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.

Vagus Nerve Stimulation outcome

Vagus Nerve Stimulation outcome

Evidence for long-term efficacy is still limited.

The true outcome of long-term VNS is difficult to assess in real-world practice. The effect may be overestimated due to confounding factors, particularly the common introduction of novel AEDs and the natural course of the disorder. Patients without perceived benefit from long-term VNS should not routinely remain on treatment and be subject to undue generator re-implantations 1).


Kawai et al. report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed 2).


VNS can affect the voice and reduced vocal cord motion on the implantation side with secondary supraglottic muscle tension. Otolaryngologists are not only capable of performing VNS implantation, but can also manage surgical complications, assess laryngeal side effects and treat them as needed 3).


VNS implantation may render patients with some forms of cortical dysgenesis (parietooccipital polymicrogyriamacrogyria) seizure-free. Patients with unilateral IEDs and earlier implantation achieved the most benefit from VNS 4).

References

1)

Brodtkorb E, Samsonsen C, Jørgensen JV, Helde G. Epilepsy patients with and without perceived benefit from vagus nerve stimulation: A long-term observational single center study. Seizure. 2019 Sep 19;72:28-32. doi: 10.1016/j.seizure.2019.09.004. [Epub ahead of print] PubMed PMID: 31563121.
2)

Kawai K, Tanaka T, Baba H, Bunker M, Ikeda A, Inoue Y, Kameyama S, Kaneko S, Kato A, Nozawa T, Maruoka E, Osawa M, Otsuki T, Tsuji S, Watanabe E, Yamamoto T. Outcome of vagus nerve stimulation for drug-resistant epilepsy: the first three years of a prospective Japanese registry. Epileptic Disord. 2017 Sep 1;19(3):327-338. doi: 10.1684/epd.2017.0929. PubMed PMID: 28832004.
3)

Al Omari AI, Alzoubi FQ, Alsalem MM, Aburahma SK, Mardini DT, Castellanos PF. The vagal nerve stimulation outcome, and laryngeal effect: Otolaryngologists roles and perspective. Am J Otolaryngol. 2017 Jul – Aug;38(4):408-413. doi: 10.1016/j.amjoto.2017.03.011. Epub 2017 Apr 4. PubMed PMID: 28390806.
4)

Ghaemi K, Elsharkawy AE, Schulz R, Hoppe M, Polster T, Pannek H, Ebner A. Vagus nerve stimulation: outcome and predictors of seizure freedom in long-term follow-up. Seizure. 2010 Jun;19(5):264-8. doi: 10.1016/j.seizure.2010.03.002. Epub 2010 Apr 1. PubMed PMID: 20362466.
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