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Keywords:

  • Deep brain stimulation;
  • Thalamus;
  • Anterior nucleus;
  • Intractable epilepsy

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Summary: Purpose: The anterior nucleus of the thalamus (ANT) modulates temporal lobe and hypothalamic activities, and relays information to the cingulate gyrus and entorhinal cortex. Deep brain stimulation (DBS) of the ANT has been reported to decrease seizure activity in a limited number of human subjects. However, long-term effect of chronic ANT stimulation on such patients remains unknown. We report long-term follow-up results in four patients receiving ANT stimulation for intractable epilepsy.

Methods: Four patients underwent stereotactic implantation of quadripolar stimulating electrodes in the bilateral ANT, guided by single-unit microelectrode recording. Electrode location was confirmed by postoperative magnetic resonance imaging (MRI). The stimulator was activated 2–4 weeks following electrode insertion; initial stimulation parameters were 4–5 V, 90–110 Hz, and 60–90 μs. Seizure frequency was monitored and compared with preimplantation baseline frequency. Intelligence quotient (IQ) test and auditory P300 response were performed before and after implantation of electrodes.

Results: Four patients (one man with generalized seizures, and three women with partial seizures and secondary generalization) aged 18–45 years old were studied with mean follow-up period of 43.8 months. The four patients demonstrated a sustained effect of 49% (range, 35–76%) seizure reduction to ANT stimulation. Simple insertion of DBS electrodes (Sham period, no stimulation) produced a mean reduction in seizures of 67% (range, 44–94%). One patient was seizure-free for 15 months with anticonvulsant medications. One patient had a small frontal hemorrhage and a second patient had extension erosion over scalp; no resultant major or permanent neurological deficit was observed. Preoperative IQ index and auditory P300 were not significantly different with those after electrodes implantation.

Conclusions: Implantation of electrodes in the ANT and subsequent stimulation is associated with a significant reduction in seizure frequency. However, our study could not differentiate whether the implantation itself, the subsequent stimulation or postimplantation drug manipulation had the greatest impact. These experimental results prompt further controlled study in a large patient population.

Approximately 30% of patients with epilepsy remain inadequately controlled despite optimal antiepileptic drugs (AEDs) therapy (Sander, 1993). Although some patients can benefit from resective treatment, a substantial proportion of patients are unsuited to conventional surgical management. Alternative therapeutic strategies are required for these patients.

Recent success of deep brain stimulation (DBS) for movement disorders and pain, combined with the advantages of reversibility and adjustability, has driven various applications of DBS for a wide-ranging clinical conditions (Theodore and Fisher, 2004; Hamani et al., 2005). In addition to vagus nerve stimulation (Handforth et al., 1998; Ben-Menachem, 2002; Amar et al., 2004), DBS targeting various brain areas have been pursued for epilepsy treatment, including the amygdalohippocampus (Velasco et al., 2000a; Vonck et al., 2002, 2005), cerebellum (Cooper et al., 1976; Wright et al., 1984; Velasco et al., 2005), caudate nucleus (Chkhenkeli and Chkhenkeli, 1997), subthalamic nucleus (STN) (Benabid et al., 2002; Charbardes et al., 2002), centromedian thalamic nucleus (Fisher et al., 1992; Velasco et al., 1995, 2000b, 2000c), and anterior nucleus of the thalamus (ANT) (Upton et al., 1985, 1987; Sussman et al., 1988; Hodaie et al., 2002; Kerrigan et al., 2004). Despite these encouraging results, the best targets and parameters for brain stimulation remain unknown and require elucidation.

Recent reports about the feasibility and efficacy of ANT stimulation for seizure control are encouraging (Hodaie et al., 2002; Kerrigan et al., 2004). Stimulation of superomedial cerebellar cortex was reported to decrease generalized tonic–clonic seizure (GTCS) and tonic seizure (Velasco et al., 2005). However, no long-term follow-up exists for these patients. In this study, four patients received electrode implant for high-frequency ANT stimulation for intractable epilepsy. We report the long-term follow-up results in ANT stimulation for seizure reduction.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Subjects and study design

Study protocol was approved by the institutional ethics board at Chang Gung Memorial Hospital. Four patients were enrolled and informed consent was obtained. Patients with a long history of frequent and intractable seizures were enrolled if they fulfilled all of the following criteria: (1) poorly controlled seizures despite optimal multiple AEDs treatment; (2) no structural abnormality on brain magnetic resonance imaging (MRI) studies and are unsuitable for resective brain surgery; (3) capable of recording reliable seizure diaries. All patients received scalp video-EEG monitoring prior to implantation to determine seizure type and to identify the epileptic focus.

Before implantation, daily seizure diaries were prospectively recorded for at least 9 months (mean 12.5 ±7.5 month; range 9–24 months); data for a 9-month baseline seizure frequency was obtained to compare with that after electrode implantation. Patients had 2–4 weeks of no stimulation (Sham period) following electrode implantation surgery. The stimulators were then turned on using standard stimulation parameters. Potential adverse events were closely monitored. All AEDs remained unchanged during month 1 of stimulation, but were subsequently adjusted to minimize side effects or to achieve seizure control. The patients were urged to take the AEDs strictly and serum drug level measurements confirmed the compliance and documented stable levels. The event-related potentials, especially auditory P300, reflect neural activity related to cognitive processing and is used to demonstrate the cognitive decline in various neurologic disorders. Stimulation of STN in Parkinson's disease patients did not change P300 latencies (Gerschlager et al., 2001). Intelligence quotient (IQ) test and auditory P300 response were performed before and after electrode implantation to evaluate the influence of ANT stimulation on cognitive function.

Surgical procedures

Patients underwent preoperative cerebral computed tomography (CT) for stereotactic determination of targets and the anterior commissure/posterior commissure (AC/PC) reference line. Under local anesthesia, microelectrode recordings were employed to identify the neuronal signals from the anterior and dorsal median thalamic nuclei. Single unit activity was recorded extracellularly with a FHC (Bowdoinham, ME, U.S.A.) intraoperative platinum iridium microelectrode (0.3–0.5 MΩ impedance). The guiding cannula was utilized as the reference electrode. Extracellular action potentials were amplified with a GS3000 (Axon Instruments, Sunnyvale, CA, U.S.A.) or Leadpoint (Medtronic, Minneapolis, MN, U.S.A.) amplifier and simultaneously recorded using standard recording techniques (300–10,000 Hz), together with a descriptive voice channel. The ANT neurons were identified based on the following criteria: (1) the position relative to other characteristic features; (2) a firing rate and pattern similar to that described for ANT in monkey and human recordings (Kerrigan et al., 2004); and, (3) characteristic burst firing pattern. Bilateral DBS stimulating quadripolar electrodes (Medtronic 3387) were inserted into the ANT. Location of stimulation leads was further confirmed by postoperative brain MRI.

Each patient received postimplantation video-EEG monitoring for 5–7 days; thalamic EEGs were recorded via implanted leads concomitant with scalp EEGs. A series of functional study to ANT stimulation, including functional MRI, short latency cortical evoked potentials and somatosensory evoked potentials was performed; then the programmable pulse generator (IPG; Medtronic 7428 Kinetra Neurostimulator, Medtronic) was placed subcutaneously into the infraclavicular pocket and connected to stimulation electrodes via a lead extension (Medtronic 7482 Lead extension, Medtronic).

Patient 1 received bilateral ANT and STN electrodes implantation. The area of STN was identified by irregular firing pattern of 30–60 Hz and neuronal response to passive movement (Chen et al., 2003). Electrodes were temporarily connected to a transcutaneous extension, and the patient received continuous stimulation to the bilateral ANT or STN alternatively for 6 days in a patient blind way. Under video-EEG monitoring, one GTCS was noted during ANT stimulation; however, four GTCSs were recorded during STN stimulation. The quadripolar electrodes targeting STN were removed 1 week later.

Stimulation parameters

Parameters setting were based on findings from DBS of STN for Parkinson's disease (Benabid et al., 2001) and other brain structures for epilepsy (Fisher et al., 1992). Initial stimulation parameters were as follows: frequency, 90–110 Hz; pulse width, 60–90 μs; and pulse amplitude, 4–5 V. Pairs of electrode contacts were selected for bipolar stimulation based on the assumption that the current generated should be more localized than monopolar. Continuous stimulation was initially applied based on experience in movement disorders (Limousin et al., 1995). Intermittent (cycling) stimulation was later used to prolong battery life, and theoretically to minimize potential injury to surrounding tissue although little tissue damage is associated with chronic DBS. Ongoing adjustments of stimulation parameters were in response to each patient clinical condition. Parameters adjustment were firstly voltage increase by 1 V to a maximum of 7 V, then frequency increase by 30 Hz to a maximum of 180 Hz, and lastly pulse width increase by 30 μs to a maximum of 120 μs.

Statistics

For each patient, baseline and postimplantation seizure frequency were analyzed to examine whether systematic upward or downward trends were present. The two-tailed single-value t-test was performed to test the differences between Sham period and after stimulation period. Average seizure frequency for the initial 6 months “cycling” stimulation was compared with that of the last 6 months “continuous” stimulation by using a paired t test. Subsequently, a one-way analysis of variance (ANOVA; F test) was used to assess the influence of AEDs adjustment on seizure frequency. A value of p < 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

General results and seizure control

Table 1 summarizes patient clinical characteristics, imaging studies, physiologic data, individual AEDs treatment, postimplantation AEDs adjustment, and the last stimulation parameters. Baseline seizure frequency was 7.8–216.7/month. Average postoperative follow-up was 43.8 months (range, 33–48 months). The overall seizure reduction was 51% with a range of 37% to 75% (Table 2).

Table 1. Clinical patient characteristics and presurgical evaluation results
CharacteristicPatient # 1Patient # 2Patient # 3Patient # 4
  1. GTCS, generalized tonic–clonic seizures; CPS, complex partial seizures; B, bilateral; L, left-sided; R, right-sided; FT, frontotemporal; F, frontal; G, generalized; SW, spike-and-wave discharge; IQ, intelligence quotient; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; AEDs, antiepileptic drugs; CBZ, carbamazepine; TPM, topiramate; CNZ, clonazepam; VPA, valproic acid; LTG, lamotrigine; PHT, phenytoin.

  2. aSystem was removed due to extension erosion at 9 months after implantation.

Age (year)18452122
SexMFFF
Seizure onset age3.5 years old41 years old13 years old9 months old
EtiologyCryptogenicCryptogenicCryptogenicCryptogenic
Seizure typeGTCSProlonged simple motor seizure, with secondarily GTCSSimple motor seizure, secondarily GTCSCPS, secondarily GTCS
Video-EEG monitoring Interictal EEGB FT independent SW with L prominentNormalB F SWB FT SW
 Ictal EEGB FT sharp waveG sharp waveB F SWB FT sharp wave
Seizure semiologyNo aura, awake from sleep, crying and hypermotor behavior, then turn head to R, followed by R arm elevated and evolved to generalized motor ictus, R arm postictal paralysisNo aura, simultaneous or alternative hand flapping and leg padding, occasional postictal R limbs paralysisAura: fearful sensation; simultaneous or alternative clonic movement of four limbs without conscious alternation; occasional followed by GTCSSwallow saliva; eye staring, oroalimentary automatism, head turn to R, vocalization and GTCS, followed by postictal confusion
Full IQ88695638
Brain MRINormalNormalNormalNormal
Brain MRSNormalNormalNormalNormal
Baseline AEDs (mg/day)CBZ (800), TPM (100), CNZ (0.5)VPA (2000), CNZ (2), LTG (100)CBZ (800), TPM (400)VPA (1500), PHT (300), TPM (200)
Post-DBS AEDs adjustment 1st adjustmentMonth 3: CBZ (400), VPA (750), CNZ (0.5)Month 2: VPA (1000), CNZ (1)Month 15: CBZ (600), TPM (300), CNZ (1), VPA (1500)Month 4: VPA (2000), PHT (300), CNZ (1)
 2nd adjustmentMonth 11: CBZ (600), VPA (1250), CNZ (0.5)Month 9: VPA (1500), CNZ (3)Month 34: TPM (200), VPA (1500)Month 14: VPA (3000), PHT (300), CNZ (1)
 3rd adjustmentMonth 29: CBZ (600), VPA (1500), CNZ (0.5)Month 46: VPA (2000), CNZ (3) 
Last stimulation parametersCycling, monopolar, 6 V, 90 μs, and 180 HzCycling, monopolar, 5 V, 120 μs, and 180 HzContinuous, bipolar, 5 V, 60 μs, and 110 HzaCycling, bipolar, 5 V, 90 μs, and 130 Hz
Table 2. Effects of ANT (anterior nucleus of the thalamus) stimulation in seizure control
Patient numberPatient sex/age (year)Baseline seizure frequency/monthSham period seizure frequency/month (% seizure reductiona)After stimulation seizure frequency/month (% seizure reductiona)Postimplantation (sham + after stimulation) seizure frequency/month (% seizure reductiona)Total follow-up (months)
  1. Seizure frequency is expressed as mean ± standard deviation.

  2. aPercentage of seizure reduction compared with the baseline.

  3. bIn this patient, the stimulator was accidentally turned off at 7–12 months; seizure frequency increased to 9.6 ± 3.2/month during this period. The stimulator was reactivated at month 12.

1M/1826.2 ± 9.88.0 (69%)16.9 ± 3.9 (35%)16.4 ± 4.3 (37%)48
2F/45216.7 ± 63.214.0 (94%)117.8 ± 42.6 (46%)111.7 ± 48.2 (48%)47
3F/21 7.8 ± 1.73.0 (61%) 1.8 ± 2.3 (76%) 1.9 ± 2.2 (75%)41
4F/22 9.0 ± 3.55.0 (44%)  5.1 ± 1.5 (43%)b  5.1 ± 1.4 (43%)b33

Fig. 1 plots the temporal pattern for percent reductions in seizure incidence. Simple insertion of the DBS electrodes reduced seizure frequency in Sham period (mean reduction, 67%; range, 44–94%). The mean reduction of seizure was 49% after starting ANT stimulation (range, 35–76%). Comparing the seizure frequency between Sham period and stimulation period by two-tailed single-value t-test had a p-value of <0.001, <0.001, 0.086, and 0.794, respectively. The patient age, seizure duration, number of baseline seizures, and seizure reduction at Sham period were not correlated with specific response groups. Table 3 demonstrated no significant difference in seizure frequency between the “cycling” and the “continuous” stimulation period.

image

Figure 1. Seizure frequencies over time after stimulator implantation, expressed as a percentage of that at baseline (BL).

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Table 3. Comparison of seizure frequency with continuous ANT (anterior nucleus of the thalamus) stimulation and cycling stimulation
Patient numberContinuous stimulation seizure frequency/monthCycling stimulation seizure frequency/monthp-value
  1. Seizure frequency is expressed as mean ± standard deviation. Averaged seizure frequency in the last 6-month continuous ANT stimulation was compared with that of the initial 6-month cycling stimulation (Paired t-test, p < 0.05). Patient 3 only received continuous ANT stimulation before removal of the stimulation electrodes.

122.0 ± 3.818.1 ± 0.70.32
297.0 ± 7.592.2 ± 4.10.30
48.2 ± 0  5.5 ± 2.10.32

In patient 2, during the Sham period, a double-blind trial for ANT stimulation during motor seizures was evaluated under video-EEG monitoring. A different investigator manipulated the stimulation code, and both of the patient and evaluator were “blinded” to the ON or OFF of the stimulation. In all 14 trials of true ANT stimulation, the motor seizures stopped 1–5 s after the stimulation was activated, and none of the 19 trials of false ANT stimulation had any change. Patient 3 seizure frequency decreased from 7.8 ± 1.7/month to 4.9 ± 1.8/month during the first 4 months. A subcutaneous seroma at the scalp and exposure of the connecting wire was noted in the fifth month after IPG implantation, and needed surgical removal of the right stimulation electrode and connecting wire. Five months after this surgery, a second extension erosion developed, and the IPG, left electrode and connection wire were removed; valproate 1,500 mg per day was added. A continuous decreasing seizure frequency was observed, and she became seizure-free for 15 months. Comparing seizure frequency between periods of each AEDs adjustment revealed a mild decrease seizure frequency in patient 3 to adjustment of AEDs (4.6 ± 1.4 vs. 1.0 ± 0.5 after valproate was added on, p = 0.021). On the other hand, possible significant increased seizure frequency was noted in patients 1 and 2 despite increasing dosages of AEDs (patient 1, 11.2 ± 2.9 vs. 17.2 ± 2.1 after second adjustment of AEDs, p = 0.048; patient 2, 123.3 ± 25.7 vs. 184.5 ± 0.0 after second adjustment of AEDs, p = 0.043).

Complications

Patient 1 noted mild left-hand weakness 2 days after removal of electrode targeting STN. A brain MRI revealed a small right frontal hemorrhage. This weakness gradually improved without permanent functional impairment. Patient 3 developed extension erosion over scalp, resulting in the removal of the whole system. In patient 4, the stimulator was accidentally turned off at 7–12 months, causing increased seizure frequency, which reduced after stimulator reactivation. No new seizure types emerged during follow-up. Neither sleep pattern disturbance nor behavior changes were reported. Preoperative IQ index and auditory P300 response were not significantly different.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Comparison of seizure frequency at baseline and at postimplantation period identified a mean seizure reduction of 51%; one patient had a ≥75% seizure reduction. Simple insertion of the ANT electrodes decreased the seizure frequency during Sham period. These findings are consistent with another report that achieved a 54% seizure reduction in five patients receiving ANT stimulation. The observed benefit did not differ between stimulation-ON and stimulation-OFF periods (Hodaie et al., 2002). The seizure reduction of the Sham period may be due to the “microlesion” (“microthalamotomy”) by electrode implantation or “carry-over” effect of brief test stimulation. Seizure-free status for patient 3 further supports the hypothetical microthalamotomy and/or carry-over effect, although the addition of valproate may affect this. Chronic STN stimulation has been reported to decrease seizure frequency (Benabid et al., 2002; Chabardes et al., 2002). Patient 1 had temporary implantation of electrodes over STN for 1 week; this STN electrodes microlesion effect may also contribute some part of seizure reduction benefit. Other studies indicate that DBS may act via local inhibition or by interfering with projections to other cortical areas. In these four patients, an immediate increase in seizure frequency and intensity occurred once ANT stimulation was turned OFF, and improved when stimulation was resumed (Kerrigan et al., 2004). A similar scenario was observed in our patient 4. For patient 2, a double-blind trial demonstrated that motor seizures stopped after the stimulator was turned ON. These observations suggest that ANT stimulation-induced inhibition is primary factor in reducing seizure frequency. In conclusion, either the microlesion or direct ANT stimulation contributes to the seizure reduction effect of DBS. A double-blind controlled study with longer Sham period is required to elucidate the therapeutic effect achieved by insertion of DBS electrodes alone, active DBS stimulation, or interaction between these factors.

The seizure reduction effect in relation to time after electrodes implantation was not well described in the literatures. A total seizure reduction of 54% was reported in five patients followed up for 15 months (range, 10.6–20.7 months) (Hodaie et al., 2002). A second report described four of the five patients had considerable variation in seizure reduction effect during a mean follow-up period of 20.4 months (range, 6–36 months) (Kerrigan et al., 2004). In this study, individual variation of seizure reduction was obvious; however, the efficacy of seizure control became consistent during months 15–48 after stimulation. In current study, patients 2 and 3 had motor seizures that achieved an overall seizure reduction of 48% and 75% compared to 37% for patient 1 with primary GTCS and 43% for patient 4 with CPS and generalization. Activation of stimulator immediately stopped motor seizures in patient 2, and patient 3 eventually was seizure-free for 15 months. Previous study reported that cerebellar stimulation is effective for GTCS and tonic seizure (Velasco et al., 2005). Current observation suggests that motor seizures responded to ANT stimulation and/or microlesion effect.

Cycling or continuous brain stimulation was applied in previous reports for seizure reduction. The patients of current study received continuous ANT stimulation initially, and changed to cycling stimulation later. No significant difference in seizure frequency was noted. However, this study precludes any definite conclusion due to possible carryover effect of “continuous” to “cycling” stimulation, and variable adjustment of other stimulation parameters. It is difficult to compare the efficacy of seizure reduction for individual parameters adjustment in this study. A double-blind randomized prospective study is needed to clarify the effect of each stimulation parameters for seizure control.

The studies of STN stimulation in Parkinson's disease reveal that adverse events may be related to the DBS surgery, hardware, the stimulation, or the disease progression. The overall complication rates can exceed 25% (Grill, 2005). Long-term followed up demonstrated a 26.2% hardware complication (Lyons et al., 2004) and 3–5% of cerebral hemorrhage. The complication of frontal hemorrhage and extension erosion in our patients is similar to that seen in patients receiving STN stimulation for Parkinson's disease. On and off stimulation of STN have rapid corresponding changes of the symptoms of Parkinson's disease. Sudden withdrawal of ANT stimulation in patient 4 did not pose a theoretical risk of developing status epilepticus.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

This 43.8-month follow-up study suggests the implantation and stimulation through electrodes in ANT might be an alternative treatment modality in reducing seizure frequency for patients with intractable epilepsy. There are still not enough findings in these four patients to suggest that reduction of seizure frequency was due to stimulation. Further multicenter, double-blinded studies are required to further clarify the patient group, efficacy, safety, and stimulation parameters of ANT stimulation for patients with intractable epilepsy.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Acknowledgments:  The authors would like to thank the National Science Council of the Republic of China, Taiwan (NSC91-2314-B-182A-039) and the National Health Research Institutes, Taiwan (NHRI-GT-EX89S926P), for financially supporting this research.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES
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