Responsive Neurostimulation System

Responsive Neurostimulation System

Patients with medically refractory temporal lobe epilepsy (TLE) are candidates for neuromodulation procedures. While vagus nerve stimulation (VNS) was historically the procedure of choice for this condition, the responsive neurostimulation system (RNS) has come into favor for its more targeted approach.


This treatment was approved by the U.S. Food and Drug Administration (FDA) in 2013.


Neuromodulation such as vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) are safe and effective strategies for medically intractable epilepsy secondary to complex partial seizures, but researchers have yet to compare their efficacies.


Wang et al. retrospectively reviewed the records of all patients with TLE who underwent VNS or RNS placement at our institution from 2003 to 2018. The primary outcome was change in seizure frequency. Other outcomes included Engel score, change in anti-epileptic medications, and complications.

Twenty-three patients met inclusion criteria; 11 underwent VNS and 12 underwent RNS. At baseline, the 2 groups were statistically similar regarding age at surgery, epilepsy duration, and preoperative seizure frequency. At last follow-up, both groups displayed reduced seizure frequency (mean reduction of 46.3% for the VNS group and 58.1% for the RNS group, p = 0.49). Responder rate, Engel score, and change in medications were statistically similar between groups. Compared to 0.0% of the VNS group, 13.3% of the RNS group experienced infection requiring re-operation.

Despite their different mechanisms, VNS and RNS resulted in similar response rates for patients with TLE. We suggest that VNS should not be excluded as a treatment for patients with medically refractory TLE who are not candidates for resective or ablative procedures 1).


The goal of a study of Ellens et al. was to compare VNS and RNS efficacy at reducing seizure frequency and complication rates in subjects with medically intractable epilepsy secondary to complex partial seizures.

This is a retrospective chart review of 30 patients with medically intractable complex partial epilepsy, who underwent either VNS or RNS placement at a single institution between June 2012 and January 2016. There was a mean follow-up of 19 months. Seizure frequency reduction and complications were identified.

The median seizure frequency reduction was similar for VNS (66%) and RNS (58%). There was no major morbidity or mortality, and the frequency of minor complications was similar between VNS (15%) and RNS (18%).

They found that VNS and RNS reduced the median seizure frequency similarly with no difference in morbidity or mortality. Further prospective studies are warranted as VNS and RNS therapy improves over time 2).

Systematic reviews

Boon et al., conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety.

For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug-resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low-quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported.

Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long-term safety 3).


Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Boggs JG, Cash SS, Cole AJ, Duchowny MS, Duckrow RB, Edwards JC, Eisenschenk S, Fessler AJ, Fountain NB, Geller EB, Goldman AM, Goodman RR, Gross RE, Gwinn RP, Heck C, Herekar AA, Hirsch LJ, King-Stephens D, Labar DR, Marsh WR, Meador KJ, Miller I, Mizrahi EM, Murro AM, Nair DR, Noe KH, Olejniczak PW, Park YD, Rutecki P, Salanova V, Sheth RD, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness P, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Skarpaas TL, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia. 2017 Jun;58(6):1005-1014. doi: 10.1111/epi.13739. Epub 2017 Apr 7. PubMed PMID: 28387951.

References

1)

Wang AJ, Bick SK, Williams ZM. Vagus Nerve Stimulation versus Responsive Neurostimulator System in Patients with Temporal Lobe Epilepsy. Stereotact Funct Neurosurg. 2020 Feb 19:1-9. doi: 10.1159/000504859. [Epub ahead of print] PubMed PMID: 32074618.
2)

Ellens NR, Elisevich K, Burdette DE, Patra SE. A Comparison of Vagal Nerve Stimulation and Responsive Neurostimulation for the Treatment of Medically Refractory Complex Partial Epilepsy. Stereotact Funct Neurosurg. 2018 Aug 27:1-5. doi: 10.1159/000492232. [Epub ahead of print] PubMed PMID: 30149389.
3)

Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. 2018 Apr;31(2):198-210. doi: 10.1097/WCO.0000000000000534. PubMed PMID: 29493559.

Tuberous sclerosis complex

Tuberous sclerosis complex

Tuberous sclerosis complex, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called “tubers,” in the brains of patients postmortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville’s disease.

Key concepts

● most cases are due to spontaneous mutation. Inherited cases are autosomal dominant. Incidence: 1 in 6K–10K live births.

● classic clinical triad: seizures, mental retardation, and sebaceous adenomas; the full clinical triad is seen in < 1/3 of cases.

● typical CNS finding: subependymal nodules (“tuber”)—a hamartoma.

● commonly associated neoplasm: subependymal giant cell astrocytoma (SEGA)

● 2 tumor suppressor genes: TSC1 (on chromosome 9q34) codes for hamartin and TSC2 (on chromosome 16p13) encodes tuberin

● CT shows intracerebral calcifications (usually subependymal).


Tuberous sclerosis complex (TSC), AKA Bourneville’s disease, is a neurocutaneous disorder characterized by hamartomas of many organs including the skin, brain, eyes and kidneys. In the brain, the hamartomas may manifest as cortical tubers, glial nodules located subependymally or in deep white matter, or giant cell astrocytomas. Associated findings include pachygyria or microgyria.

Tuberous sclerosis complex (TSC) was initially described approximately 150 years ago by von Recklinghausen in 1862 1).

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease usually diagnosed in childhood.

Subependymal giant cell astrocytomas (SEGA) are benign brain lesions occurring in up to 20% of patients with TSC.

Epidemiology

Studies estimate a frequency of 1/6000 to 1/10,000 live births and a population prevalence of around 1 in 20,000 2) 3).

Etiology

Autosomal dominant inheritance; however, spontaneous mutation accounts for the majority of cases.

Two distinct tumor suppressor genes have been identified: the TSC1 gene (located on chromosome 9q34) codes for TSC1 (AKA hamartin), and the TSC2 gene (on chromosome 16p13.3) codes for TSC2 (tuberin). Only 1 gene needs to be affected to develop TSC. These proteins work together to inhibit the activation of rapamycin (mTOR). Genetic counseling for unaffected parents with one affected child: 1–2% chance of recurrence 4) 5).

Clinical features

This rare multi-system genetic disease causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung and kidney disease.

classic clinical triad: seizures, mental retardation, and sebaceous adenomas; the full clinical triad is seen in < 1/3 of cases.

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option.


The diagnosis of TSC is based on clinical features, but the variability of phenotype and age at symptom onset makes this challenging.

In the infant, the earliest finding is of “ash leaf” macules (hypomelanotic, leaf-shaped) that are best seen with a Wood’s lamp. Infantile myoclonus may also occur.

In older children or adults, the myoclonus is often replaced by generalized tonic-clonic or partial complex seizures, which occur in 70–80%. Facial adenomas are not present at birth but appear in > 90% by age 4 yrs (these are not really adenomas of the sebaceous glands, but are small hamartomas of cutaneous nerve elements that are yellowish-brown and glistening and tend to arise in a butterfly malar distribution, usually sparing the upper lip).

Retinal hamartomas occur in ≈ 50% (central calcified hamartoma near the optic disc or a more subtle peripheral flat salmon-colored lesion). A distinctive depigmented iris lesion may also occur.

Diagnosis

Pathology

Subependymal nodules (“tubers”) are benign hamartomas that are almost always calcified, and protrude into the ventricles.

▶ Subependymal giant cell astrocytoma (SEGA). Almost always located at the foramen of Monro. Occurs in 5–15% of patients with TSC.

Treatment

Outcome

In a nationwide multi-center study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient 6).

Case series

Liu et al. reported a nationwide multicentre retrospective study and analyzed the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients’ clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients’ ages at surgery were 10.35 ± 7.70 years (range: 0.5-47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient 7).


Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests.

Eight of 110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample.

Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects 8).

Case reports

A novel technique is presented for the application of MRgLITT in a 6-month-old infant for the treatment of epilepsy associated with tuberous sclerosis complex (TSC) .

To Hooten et al. from the Tuberous Sclerosis Complex Clinic, Duke University, Durham, North Carolina; and University of Florida, Gainesville, knowledge this is the youngest patient treated with laser ablation. They used a frameless navigation technique with a miniframe tripod system and intraoperative reference points. This technique expands the application of MRgLITT to younger patients, which may lead to safer surgical interventions and improved outcomes for these children 9).

References

1)

von Recklinghausen F. Die Lymphelfasse und ihre Beziehung zum Bindegewebe. [German]. Berlin: A. Hirschwald; 1862.
2)

O’Callaghan F, Shiell A, Osborne J, Martyn C. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet. 1998;352:318–319.
3)

Sampson J, Scahill S, Stephenson J, Mann L, Connor J. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet. 1989;26:28–31.
4)

European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315.
5)

van Slegtenhorst M, deHoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808.
6) , 7)

Liu S, Yu T, Guan Y, Zhang K, Ding P, Chen L, Shan Y, Guo Q, Liu Q, Yao Y, Yang M, Zhang S, Lin Y, Zhao R, Mao Z, Zhang J, Zhang C, Zhang R, Yang Z, Qian R, Li Y, Zhang G, Yuan L, Yang W, Tian H, Zhang H, Li W, Zhang X, Yin J, Guo Y, Zou L, Qin J, Fang F, Wang X, Ge M, Liang S. Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain. 2020 Jan 18. pii: awz411. doi: 10.1093/brain/awz411. [Epub ahead of print] PubMed PMID: 31953931.
8)

Manara R, Brotto D, Bugin S, Pelizza MF, Sartori S, Nosadini M, Azzolini S, Iaconetta G, Parazzini C, Murgia A, Peron A, Canevini P, Labriola F, Vignoli A, Toldo I. Rhinencephalon changes in tuberous sclerosis complex. Neuroradiology. 2018 Jun 17. doi: 10.1007/s00234-018-2045-x. [Epub ahead of print] PubMed PMID: 29909560.
9)

Hooten KG, Werner K, Mikati MA, Muh CR. MRI-guided laser interstitial thermal therapy in an infant with tuberous sclerosis: technical case report. J Neurosurg Pediatr. 2018 Sep 28:1-6. doi: 10.3171/2018.6.PEDS1828. [Epub ahead of print] PubMed PMID: 30265228.

Operculoinsular cortectomy

Operculoinsular cortectomy

Operculoinsular cortectomy for refractory epilepsy is a relatively safe therapeutic option but temporary neurological deficits after surgery are frequent. A study of Bouthillier et al. highlighted the role of frontal/parietal opercula resections in postoperative complications. Corona radiata ischemic lesions are not clearly related to motor deficits. There were no obvious permanent neurological consequences of losing a part of an epileptic insula, including on the dominant side for language. A low complication rate can be achieved if the following conditions are met: 1) microsurgical technique is applied to spare cortical branches of the middle cerebral artery; 2) the resection of an opercula is done only if the opercula is part of the epileptic focus; and 3) the neurosurgeon involved has proper training and experience 1).


The goal of a study of Bouthillier et al. of the Sainte-Justine University Hospital CenterMontrealQuebecCanada, was to document seizure control outcome after operculoinsular cortectomy in a group of patients investigated and treated by an epilepsy team with 20 years of experience with this specific technique.

Clinical, imaging, surgical, and seizure control outcome data of all patients who underwent surgery for refractory epilepsy requiring an operculoinsular cortectomy were retrospectively reviewed. Tumors and progressive encephalitis cases were excluded. Descriptive and uni- and multivariate analyses were done to determine seizure control outcome and predictors.

Forty-three patients with 44 operculoinsular cortectomies were studied. Kaplan-Meier estimates of complete seizure freedom (first seizure recurrence excluding auras) for years 0.5, 1, 2, and 5 were 70.2%, 70.2%, 65.0%, and 65.0%, respectively. With patients with more than 1 year of follow-up, seizure control outcome Engel class I was achieved in 76.9% (mean follow-up duration 5.8 years; range 1.25-20 years). With multivariate analysis, unfavorable seizure outcome predictors were frontal lobe-like seizure semiology, shorter duration of epilepsy, and the use of intracranial electrodes for invasive monitoring. Suspected causes of recurrent seizures were sparing of the language cortex part of the focus, subtotal resection of cortical dysplasia/polymicrogyria, bilateral epilepsy, and residual epileptic cortex with normal preoperative MRI studies (insula, frontal lobe, posterior parieto-temporal, orbitofrontal).

The surgical treatment of operculoinsular refractory epilepsy is as effective as epilepsy surgery in other brain areas. These patients should be referred to centers with appropriate experience. A frontal lobe-like seizure semiology should command more sampling with invasive monitoring. Recordings with intracranial electrodes are not always required if the noninvasive investigation is conclusive. The complete resection of the epileptic zone is crucial to achieving good seizure control outcome 2).


In 2017 Bouthillier et al. published twenty-five patients underwent an epilepsy surgery requiring an operculoinsular cortectomy: mean age at surgery was 35 y (9-51), mean duration of epilepsy was 19 y (5-36), 14 were female, and mean duration of follow-up was 4.7 y (1-16). Magnetic resonance imaging of the operculoinsular area was normal or revealed questionable nonspecific findings in 72% of cases. Investigation with intracranial EEG electrodes was done in 17 patients. Surgery was performed on the dominant side for language in 7 patients. An opercular resection was performed in all but 2 patients who only had an insulectomy. Engel class I seizure control was achieved in 80% of patients. Postoperative neurological deficits (paresis, dysphasia, alteration of taste, smell, hearing, pain, and thermal perceptions) were frequent (75%) but always transient except for 1 patient with persistent mild alteration of thermal and pain perception. 3).

References

1)

Bouthillier A, Weil AG, Martineau L, Létourneau-Guillon L, Nguyen DK. Operculoinsular cortectomy for refractory epilepsy. Part 2: Is it safe? J Neurosurg. 2019 Sep 20:1-11. doi: 10.3171/2019.6.JNS191126. [Epub ahead of print] PubMed PMID: 31597116.
2)

Bouthillier A, Weil AG, Martineau L, Létourneau-Guillon L, Nguyen DK. Operculoinsular cortectomy for refractory epilepsy. Part 1: Is it effective? J Neurosurg. 2019 Sep 20:1-10. doi: 10.3171/2019.4.JNS1912. [Epub ahead of print] PubMed PMID: 31629321.
3)

Bouthillier A, Nguyen DK. Epilepsy Surgeries Requiring an Operculoinsular Cortectomy: Operative Technique and Results. Neurosurgery. 2017 Oct 1;81(4):602-612. doi: 10.1093/neuros/nyx080. PubMed PMID: 28419327.

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