Recently, we have met several patients in succession who have asked about the treatment of tuberous sclerosis with epilepsy, and we feel it is necessary to summarize it to save the patients from inconvenience. For epileptologists, tuberous sclerosis, although frequently encountered, is still relatively rare. To be precise, it is an autosomal dominant disorder. (Incidentally, it is only inherited in a very, very small percentage of the epilepsy field, and patients with epilepsy have nothing to worry about inheriting it to their offspring.) The common main manifestations are: punctate calcified foci around the ventricles visible on CT scans of the head; fibrovascular tumors (or sebaceous adenomas) predominantly in the cheeks, with patches of depigmented skin (white spots or coffee-colored shifts) visible in multiple areas of the body; rhabdomyosarcoma of the heart or angiomyolipoma of the kidney; mental retardation; and seizures.
Most of the epilepsy associated with tuberous sclerosis begins in infancy and childhood and rarely appears when one grows up. It is still mainly associated with brain damage, some of which is accompanied by mental retardation. All other manifestations of tuberous sclerosis are basically untreatable or do not require treatment, so seizure control is the primary goal of treatment.
But unfortunately, in my experience, epilepsy with tuberous sclerosis is really not treatable! Most of them are even more difficult to treat when combined with mental retardation, and most patients rely on several medications to maintain them and still fail to fully control their seizures, or they are simply ineffective! The choice of medication requires the doctor to slowly figure out and summarize. It is advisable for patients to choose an experienced doctor and adjust the medication regimen several times to perhaps find an optimal pairing. Do not change doctors frequently, and do not expect any special miracle cure, which will only delay the disease.
Finally, a word about surgical treatment. In the past, surgery was not advocated for this disease because even surgery was ineffective. In recent years, through continuous efforts, some new insights have been gained. The cause of seizures is still brain damage, but the nodular-like calcified foci seen on CT are not always associated with seizures. In some patients, more nodular-like foci in the brain can be found through detailed MRI of the brain (these foci are not shown on CT because they are not calcified), and these foci found on MRI are not always epileptic foci. Therefore, the key to surgical treatment of nodular sclerosis is to identify the true “epileptogenic foci” and the extent of resection required, which is indeed a complex process. In the last five years, as of the end of 2010, I have treated a total of 9 patients with epilepsy clearly diagnosed as tuberous sclerosis, and so far, only 1 case was ineffective, which seems to be a good result (more than 20% of the epilepsy surgeries I have performed were ineffective overall), I think it has to do with patient selection, most of the more complicated tuberous sclerosis eventually gave up surgery. Also some patients have had surgery for a short time and there is a possibility of future relapses.
Tuberous sclerosis, also known as tuberous cerebral sclerosis and Bourneville’s disease, is a rare multisystem genetic disease that is caused by abnormal development of organs in the ectoderm. The disease can be classified as a neurocutaneous syndrome (also known as pemphigoid malignant nevus disease), first reported by Désiré-Magloire Bourneville in 1880, and is an autosomal dominant disorder with variable ectodomain rate.
TSC is caused by mutations in the TS1 and TS2 genes, which encode hamartin and tuberin proteins, respectively, that act to inhibit tumor growth and regulate cell proliferation and differentiation.
[Epidemiology].
The incidence of the disease is 1/9500 to 1/20000. The ratio of male to female is about 2~3:1. 20%-30% of the patients have a positive family history of the disease and 60%-70% do not have a positive family history. There are two types of causative genes, type I is located on chromosome 9 (9q34) and type II is located on chromosome 16 (16p13.3).
The phenotypes caused by type I and type II can be identical. There is a greater proportion of positive family history in type I, while there are more disseminated cases in type II.
[Pathogenesis].
Gliosis sclerosing nodules occur widely in the white matter of the cerebral cortex, basal ganglia and subventricular canal often accompanied by calcium deposits, and may appear as heterotopias and vascular hyperplasia
The pathological changes in the brain are many hard solid nodules in the cerebral cortex with ectopic cell clusters in the white matter and small nodules in the ventricular wall. The number of cortical nodules varies from 1 to 40, with the frontal lobes being the most numerous, but they can also occur in the thalamic basal ganglia, cerebellum, brainstem and spinal cord. The size of the nodules varies and some can be more than 3 cm in diameter and appear as megalencephalic gyrus malformations.
Histologically, the nodules are composed of very dense fine glia fibers containing abnormal morphology of glial cells and normal or atypical neuronal nodules that may have calcium salt deposits or cystic changes. The normal cortical structure is often disturbed by small subventricular nodules that protrude into the ventricles and appear shiny white and hard, forming the so-called “candle tear” sign. Sometimes they can block the cerebrospinal fluid circulation pathway and cause hydrocephalus. The ectopic nuclei in the white matter are also composed of glial cells and deformed ganglion cells with few nerve fibers mainly located between the ventricular wall and the cerebral cortex.
Cerebral lesions generally have no malignant potential. Sebaceous adenomas of the skin are composed of overgrown sebaceous connective tissue and dilated capillaries.
The disease is often associated with retinal glioma, heart and kidney tumors or malformations. Tumors of the thyroid, thymus, breast, stomach, intestines, liver, spleen, pancreas, adrenal glands, ovaries, bladder and uterus are also found.
Genetic characteristics]: It generally means that the parental autosomes carry a pathological gene. As long as one such gene is passed to the next generation, the offspring can get the disease. The characteristics of inheritance are: (1) at least one of the two parents has the disease (heterozygous), and the disease is passed from generation to generation with late onset; (2) both male and female offspring can develop the disease; (3) basically 1/2 of the offspring have the disease; (4) consanguineous marriage is meaningless, if both parents are disease free, the children generally will not develop the disease (unless a new gene mutation occurs).
【Clinical manifestations】.
1. Skin manifestations
Typical skin changes include depigmented spots, facial angiofibromas, finger (toe) nail fibromas and sharkskin-like spots. Not every child may have all these changes. The disease can sometimes have coffee milk spots, but the number is not large.
In 90% of children, depigmented patches of skin are found at birth and are white, well-defined from the surrounding skin, and oval or otherwise shaped. Because of the eucalyptus leaf-like shape of the depigmented spots, some literature refers to them as eucalyptus leaf spots. They vary in size from 1 cm to several cm in length and diameter. It can be seen on the trunk and extremities with asymmetric distribution, and rarely on the face. It is sometimes seen on the scalp, where the hair also turns white. Pigment loss spots are easily detected on physical examination in yellow or black individuals, but are sometimes more difficult to detect in Caucasians, but are easily visible under ultraviolet light (Wood’s lamp).
The number of depigmented spots varies from one patient to another, from a few to more than 10. In normal people, 1 or 2 pigment loss spots can sometimes be seen, which has no diagnostic significance. Some patients can also see clusters, a larger number of irregularly shaped, small areas of small pieces of pigment loss spots like confetti.
They are not sebaceous glands, but are composed of blood vessels and connective tissue. They are reddish-brown in color or of the same shade as the skin and are raised in the skin, papular or fused into small patches, indicating smoothness without exudation or secretions. They are scattered on the sides of the nose and on the skin of the nasolabial folds, and in large numbers may extend to the lower jaw and sometimes to the forehead.
Facial angiofibroma is not seen at birth, but gradually increases after the age of 4-10 years. This sign has diagnostic value, but not all patients have this manifestation. Fibromas of the finger (toe) nail are located around the finger (toe) nail and under the nail, like a small, fleshy nodule. They are more common in girls than in boys, but are less common before puberty. Multiple finger (toe) nail fibroids have diagnostic value for this disease. Some patients have more sharkskin-like spots on both sides of the trunk or back, slightly elevated on the skin, with irregular borders and rough epidermis, and this lesion can be seen in 20%-30% of patients after puberty. Some children can be seen at birth with slightly elevated patches of skin on the forehead, which is helpful for the diagnosis of the disease.
2.Ocular lesions
TSC retinal lesions were first described by Vander Hoeve in 1921, who described the composition of retinal nevus-like misshapen tumors, and it is now clear that retinal nevus-like misshapen tumors are astrocytomas. The most common tumor pattern was flat translucent damage (70%), followed by strawberry-like nodular damage (55%), and a transitional pattern between these two types (9%). 30% of patients had two or more forms of retinal malformations at the same time. In addition to retinal malformations, other ocular lesions such as angiofibromas of the eyelids, nonparalytic strabismus, and defects of ocular structures have been identified.
3. Cardiovascular lesions
Cardiac lesions in TSC are mainly rhabdomyosarcoma of the heart, which usually occurs in multiple chambers. Before the age of 6 years, more than half of the patients may be asymptomatic or have degenerative changes in the tumor. The most frequent clinical symptom is arrhythmia, which can be fatal. TSC arrhythmias can lead to sudden death in infants, but can be cured surgically as they are first diagnosed prenatally with sonography.
The main vascular lesion in TSC is an aneurysm, but it is not common. They can occur in the aorta, carotid artery, axillary artery, renal artery, and intracranial artery. Individuals present as giant or multiple, and some intracranial aneurysms are associated with polycystic liver, which may be a manifestation of adjacent genetic syndrome. Histologically, the aneurysm has a loss of elasticity in the arterial wall, similar to Marfan disease. Due to the high probability of rupture of the aneurysm, elective repair surgery is currently favored
4.Pulmonary lesions
The main lesion in the lungs of TSC is lymphangioleiomyomatosis. The incidence of this lesion is significantly higher in TSC than in the general population. It is characterized by pulmonary tissue vesicles distorted by highly elastic smooth muscle cells. A CT scan of the chest shows thin-walled alveoli. Histologically, it shows nodular fibromatous tissue scattered in the bronchial tree and alveolar septa.The most frequent pulmonary symptoms of TSC are dry cough, hemoptysis, dyspnea or spontaneous pneumothorax, and in severe cases, respiratory failure, most often in the reproductive age group. Pulmonary lymphangioleiomyomatosis has a poor prognosis and no specific treatment is available. Almost all reported cases occur in women.
5. Renal lesions
Renal lesions in TSC are second only to the neurological system and are one of the main clinical manifestations and causes of death in TSC. Renal angiomyolipomas are the most common type of renal damage in TSC, are more common in women than men, and are overwhelmingly bilateral. renal cells in TSC are derived from the migration and differentiation of chromophobe neural crest cells. Almost half of the TSC renal angiomyolipoma smooth muscle cells stained positive for progesterone receptors, and all progesterone receptor-positive TSC angiomyolipomas occurred in women under 50 years of age, suggesting that sex hormones may be involved in the course of TSC nephropathy. Sarcopenic hematuria is the most common symptom of angiomyolipoma, followed by pain in the ribbed abdomen, palpable abdominal masses, and hypertension. The likelihood of hemorrhage for tumors >3?5 cm in diameter is 35%, so elective surgery should be performed for renal angiomyolipoma >3?5 cm in diameter to prevent hemorrhage.
Dabora et al. found that 76% of patients with TSC complicated by renal angiomyolipoma had mental retardation, which was more severe; only 44% of patients with TSC without renal angiomyolipoma had mental retardation. O′Callaghan et al. also found that 100% of children with TSC with combined learning deficits had renal angiomyolipoma, while only 38% of TSC patients with normal intelligence had renal angiomyolipoma.
Renal cystic disease is the second most common renal lesion in TSC patients. Nearly half of all TSCs have renal cysts, which can occur in conjunction with renal angiomyolipomas. Most of the cysts are multiple and bilateral. The size and number of cysts generally increase over time, but Ewalt et al. found that cysts disappeared spontaneously in 5 out of 10 children. Renal cysts are more likely to cause hypertension and renal insufficiency than renal angiomyolipoma.
6. Other manifestations
Retinal crystal tumor is also one of the characteristic manifestations of this disease, usually located in the posterior pole of the eye, yellowish or grayish yellow with a slight glitter, round or oval, with a slightly elevated and irregular surface, and a cogwheel-shaped rim half to twice the size of the optic disc. Other ocular manifestations include microphthalmia, proptosis glaucoma, crystal opacities, cataracts, vitreous hemorrhage retinitis pigmentosa, retinal hemorrhage and primary optic nerve atrophy.
Complications: The disease often invades multiple organs and tissues, and almost any organ or tissue can be involved. Complications such as renal failure, heart failure, persistent epilepsy, and respiratory failure can occur
Imaging
X-ray: intracranial calcification points can be found on plain film.
CT.
1, CT plain scan can be seen on both sides of the subventricular canal and around the ventricles with multiple high-density nodular shadow, partly with calcification, and sometimes multiple small nodular calcifications are seen in the cortex or white matter, whose density is lower than the ventricular wall calcification, and the edge is not clear.
2.Enhanced scan of non-calcified nodules can be enhanced without occupancy effect.
3. Brain atrophy such as widening of the cerebral sulcus can be seen.
4. Soft tissue mass in the interventricular foramen of the lateral ventricle can be seen in the case of intracranial giant cell astrocytoma, and the necrotic part shows hypodensity. The solid part of the tumor can be enhanced on enhancement scan. It is also accompanied by obstructive hydrocephalus.
MRI manifestations: ① subventricular nodules; ② abnormal white matter of brain; ③ cortical nodules; ④ subventricular giant cell astrocytoma; ⑤ cystic abnormal signal.
【Diagnostic criteria】.
Main indices.
1, facial angiofibroma.
2, multiple finger (toe) nail fibromas.
3, cerebral cortical nodules (histologically confirmed).
4, subventricular nodules or giant cell astrocytoma (histologically confirmed).
5. multiple subventricular calcified nodules extending into the ventricles (radiologically confirmed)
6, multiple retinal astrocytomas.
Secondary indicators
1, cardiac rhabdomyosarcoma (histologically or radiologically confirmed)
2, other retinal malformations or achromatic plaques.
3, brain nodules (radiologically confirmed).
4, non-calcified subventricular nodules (radiologically confirmed).
5, sharkskin-like plaques.
6, prefrontal plaques.
7, pulmonary lymphangioleiomyomatosis (histologically confirmed).
8, renal angiomyolipoma (histologically or radiologically confirmed).
9, tuberous sclerosis polycystic kidney (histologically confirmed).
Tertiary indicators
1, depigmented spots.
2, skin “confetti-like” pigment loss spots.
3, renal cystic lesions (radiologically confirmed).
4. Irregular enamel destruction depressions in milk teeth or permanent teeth.
5, rectal polyp malformation (histologically confirmed).
6, cystic change of bone (radiologically confirmed)
7, lymphangioleiomyoma of the lung (radiologically confirmed).
8. white matter “migratory traces” or gray matter heterotopia (radiologically confirmed).
9, gingival fibroma.
10, angiomyolipoma of organs other than the kidney (histologically confirmed).
11. Infantile spasms.