Clinical Study Stereotact Funct Neurosurg DOI: 10.1159/000509318 Received: February 14, 2020 Accepted: June 10, 2020 Published online: September 7, 2020 Clinical Outcome and Intraoperative Neurophysiology of the Lance-Adams Syndrome Treated with Bilateral Deep Brain Stimulation of the Globus Pallidus Internus: A Case Report and Review of the Literature Hideo Mure a, b Naoto Toyoda a Ryoma Morigaki a, b, d Koji Fujita b, c Yasushi Takagi a, d a Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; b Parkinson’s Disease and Dystonia Research Center, Tokushima University Hospital, Tokushima, Japan; c Department of Clinical Neuroscience, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; d Department of Advanced Brain Research, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan Abstract Background: The Lance-Adams syndrome (LAS) is a myoclonus syndrome caused by hypoxic-ischemic encephalopathy. LAS cases could be refractory to first-line medications, and the neuronal mechanism underlying LAS pathology remains unknown. Objectives: To describe a patient with LAS who underwent bilateral globus pallidus internus (GPi) stimulation and discuss the pathophysiology of LAS with intraoperative electrophysiological findings. Patients: A 79-yearold woman presented with a history of cardiopulmonary arrest due to internal carotid artery rupture following carotid endarterectomy after successful cardiopulmonary resuscitation. However, within 1 month, the patient developed sensory stimulation-induced myoclonus in her face and extremities. Because her myoclonic symptoms were refractory to pharmacotherapy, deep brain stimulation of the GPi was karger@karger.com www.karger.com/sfn © 2020 S. Karger AG, Basel performed 1 year after the hypoxic attack. Results: Continuous bilateral GPi stimulation with optimal parameter settings remarkably improved the patient’s myoclonic symptoms. At the 2-year follow-up, her Unified Myoclonus Rating Scale score decreased from 90 to 24. In addition, we observed burst firing and interburst pause patterns on intraoperative microelectrode recordings of the bilateral GPi and stimulated this area as the therapeutic target. Conclusion: Our results show that impairment in the basal ganglion circuitry might be involved in the pathogenesis of myoclonus in patients with LAS. © 2020 S. Karger AG, Basel Introduction The Lance-Adams syndrome (LAS) is a syndrome of action, intention, and/or stimulus-induced myoclonus that occurs in patients in the chronic phase after cerebral H.M. and N.T. contributed equally to this work. Hideo Mure Department of Neurosurgery Graduate School of Biomedical Sciences, Tokushima University 3-18-15 Kuramoto-cho, Tokushima 770-8503 (Japan) hmure @ tokushima-u.ac.jp Downloaded by: Auckland University of Technology 156.62.3.11 - 10/26/2020 12:33:50 PM Keywords Lance-Adams syndrome · Myoclonus · Deep brain stimulation · Globus pallidus internus · Microelectrode recording Immediately after the hypoxic attack SEP from the median nerves Left median nerve a One year after the hypoxic attack c Right median nerve b Fig. 1. a, b MRI acquired immediately and 1 year after the hypoxic event. There was no other abnormality than diffuse atrophy. c Somatosensory evoked potentials (SEPs) from the left and right median nerves. Case Report A 79-year-old woman in the chronic phase after hypoxic-ische­ mic encephalopathy presented with involuntary movements in her extremities. One year ago, she underwent a left carotid endarterectomy at another hospital. Four days postoperatively, she experienced left carotid artery bleeding, which resulted in cardiopulmo- 2 Stereotact Funct Neurosurg DOI: 10.1159/000509318 nary arrest due to hematoma-induced tracheal compression. Although she was successfully revived by cardiopulmonary resuscitation, she experienced continuous disturbance of consciousness. Her Glasgow Coma Scale (GCS) score was 8 (E3VTM5), and myoclonic seizures established on her face and extremities. The myoclonic seizures were triggered by sensory stimulation and spontaneous movements, such as opening or closing of the eyes and mouth. Combined treatment with levetiracetam (3,000 mg/ day), clonazepam (1.5 mg/day), and phenobarbital (160 mg/day) was administered, but the myoclonic seizure was medically intractable. The patient could not maintain a sitting position and was mostly bedridden because of persistent myoclonus, which rendered her incapable to participate in rehabilitation therapy (see www.karger.com/doi/10.1159/000509318 for the online suppl. Video). She was referred to our hospital for further evaluation of the indication of DBS surgery. Magnetic resonance imaging revealed diffuse brain atrophy without any other abnormalities (Fig. 1a, b). A resting electroencephalogram (EEG) demonstrated a generalized, slow activity in her reference electrodes without any epileptic discharges. Somatosensory evoked potential (SEP) from her median nerves is shown in Figure 1c. Although P24 amplitude increased, the difference between the amplitudes of P24 and N20 was <10 μV; therefore, P24 was not considered as a predominant SEP [2–4]. These results suggested that her myoclonic seizure was not a cortical myoclonus [2–5]. Three previously published case reports have described successful treatment of myoclonic seizure in patients with LAS with GPi-DBS [6–8]. Her myoclonic seizure did not permit ambulation, and her family strongly hoped for a Mure/Toyoda/Morigaki/Fujita/Takagi Downloaded by: Auckland University of Technology 156.62.3.11 - 10/26/2020 12:33:50 PM hypoxia. This condition was first described by Lance and Adams in 1963, and only about 150 cases have been reported. Little is known about the pathophysiology of LAS. The first-line treatment of LAS comprises levetiracetam, zonisamide, clonazepam, valproate sodium, 5-hydroxy tryptophan (5-hydroxy tryptamine), γ-amino butyric acid, baclofen, and L-dopa [1]. However, LAS generally has limited response to pharmacotherapy. Although recent reports of LAS patients demonstrated successful outcomes after deep brain stimulation (DBS), neurophysiological aspects were not assessed. To better understand the pathophysiology of LAS, we present a case of LAS caused by cardiorespiratory arrest after carotid endarterectomy who was successfully treated with globus pallidus internus (GPi)-DBS. Moreover, we present the findings of intraoperative neuronal cell firing in the basal ganglia. Color version available online –10 mm from target; only increased background activity 1 : Amp 11 : Amp 11 : 1 ch L TR1 : 12 : –10,000 mm, 10,000 s a –1 mm from target; burst and suppression firing pattern 1 : Amp 11 : Amp 11 : 1 ch L TR1 : 23 : –1,000 mm, 10,000 s b 100 ms Burst 200 ms 300 ms 400 ms Pause 500 ms 600 ms 700 ms 800 ms 900 ms 1,000 ms Fig. 2. Intraoperative microelectrode recordings of the globus pallidus (GP): –10 mm from the GP externus (GPe) and –1 mm from the GP internus (GPi). These recordings showed increased background activity in GPe and burst firing and interburst pause patterns in GPi. Discussion The mechanism underlying the pathogenesis of LAS remains unknown. Lance and Adams indicated that abnormal synchronous and recurrent excitation of the venGPi-DBS for Lance-Adams Syndrome trolateral thalamic nucleus and cerebral cortex pathways causes LAS [10]. Fluorodeoxyglucose-positron emission tomography study revealed saccharometabolic acceleration in the ventrolateral thalamic nucleus and pontine tegmentum in a patient with LAS [11]. Biochemical investigation revealed that the concentrations of serotonin and dopamine metabolites decreased in the cerebrospinal fluid of patients with LAS, indicating that both the serotonergic and dopaminergic systems were depressed in these patients [12]. Recently, a case study reported the use of ventral intermediate nucleus (Vim) DBS for LAS after cerebral infantile palsy [13], while 3 cases reported on the use of GPi-DBS for LAS [6–8, 13] (Table 1). From these reports, GPi-DBS showed improvement in UMRS by 63% on average; in addition, Vim-DBS improved UMRS by 81%. The present case also had a 73% improvement in UMRS, comparable to previous reports, suggesting that DBS is effective for myoclonus in LAS. The programming parameters for these prior cases, except for a study by Ramdhani et al. [8], utilized a bipolar configuration to achieve therapeutic gain, and amplitudes tend to be > 2.5 V/mA. Yamada et al. [6] and the present case Stereotact Funct Neurosurg DOI: 10.1159/000509318 3 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/26/2020 12:33:50 PM surgical intervention. Therefore, we performed GPi-DBS for her intractable myoclonic seizure. Figure 2a, b shows the intraoperative microelectrode recordings of the GPi. The external segment of the globus pallidus (GPe) showed increased background activity, but there were abnormal bursts and interburst pauses, indicative of dystonia, in the GPi. The patient was implanted with a quadripolar electrode and an implantable pulse generator (Brio; St. Jude Medical, St. Paul, MN, USA). Postoperatively, her myoclonic seizure reduced remarkably; she could now keep a sitting position and undergo rehabilitation (see online suppl. Video). We used bipolar stimulations on both GPi. The following parameters were used: 237 μs, 110 Hz, 4.25 mA on the left side and 212 μs, 110 Hz, and 2.50 mA on the right side (Table 1). The patient still remains in a minimally conscious state; however, suppression of the action myoclonus remains stable 2 years after GPi-DBS. Her preoperative Unified Myoclonus Rating Scale (UMRS) score [9] of 90 preoperatively and was reduced to 24 postoperatively at the 2-year follow-up (Table 1). Stereotact Funct Neurosurg DOI: 10.1159/000509318 Conclusions We successfully treated a case of severe myoclonic seizure in a patient with LAS using GPi-DBS. GPi-DBS may be an effective and safe treatment option for LAS. The intraoperative burst firing with interburst pauses detected by microelectrode recordings of the GPi and the efficacy of GPi-DBS for our patient suggest the involvement of the basal ganglion circuity in the pathogenesis of myoclonic seizures in a patient with LAS. Statement of Ethics The published research complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The patient provided informed consent for participation in this study. Formal ethical approval for this type of study was not required (per University guidelines). Mure/Toyoda/Morigaki/Fujita/Takagi Downloaded by: Auckland University of Technology 156.62.3.11 - 10/26/2020 12:33:50 PM CPA, cardiopulmonary arrest; Gpi, globus pallidus internus; ICA, internal carotid artery; pre/post, pre-/postoperatively; UMRS, Unified Myoclonic Rating Scale; Vim, ventral intermediate nucleus of thalamus. R: 3+2–1–, 2.5 mA/212 μs/110 Hz L: 3+2–1–, 4.25 mA/237 μs/110 Hz Bilateral GPi Generalized 79 F Current case ICA rupture and CPA 24 90 Clonazepam, levetiracetam, phenobarbital 73 R: C+3–, 2.8 V/90 μs/130 Hz L: C+3–2–1–, 2.5 V/60 μs/130 Hz Bilateral GPi Generalized 26 M Ramdhani et al. [8] Asthmatic attack and CPA 32 52 Gabapentin, levetiracetam, valproate 38 R: 1–2+, 2.5 V/1+0–, 2.0 V, 60 μs/125 Hz L: 1–2+, 3.0 V/1+0–, 2.5 V, 60 μs/125 Hz Bilateral GPi Generalized CPA 54 M Asahi et al. [7] Upper limbs 36 M Kobayashi et al. [13] Perinatal anoxia 5 25 Valproate, clonazepam, baclofen (intrathecal) 80 Bilateral: 1–3+ settings unavailable Bilateral Vim 4 21 N/A 71 15 Right hemibody 71 M Yamada et al. [6] Putaminal hemorrhage and CPA Clonazepam, valproate, gabapentin 52 81 Left GPi L: 1–2+, 1.8 V/450 μs/130 Hz DBS parameters, contacts: amplitude/pulse width/frequency DBS target Improvement, % post UMRS pre Preoperative medication Dystonic body region Etiology Age/ gender Table 1. Cases of Lance-Adams syndrome treated with deep brain stimulation 4 produced robust responses using long pulse widths (>200 μs). In addition, 6 cases of myoclonus dystonia, a syndrome which presents myoclonus, showed abnormal neuronal activity in the GPi with faster and shorter bursts, and shorter pauses at DBS surgery [14], in comparison with what is typically observed in pure idiopathic or hereditary dystonia. Vitek et al. [15] first reported irregular neuronal activity in the form of intermittent grouped discharges and pauses in the pallidum in patients with dystonia and hemiballismus; therefore, it is believed that this abnormal discharge pattern in GPi may be associated with the generation of abnormal movements [15–18]. The findings of microelectrode recordings in myoclonic dystonia are very similar to our case. Myoclonic dystonia is typically characterized by childhood-onset subcortical myoclonus that predominates over dystonia with prominent upper body involvement [1, 19]. SGCE is the main causative gene [20]. Therefore, LAS differs from myoclonic dystonia both etiologically and clinically. Although, in myoclonic dystonia, basal ganglia and cortical pathogenic mechanisms are implicated from neurophysiological findings [14, 19], LAS is also potentially related to basal ganglion abnormality. To the best of our knowledge, this is the first report of neuronal activity in the globus pallidus in a patient with posthypoxic myoclonus. The electrophysiological findings and the efficacy of GPi-DBS in the present case suggests that myoclonus in LAS could be due to abnormalities in the basal ganglion circuitry [1]. Conflict of Interest Statement Author Contributions The authors declare no conflict of interest associated with this manuscript. Funding Sources Conception and design: H.M.; acquisition of data: H.M., N.T., R.M.; analysis and interpretation of data: all authors; drafting of the article: N.T.; critically revising the article: K.F., Y.T.; review of the submitted version of the paper: all authors; approval of the final version of the paper on behalf of all authors: H.M. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grants in aid for Scientific Research Nos. 16K10788, 16KK0182, 17K10899, and 20K17932). The Department of Advanced Brain Research is supported by Beauty Life Corporation. References GPi-DBS for Lance-Adams Syndrome 8 Ramdhani RA, Frucht SJ, Kopell BH. Improvement of post-hypoxic myoclonus with bilateral pallidal deep brain stimulation: a case report and review of the literature. Tremor Other Hyperkinet Mov (N Y). 2017 May;7: 461. 9 Frucht SJ, Leurgans SE, Hallett M, Fahn S. The unified myoclonus rating scale. 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