Background
The cerebellum plays an important role in motor control. The cerebello-thalamo-cortical loop modulates the cerebro-basal ganglia loop. Cerebellar ataxia is one of the four cardinal features of progressive myoclonus epilepsy. Pathological involvement of cerebellum has been demonstrated in juvenile myoclonus epilepsy (JME) [
1], benign adult familial myoclonic epilepsy (BAFME) [
2], juvenile absence epilepsy [
3], and nonconvulsive partial status epileptics [
4]. Furthermore, cerebellar hemisphere is one of the target sites of neuromodulation using electric stimulation in intractable epilepsy. Cerebellar stimulation was reported to decrease seizure activity in animal models of epilepsy [
5]. In patients with intractable epilepsy, previous reports showed effectiveness of cerebellar stimulation to seizure suppression, while the effectiveness and procedures of cerebellar stimulation are still controversial [
6]. To elucidate the mechanism of influence of the cerebellum on the cerebral cortex is very important in further development of treatment strategies in patients with epilepsy.
Arterial spin labeling (ASL) is a noninvasive method to evaluate cerebral blood flow (CBF) using magnetically-labeled water in the blood as an endogenous tracer. Hyperperfusion of ASL with post labeling delay (PLD) of approximately 1500 msec more sensitively correlates with epileptic seizures than high intensity of diffusion weighted images and hypoperfusion with PLD of 1500 msec is seen during interictal period [
4,
7]. Thus far, little is known about involvement of cerebellum to pathology of epilepsy.
Our objective is to investigate cerebellar perfusion in patients with epileptic seizures using arterial spin labeling perfusion magnetic resonance image. Part of this manuscript was presented in the American Academy of Neurology Annual Meeting 2020 in an abstract form [
8].
Methods
In this case-series study, we retrospectively checked medical record of patients who visited the Adult Epilepsy Clinic in the National Hospital Organization Utano National Hospital between August 2017 and May 2018, and enrolled patients who fulfilled inclusion criteria; 1) adult patients with epileptic seizures, 2) underwent ASL in three PLD conditions (1525, 1800, and 2500 msec) (Ingenia 3.0 T CX, Philips), 3) anatomical images using fluid-attenuated inversion recovery, diffusion weighted imaging, or susceptibility weighted imaging sequences were obtained in combination with ASL images, 4) conventional electroencephalography (EEG) (EEG1214, Nihon Kohden) was recorded on the same day, and 5) whose ASL images showed spotty hyperperfusion in the cerebellar hemisphere. Clinical and EEG characteristics of them were retrospectively analyzed. MRI scan took approximately 30 min, and EEG was recorded for approximately 30 min. In patients treated with antiepileptic drugs, regular medications were taken as usual.
The recordings were performed as a part of an intensive clinical evaluation. On the basis of the noninvasive case-accumulation study design with assured anonymity, the current study was exempt from the need for the institutional ethics committee approval and informed consent.
Discussion
The present study evaluated cerebellar perfusion by using ASL in three PLD conditions in adult patients with epilepsy. To the best of our knowledge, this is the first study to demonstrate hyperperfusion in the cerebellar paravermis of lobule VIIb. Thus, the cerebello-thalamo circuit can participate in epileptic functional network in human epilepsy.
Previous reports have shown the relationship between several epilepsy syndromes and the cerebellum. Studies using functional MRI found an enhanced functional connectivity between the left cerebellar lobule VIIb and the right frontal pole in BAFME [
2] and decreased volume of the cerebellum in JME patients [
1]. Cerebellar hemispheres mainly consist of VI–X lobules, and the VIIb lobules are at the bottom. Each of VII–VIII lobules modulates voluntary movement of hands, e.g., reaction to force or to visual stimuli [
9]. Lobules VII are activated during tasks that demands on cognitive functions including language, working memory, and executive function [
10]. However it is unlikely that the hyperperfusion of lobules VIIB in this study is physiological phenomenon because was demonstrated during MRI imaging at rest.
Efferent projections originate from the cerebrum synapse to the pontine nuclei and then primarily to the contralateral cerebellar cortex. Purkinje cell axons conduct the entire output of the cerebellar cortex, projecting to the deep cerebellar nuclei (e.g., dentate nucleus, interposed nucleus) in the underlying white matter, where the gamma-aminobutylic acid released by their terminals has an inhibitory effect. The cerebral cortex receives excitatory synapse from cerebellar nuclei via ventrolateral nucleus of the thalamus [
11]. In mouse model of absence epilepsy, group discharges of Purkinje cells are recorded during generalized rhythmic spike discharges [
12]. Hyperperfusion of the right lobule VIIB and hypoperfusion of the opposite side of the thalamus in Patient 1 before medication can be the result of activation of Purkinje cells caused by epileptic discharge of the cerebrum, which then inhibits the thalamic activities. After medication, along with decrease of SWC, these phenomena disappeared.
In patients with focal epilepsy, side of hyperperfusion was related to clinical presentation. Patient 4 and Patient 5, whose seizure focus resides in the left frontal lobe manifesting with asymmetrical motor symptoms, showed hyperperfusion of right lobules VIIb. Patient 4, who was in status epilepticus during the examinations, showed hyperperfusion of both cerebellar hemispheres in concordant with a previous report on nonconvulsive status epilepticus [
4], however, remarkably significant hyperperfusion of VIIb can suggest marked involvement of motor circuit of hand movement. In addition, inflammatory etiology such as autoimmune encephalitis can exaggerate excitability of motor network. Patient 6 showed cerebellar hyperperfusion ipsilateral to the seizure focus presumed by the initial seizure semiology, but EEG with generalized epileptiform discharges suggests involvement of both hemispheres. Visual motor integration can also be important because seizures of Patient 2 and Patient 3 originate from occipital lobe and photoparoxysmal responses were noticed in Patient 1, Patient 3, and Patient 6.
ASL reflects CBF, and quantitative measurement of CBF by ASL depends on arterial transit time which is the time delay between the labeled blood in the cervical arteries and the arrival of the labeled blood in cerebral tissue. Therefore, the setting of PLD is very important to evaluate CBF correctly. In patients with chronic occlusive cerebrovascular disease, PLD 1500 msec underestimates CBF of affected side whereas PLD 2500 msec can evaluate hemodynamic state precisely [
13]. Neuronal activation also causes changes in cerebral microcirculatory. Microcirculatory response to functional stimulation leads to a pronounced decrease in vascular transit time and a dilatation of the capillary bed [
14]: mean transit time in cerebral capillaries drops from 1.34 ± 0.4 s at rest to 0.78 ± 0.02 s during activation. Epileptic seizure originates from firing of neuron, and thus resultant microcirculatory change may occur.
We evaluated CBF of the brain with three PLD conditions (1525, 1800, and 2500 msec). In addition to the hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. Hypoperfusion may reflect the decrease of the vascular transit time and hyperperfusion may reflect a dilatation of the capillary bed evoked by neural activation. The phenomena can be associated with characteristics of the cerebellar vasculature which is mainly comprised of the capillary net.
A decrease of metabolism and blood flow in the cerebellar hemisphere contralateral to a supratentorial infarct is called as crossed cerebellar diaschisis (CCD). CCD has been evaluated using single-photon emission computed tomography (SPECT) or positron-emission tomography whose special resolution is relatively low. A recent study evaluated CBF derived from ASL and showed that was equivalent to CBF derived from SPECT, and CCD was shown in diffusely in cerebellar hemisphere [
15]. In contrast, hyperperfusion and hypoperfusion of our patients were detected in restricted region of the cerebellar paravermis of lobule VIIb, suggesting a totally different mechanism from CCD.
Conclusions
The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic functional network in humans. Further studies to correlate hyperperfusion of the VIIb to precise motor manifestation, etiology, and prognosis, and to explore how to modulate motor circuit, may reveal utility of the phenomenon in clinical practice of patients with epilepsy. Accumulation of ASL data with several PLD conditions is warranted to elucidate functional network of the brain, neurovascular coupling, and treatment strategy for intractable epilepsy.
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