Seizures and electrophysiological features in familial cortical myoclonic tremor with epilepsy 1

Patients

In this observational cohort study, 125 patients were enrolled from 28 families diagnosed with FCMTE at the Second Affiliated Hospital, Zhejiang University School of Medicine between January 2012 and December 2019. The clinical diagnosis of FCMTE was based on previously described criteria, including: (1) autosomal-dominant inheritance, (2) tremulous finger movement, increasing with action and posture, (3) epileptic seizures, (4) cortical origin of the tremulous finger movement demonstrated by electrophysiological studies (i.e., giant SEP, C-reflex, or jerk-locked averaging), and (5) the absence of cognitive decline and other neurological symptoms or prominent progression impairing daily activities in the early stage of disease. “Probable” FCMTE was defined when (1), (5), and two items out of (2), (3), or (4) were satisfied. “Possible” FCMTE was defined when (1), (5), and one item out of (2), (3), or (4) were satisfied.^{15, 16} The “Probable” and “Possible” FCMTE patients were recommended for further genetic testing. All enrolled patients were confirmed to carry the pathogenic pentanucleotide (TTTCA) repeat expansion in SAMD12 by repeat-primed polymerase chain reaction and long-range polymerase chain reaction as described in our prior study.⁸

The study protocol conformed to the recommendations of the Declaration of Helsinki and was approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine. Written informed consent was obtained from all study participants.

Clinical data

All participants were interviewed by experienced physicians (Z.D.C. and W.L. for movement disorders and D.Y. and W.S. for epilepsy) in person and were subjected to neurological examinations in the hospital or at the home of patient's. Clinical assessments included rating of tremulous myoclonus, photosensitivity phenomenon, prodromes, and trigger evaluation. The organization of the semi-structured interview drew upon to previous studies,¹⁷ and contains both structured questions, which could be answered in discrete categories (e.g., “yes,” “no,” or “don't know”), and open-ended questions answered more expansively. Seizure frequency was self-reported as rare (<1/year), occasional (1-6/year), or frequent (>6/year). The self-rating tool for evaluating the severity of cortical tremor consisted of five levels: 0, absence of myoclonus; 1, mild myoclonus without disturbance of daily activity; 2, moderate myoclonus with some disturbance of daily activity; 3, severe myoclonus with clear disturbance of daily activity; and 4, marked myoclonus causing incapacity.¹⁸

Electroencephalogram (EEG)

Electroencephalogram recordings were recorded on a 32-channel system according to the international 10/20 system. Overnight video EEG recordings were conducted in the patients who were interviewed at the hospital, and the results were reviewed by two experienced clinical neurophysiologists (X.Q. and Z.J.W.). Different stages, including wakefulness (W), non-rapid eye movement (NREM) stage I, NREM stage II, and rapid eye movement (REM), were defined based upon standard sleep staging criteria.¹⁹ Both posterior background activity and frequency of IEDs were calculated. The IED index was defined as the number of IEDs per minute. Portable EEG recordings were conducted for at least 30 minutes at home for patients who were unable to visit the hospital.

Intermittent photic simulation (IPS)

Intermittent photic simulation was performed at the hospital, using a standard procedure following an updated algorithm for visual stimulation, as previously described.²⁰ Because photic simulation can potentially induce increase strong reactions and increase the risk of seizures, all patients were informed of the procedural details and possible adverse effects. Only epileptiform discharges that appeared de novo upon IPS compared with baseline EEG were defined as abnormal. Photoparoxysmal responses (PPRs) were classified into four types according to Waltz's criteria: PPR 1, spikes within the occipital rhythm; PPR 2, parieto-occipital spikes with biphasic slow waves; PPR 3, parieto-occipital spikes and slow waves with spread into the frontal region; and PPR 4, generalized spikes or poly-spikes and waves.²¹ Photomyoclonic response (PMR) positivity was defined as myoclonus time-locked to the flash, building in intensity as the stimulus continued, and terminating once the stroboscope was switched off.

Statistical analysis

A single-level variance component model was used to analyze tremor severity as well as potential contributing factors, including sex, age at tremor onset, and duration of tremor. Comparisons between the number and frequency of epileptiform discharges during each sleep stage were conducted using Wilcoxon signed rank tests. P < 0.05 was considered statistically significant.

Demographics

A total of 125 symptomatic carriers of the SAMD12 pentanucleotide (TTTCA) repeat expansion from 28 FCMTE pedigrees were enrolled. These subjects were from 11 different Chinese provinces, representing the Eastern, Center, and Northeast regions of the country (Figure S1). All patients (68 males) presented with cortical tremors with or without epileptic seizures (Table 1). All patients were normal or had nonspecific abnormalities upon brain MRI. Among the 28 probands, the reason for their initial neurologist visit was most often epileptic seizures (n = 27) and rarely cortical tremors (n = 1). The mean age at the time of interview was 48.7 ± 15.5 years, ranging from 14 to 81 years. The mean onset age of cortical tremors was 29.3 ± 9.4 years (median: 30; range: 9–53), with >95% penetrance by 43 years and full penetrance by 53 years (Fig. 1A, Table S1). Ninety-seven patients (77.6%, 97/125) had previously experienced seizures. The mean onset age of seizures was 36.5 ± 9.0 years (median: 35; range: 16–63), with a penetrance of >90% by 51 years and >95% by 62 years (Fig. 1A, Table S2). Notably, >95% patients experienced seizures after the age of 24.

Epileptic seizures

Semi-structured interviews revealed that 97 patients had a history of epileptic seizures. All seizures presented as BTCSs, often preceded by myoclonic jerks. Six patients (6.2%, 6/97) experienced eye or head deviation preceding BTCSs. The seizures had an average onset age much later than cortical tremors, with a mean interval of 6.9 ± 8.4 years (P < 0.001, Fig. 1B). Chronologically, the seizures occurred at a significantly later age than cortical the tremors in 69.1% (67/97) of patients, at a similar time in 27.8% (27/97) of patients, and earlier than cortical tremors in 3.1% (3/97) of patients. The frequency of BTCSs was rare (<1/year) in 58.8% (57/97) of patients, occasional (1–6/year) in 37.1% (36/97) of patients, and frequent (>6/year) in 4.1% (4/97) of patients (Table 1). Self-rating demonstrated that cortical tremors progressively worsened over the course of the disease (P < 0.01, Table 1), while the frequency of BTCSs did not. At the time of the last follow-up, seizure frequency and severity of cortical tremors had a small, but nonsignificant, correlation (P = 0.055). Nearly all seizures occurred while patients were awake, except for one patient who experienced a BTCS during sleep.

Seizure triggers and prodromes

All patients with a history of seizures reported discrete triggers for the majority of their seizures. Seizure triggers included fatigue (70.0%, 68/97), emotional stress (41.2%, 40/97), sleep deprivation (37.1%, 36/97), photic stimulation (28.9%, 28/97), noise (25.8%, 25/97), and hunger (8.2%, 8/97) (Fig. 1C). The same triggers resulted in cortical tremors in each patient. Interestingly, 10 patients experienced their first BTCS during traditional Chinese funerals or weddings, upon exposure to a combination of multiple triggers including emotional stress, prolonged sleep deprivation, and noise. Unfortunately, three patients drowned in paddy fields as confirmed by witnesses. These three farmers experienced several BTCSs trigged by sunlight glare in paddy fields as well as fatigue. With increased experience of seizure triggers, some patients achieved seizure control later in life through avoidance.

Notably, over half (57.7%, 56/97) of the patients with seizures described a prolonged prodrome prior to the onset of an attack. These prodromes included palpitation, chest distress, shaking, dizziness, headache, blurred vision, and irritability, lasting minutes to hours, or sometimes up to a day. Some patients took anti-seizure medications (ASMs) once they felt the prodrome, which could halt the progression to seizures. The seizure triggers could also induce isolated prodromes without resulting in a seizure. Notably, compared with infrequent seizures, isolated prodromes occurred more frequently and resulted in greater distress in daily life. Overall, triggers and prodromes were reported as important and helpful approaches in prevention against seizure attacks. A time line of a typical seizure attack from trigger to BTCS in FCMTE patients is shown in Figure 1E.

Photosensitivity

Nearly a quarter of patients with FCMTE (n = 31, 24.8%), including 28 with seizures and three without seizures, reported photosensitivity characterized by an increased feeling of discomfort, myoclonic jerks or BTCSs in response to environmental photic stimulation (Table 1, Fig. 1D). All 31 patients were sensitive to strong light and/or flickering light, such as a glare reflected by snow or paddy fields, or flashing lights (e.g., in a nightclub). Additionally, five patients reported severe photosensitivity which impaired their daytime activities, and they therefore developed nocturnal lifestyles to avoid sunlight. Notably, seven patients exhibited strong “pattern sensitivity,” which was characterized by susceptibility to seizure occurrence or isolated prodromes viewing striped patterns (e.g., sunlight and shade under trees, a moving escalators in a shopping mall, or a zebra crossing the street). In response to photic stimulation, patients displayed discomfort, shaking, myoclonus, and in some cases, BTCSs. Three patients exhibited both pattern sensitivity and scotosensitivity. The scotosensitivity presented as serious discomfort, myoclonus, and even BTCSs in dark environments, leading to severe insomnia.

To further evaluate photosensitivity in FCMTE patients, intermittent photic simulation (IPS) was conducted throughout VEEG evaluation in 39 patients, including 35 with both cortical tremors and BTCSs, and four with cortical tremors only. Based on the classification described by Waltz et al.,²⁰ 31 patients (79.5%) were photoparoxysmal responses (PPR)-positive (Table 2, Fig. 2A), including 29 with a history of seizures and two without. Twelve patients were classified as PPR I–III and 19 patients were classified as PPR IV. Eighteen patients (46.2%) were positive for a photomyoclonic response (PMR) upon IPS, while in one patient (2.6%), this PMR was accompanied by fixation-off sensitivity.

EEG

EEG examination was conducted in 81 patients, including 64 with both cortical tremors and seizures, and 17 with cortical tremors only. Jerk-locked averaging (JLA) with EEG monitoring during a cortical myoclonus demonstrated a premovement time-locked cortical activity, rather than concurrent epileptic spikes (Fig. 2C, D). No seizure attacks were captured throughout the duration of EEG recording. The frequency of the posterior dominant rhythm (PDR) was 9.2 ± 1.2 Hz, which did not significantly differ from that in age-matched controls from our center (10.3 ± 0.8 Hz). Interictal epileptiform discharges were recorded in 56 patients (56/81, 69.1%), including 50 with a history of seizures, and six without. Thirty-seven patients (56.6%, 37/56) presented with spike/polyspike waves, 12 had both spikes and sharp waves, and seven presented with sharp waves only. Thirty-three patients had generalized IEDs, including 24 (72.7%, 24/33) with occipital dominance and nine (27.3%, 9/33) with frontotemporal dominance (Fig. 2B). Twenty-three patients had focal IEDs, with 15 (65.2%, 15/23) having IEDs over the occipital lobe, and eight patients (34.7%, 8/23) over the frontal, temporal, or parietal lobe (Table 2). In addition, a high frequency of historical seizures was correlated with the presence of IEDs upon EEG (Table 2, P < 0.01).

Overnight EEG recording was performed in 34 of 81 patients, and IEDs were detected in 70.6% (24/34). The IED index during awake or sleep periods was calculated for the 24 patients with IEDs. The average IED index was 0.82 ± 0.88/min during awake periods and 0.04 ± 0.06/min during NREM I-II (Fig. 2E, F). No IEDs were recorded during REM sleep.

Response to anti-seizure medications

Sixty-four (64/97, 66.0%) patients with a history of seizures had treatment with ASMs, all of whom had a positive drug response. Forty-eight of the ASM regimens were monotherapies, 16 were multidrug regimens, while 33 patients were unmediated. As of the most recent follow-up, valproic acid was the most commonly administered ASM (n = 29), followed by benzodiazepines (clonazepam/diazepam/phenobarbital) (n = 19) and sodium channel blockers (phenytoin/oxcarbazepine/carbamazepine) (n = 16). Valproic acid and sodium channel blockers were the most frequently prescribed combination of ASM for individuals on multi-drug. Some patients described that taking benzodiazepines during prodromal phase might help prevent the prodrome from progressing to the seizures. It is worth noting that no patients experienced exacerbated cortical tremor or seizures when using sodium channel blockers.