred most
often when standing. Brain MRI showed a cerebellar
mass lesion involving the left inferior, middle, and superior cerebellar peduncles, the left dentate, emboliform,
and globose nuclei, white matter of the left simple and
superior semilunar lobules, and the region of the left
superior and lateral vestibular nuclei. The lesion crossed
the midline involving fastigial nuclei bilaterally and the
right dentate nucleus, with slight mass effect and compression of the fourth ventricle. Video-EEG monitoring
showed normal background rhythm and no change associated with the myoclonic jerks. The myoclonus completely resolved with resection of the tumor, but the
patient was left with dysarthria and ataxia that have continued to improve over the 2 years since the tumor was
removed.54
Furthermore, a higher occurrence of epilepsy and
mental retardation in comparison with the general
population was observed in patients with cerebellar
hypoplasia, with or without associated cerebral lesions.
Those patients presented with partial seizures with or
without secondary generalization and their EEG either
showed diffuse or bifrontal slowing of background
activity, or focal or multifocal paroxysms.55,56
The cerebellum is known to contain somatotopic
representations of the head, face, and eyes, so the
complex motor ictal symptoms are consistent with
primary dysfunction in this area. As cerebellar neurons have strong connections with the thalamus and
cerebral cortex, these seizures may be modulated by
cortical spread. Alterations of consciousness are also
consistent with secondary spread involving bilateral
cortical structures. Furthermore, despite bilateral
EEG abnormalities on scalp recordings, bilateral cortical dysfunction is unlikely to be the origin for those
patients epilepsy given the discrete cerebellar activation seen on ictal SPECT and focal cerebellar seizure
discharges recorded intraoperatively (figure 2). The
data thus suggest that at least in cases of cerebellar
pathology, seizure activity may commence within the
cerebellum. This warrants consideration when formulating the management plans of refractory epilepsy
patients presenting with such lesions.
Basal ganglia. Several seizure manifestations have been

suggested to be compatible with the involvement of

basal ganglia, namely, ictal dystonic posturing during
temporal lobe seizures, rotatory seizures, and paroxysmal dyskinesia-like seizures.57 Dystonic posturing has

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been attributed to the spread of the discharge to the

ipsilateral basal ganglia, mainly the sensorimotor part
of the putamen, as supported by ictal SPECT data
showing increased perfusion during seizures with unilateral dystonic posturing.58 This is supported by
reports of focal upper limb dystonias in patients without epilepsy who have lesions of the basal ganglia.59 In
addition, some patients with rotatory seizures have
subcortical lesions involving the lenticular nuclei and
thalami.60 These features are mainly thought to be
mediated by projections from hippocampus and amygdala to basal ganglia structurese1; however, evidence of
actual seizure initiation remains sparse.
In a recent report, a child presenting with intractable
epilepsy, MRI evidence of a poorly defined corticomedullary boundary in the left frontal lobe on MRI, and
spike dipoles localized to the left ventral striatum on
magnetoencephalography underwent partial resection
of the frontal lobe.e2 Initially, the child was seizure-free,
but seizures recurred within 2 months and remained
intractable. Neuropathologic examination confirmed
the presence of focal cortical dysplasia in the resected
brain tissue. Ictal SPECT from this period displayed
hyperperfusion of the left anterior striatum. A second
surgery was performed and intraoperative electrocorticography exhibited spike discharges from the anterior
striatum. After the removal of this structure and adjacent brain tissues, the patient remained seizure-free for
33 months, without any neurologic deficits. Histopathologic examination of the resected tissue revealed a large
number of dysmorphic neurons widely distributed in
the cerebral cortex, subcortical white matter, striatum,
and insular cortex. Based on this, the authors postulated
that microscopic dysplasia of basal ganglia can accompany certain cases of focal cortical malformations, and
may play a critical role in the epileptogenesis through
their interaction with cortical structures. This prompted
them to search for similar cases. They reviewed the
records of 8 children with frontal lobe epilepsy who
underwent resections including deep brain structures.
Dysmorphic neurons were found in the cortex and
subcortical white matter of 5 patients. The striatum
was verified in 3 patients in whom dysmorphic neurons
were scattered.e3 There are other earlier reports of epilepsy cases associated with striatal lesions such as a tumor.e4 In addition, there is some evidence supporting
striatal epileptogenicity. One report described a patient
with tuberous sclerosis and epilepsy who became seizure-free treated by stereotactic electrolytic lesions.e5
Another showed a patient with intractable epilepsy
due to cortical dysplasia who achieved transient seizure
freedom for 6 months following bilateral striatal necrosis.e6 Although the evidence in these cases is indirect, the
overall features suggest that the dysgenetic striatum
itself may participate in the epileptogenesis in certain
cases.

Brainstem. No clear role has been established for the

brainstem in seizure initiation; however, there is a suggested involvement in infantile spasms. This is supported by evidence of brainstem activation on PETe7
and abnormal brainstem evoked potentials and brainstem atrophy on MRIe8 in some of these patients. There
is also evidence of decreased numbers of brainstem
catecholaminergic neurons on immunohistochemical
experiments.e9 However, these findings are not seen
in all patients. Thus it remains difficult to determine
whether this is related to the etiology of infantile spasms
or a consequence of multiple seizures.
THERAPEUTIC APPLICATIONS Targeting subcortical structures is increasingly being used in patients with
refractory epilepsy in the hope of achieving seizure control. Left cervical vagus nerve stimulation (VNS) is now
a well-established tool for treatment of medically refractory epilepsy.e10 The mechanism by which VNS reduces seizure frequency is unknown, though some
animal evidence points to the thalamus and other diencephalic structures as critical elements.e11 Vagal afferents indirectly project to a variety of brainstem nuclei
including medullary reticular formatione12 and the
thalamus.e13 PETe14,e15 and SPECTe16,e17 studies
have revealed thalamic blood flow changes during
acute VNS in patients with intractable epilepsy.
However, the small number of studies that have
examined thalamic blood flow during VNS yielded
conflicting results regarding the direction and magnitude of change. Deep brain stimulation (DBS) has
been promoted as a possible therapy for epilepsy for
more than 30 years and now is moving to the point
of clinical utility.e18 The proposed hypothesis is that
DBS leads to disruption at the level of individual
neurons, synapses (in the form of increased inhibitory or decreased excitatory potentials), and neuronal
networks.e19 Network effects rely significantly on
stimulation parameters and may ultimately result in
either excitation or inhibition at sites remote from the
local region of stimulation. The results of clinical trials
are promisinge18; however, more studies are needed to
identify which target, parameters, and stimulation
strategies result in the most efficacious mode for seizure control.
DISCUSSION A wide range of interictal and ictal animal and human studies demonstrate a critical role for
subcortical structures in epilepsy. There is little doubt
that the thalamus is very important in modulation and
propagation of many forms of generalized and focal
epileptic activity and seizures. In addition, there is
some suggestion it can actually initiate seizures and
may masquerade as atypical or refractory epilepsy.
The basal ganglia and cerebellum also seem to play
an important role in the generation and propagation
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of both generalized and focal epileptiform discharges and

seizures. There is also a suggestion that akin to hypothalamic hamartomas, cerebellar seizures can arise in the setting of unilateral lesions in the cerebellum (figure 2).
While epileptogenicity of these regions seems to be
mostly related to the presence of specific types of intrinsically epileptogenic lesions such as cortical dysplasias,
gangliogliomas, and hamartomas, this would still be
compatible with the concept of subcortical epilepsies.
It is hoped that the development of more sophisticated functional and structural imaging and electrophysiologic tools will lead to further clarification of
the role of these structures in epilepsy and the potential epileptogenicity of each. This is likely to aid the
development of better management and preventative
techniques that will improve the quality of life for
those living with this disorder.
AUTHOR CONTRIBUTIONS
Dr. Badawy initiated and designed the structure of the review, performed
the literature review, and was responsible for manuscript preparation.
Dr. Lai helped with literature review, figures, and manuscript preparation. Mr. Vogrin helped with figures and manuscript preparation. Prof.
Cook supervised the manuscript preparation process.

8.

9.

10.

11.

12.

13.

14.

15.

16.

ACKNOWLEDGMENT
The authors thank Dr. Fatema Abdulla and Professor Neelan Pillay for
sparking interest in the subject and helping with the literature review,
Dr. Danny Flanagan for helping to formulate the scope and structure of
the manuscript, and Professor Graeme Jackson for providing the motivation to pursue it.

STUDY FUNDING

17.

18.

19.

No targeted funding reported.

DISCLOSURE
R. Badawy, A. Lai, and S. Vogrin report no disclosures. M. Cook
received funding for a conference trip from SciGen (2011) and received
speaker honoraria and travel reimbursements from UCB Pharma (2011
and 2012), Sanofi (2011 and 2012), and SciGen (2012). Go to
Neurology.org for full disclosures.

20.

Received July 24, 2012. Accepted in final form February 1, 2013.

21.

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