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Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report

      Abstract

      Background

      Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug.

      Case presentation

      A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved.

      Conclusion and discussion

      Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.

      Keywords

      1. Introduction

      Leigh syndrome (LS) is a mitochondrial disorder. Among mitochondrial disorders, LS and mitochondrial encephalopathy with lactic acidosis are relatively common, especially in childhood. LS is characterized as an intractable chronic progressive disease that shows regression of psychomotor development due to impaired energy production in the central nervous system (CNS). In addition, bilateral symmetrical degenerative lesions in the brain stem and basal ganglia are seen on brain imaging and in neuropathological specimens. The causative genes are not only in the mitochondria but also in the nuclei, and there are three hereditary forms: maternal inheritance, autosomal recessive inheritance, and X-linked inheritance. Psychomotor regression occurs subacutely in infancy, and motor dysfunction is often an initial symptom. Meanwhile eye symptoms such as ptosis and strabismus follow, and then difficulty swallowing, epileptic seizures, and inability to grow become obvious. Epileptic seizure is one of the main symptoms of LS and the types of epileptic seizures have been reported as generalized seizures (22.3%), focal seizures (14.6%) and epileptic spasms (6.1%) [

      Thorburn DR, Rahman J, Rahman S. Mitochondrial DNA-associated Leigh syndrome and NARP. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2019. [Initial posting 30 Oct 2003, Updated 28 Sep 2017].

      ,
      • Sofou K.
      • De Coo I.F.
      • Isohanni P.
      • Ostergaard E.
      • Naess K.
      • De Meirleir L.
      • et al.
      A multicenter study on Leigh syndrome: disease course and predictors of survival.
      ,
      • Leigh D.
      Subacute necrotizing encephalomyelopathy in an infant.
      ,
      • Gropman A.L.
      Neuroimaging in mitochondrial disorders.
      ]. Various treatments have been proposed for LS, including vitamin B1, vitamin C, and carnitine, but their efficacy is not satisfactory and an effective, long-term therapeutic strategy remains to be developed.
      Perampanel (PER) is a unique antiepileptic drug that is an oral non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist. It selectively and non-competitively antagonizes AMPA receptors present in excitatory nerves and prevents excessive inflow of calcium into cells. It thereby suppresses neuronal hyperexcitability, which enables it to exert antiepileptic effects, as demonstrated by animal experiments [
      • Hanada T.
      • Hashizume Y.
      • Tokuhara N.
      • Takenaka O.
      • Kohmura N.
      • Ogasawara A.
      • et al.
      Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
      ]. Its inhibition of AMPA receptors suggests a strong ability to suppress paroxysmal depolarization shifts. PER is effective for epilepsy and other diseases thought to be caused by AMPA receptor hyperactivity by improving the imbalance with inhibitory nerves and suppressing neuronal apoptosis. In Unverricht-Lundborg disease, Lafora disease and dentatorubral-pallidoluysian atrophy, which are classified as forms of progressive myoclonus epilepsy, PER leads to not only disappearance of epileptic seizures, but also reduction of involuntary movement and improvement in activities of daily living (ADL) [
      • Crespel A.
      • Gelisse P.
      • Tang N.P.
      • Genton P.
      Perampanel in 12 patients with Unverricht-Lundborg disease.
      ,
      • Goldsmith D.
      • Minassian B.A.
      Efficacy and tolerability of perampanel in ten patients with Lafora disease.
      ,
      • Shiraishi H.
      • Egawa K.
      • Ito T.
      • Kawano O.
      • Asahina N.
      • Kohsaka S.
      Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).
      ]. Herein, we report efficacy of PER not only for epileptic seizures but also ADL in a patient with relatively moderate LS. This patient had grown up without chronic epileptic seizures but frequent drug-resistant seizures developed in his 20 s and his ADL declined significantly.

      2. Case report of a 26-year-old man

      There was no abnormal history in the perinatal period, but he showed psychomotor delay and short stature at the age of 1 year. His blood test showed elevations of lactic acid and pyruvic acid at the age of 1 and a half, and at 2 years of age, T2-weighted magnetic resonance image showed high signal intensity in the bilateral striatum (Fig. 1). His cerebrospinal fluid examination showed elevations of lactic acid and pyruvic acid. Genetic testing showed a mitochondrial DNA 8993 T → C mutation, so he was diagnosed with LS. Although vitamin B1 was administered from the age of 3 years, exercise dysfunction, speech dysfunction, involuntary movements, and sleep apnea gradually worsened. He found it possible to walk using a walker until about 9 years old, but from approximately 11 years old, he used a wheelchair. Despite continued rehabilitation, the symptoms progressed slowly, but no intellectual regression was apparent. At the age of 23 years, epididymitis triggered a worsening of his symptoms. All assistance was required, but he was awake, firmly able to communicate and take food orally, and was able to sit without support. At 24 years of age, weighing 48 kg, he experienced sudden muscle weakness, making it difficult to maintain a sitting position. Intermittent decline in his awareness level appeared, while first generalized tonic-clonic seizures occurred and continued frequently. Diazepam suppositories and intravenous levetiracetam (LEV) stopped generalized tonic-clonic seizures temporarily, but contractions of his right arm continued intermittently. There were no obvious abnormal electroencephalographic (EEG) discharges interictally, or even during his symptoms. Regular administration of LEV, clobazam and diazepam was started to treat his symptoms, but they could not stop them. After these events, oral intake became very difficult, and he required tube feeding, and he was unable to obtain movement recovery, such as voluntary movement of the upper limbs or sitting retention. Two months after the initial treatment of epididymitis, oral administration of PER was started. After starting PER, there were no further contractions of his right arm, and he was able to maintain a sitting position on the buggy, allowing voluntary movements of his upper limbs. The efficacy of PER was dose-dependent and we could decrease clobazam and LEV. His awareness also improved, and recovery of oral intake was observed. Eight months after starting PER, he achieved full oral intake, and tube feeding was terminated. Since then, his epileptic seizures have ceased, his general condition has recovered to where it was before the sudden onset of muscle weakness, and he has had no progression of symptoms (Fig. 2).
      Figure thumbnail gr1
      Fig. 1T2-weighted magnetic resonance image at the age of 2 years, showing high signal intensity in the bilateral striatum.
      Figure thumbnail gr2
      Fig. 2Clinical course of anti-seizure medicines. LEV, levetiracetam; CLB, clobazam; DZP, diazepam; PER, perampanel; GTCs, generalized tonic-clonic seizures.

      3. Discussion

      We encountered a patient with LS who had intractable seizures uncontrolled by some antiepileptic drugs, but well controlled by PER. In addition, we observed an improvement in the patient’s general condition and ADL. There have been several recent reports describing the dramatic efficacy of PER for intractable epileptic seizures [
      • Strzelczyk A.
      • Knake S.
      • Kälviäinen R.
      • Santamarina E.
      • Toledo M.
      • Willig S.
      • et al.
      Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain.
      ]. Since PER has a unique mechanism against epileptic potential in neuronal cells, recent reports have demonstrated unpredictable success in various kinds of epileptic seizures or degenerative neural conditions. We considered that improvement of the patient’s ADL was associated mainly with the improvement in epileptic seizures, and although we could not detect appropriate EEG findings during the described symptom, subtle seizures might still occur. In addition, PER sometimes improves CNS function and stimulates neurotropic function in patients with progressive myoclonus epilepsy, thus PER might have induced the improvement in ADL directly via such function. We have supposed that it was possible that PER could suppress subtle seizures that are not detected by EEG but would interfere with his ADL. So PER could improve his awareness level and lead to recovery of ADL. Recent reports have shown that the efficacy of PER in patients with progressive myoclonus epilepsy could not be explained solely by suppression of epileptic seizures [
      • Crespel A.
      • Gelisse P.
      • Tang N.P.
      • Genton P.
      Perampanel in 12 patients with Unverricht-Lundborg disease.
      ,
      • Goldsmith D.
      • Minassian B.A.
      Efficacy and tolerability of perampanel in ten patients with Lafora disease.
      ,
      • Shiraishi H.
      • Egawa K.
      • Ito T.
      • Kawano O.
      • Asahina N.
      • Kohsaka S.
      Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).
      ]. A positron-emission tomography study using AMPA-specific ligands demonstrated hyperactivity in AMPA receptors in several diseases of the CNS [
      • Takahata K.
      • Kimura Y.
      • Seki C.
      • Tokunaga M.
      • Ichise M.
      • Kawamura K.
      • et al.
      A human PET study of [11C]HMS011, a potential radioligand for AMPA receptors.
      ]. Our study also supports the possibility that the enhanced binding capacity of AMPA receptors in the patient’s CNS was corrected by PER, resulting in improved ADL.

      4. Ethical publication statement

      The patient consented to publication of this manuscript which includes potentially identifying information. Informed consent was obtained from the patient's caregiver. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The study design was approved by the Ethical Committee of Nikko Memorial Hospital.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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