Tuberous Sclerosis

Overview

Epidemiology

• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 in 6000–10,000 newborns in the United States
• Men and women are equally affected.

Etiology

• Autosomal dominant inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance
• Loss-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the:
  • TSC1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (25% of cases):
    • Located on chromosome 9 Chromosome 9 Friedreich Ataxia (long arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy)
    • Encodes hamartin → tumor-suppressor protein
  • TSC2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (75% of cases):
    • Located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 16 (short arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy)
    • Encodes tuberin → tumor-suppressor protein
• Spontaneous mutations in 80% of cases

Pathophysiology

• Pathology occurs when the physiologic basis of cellular quiescence is disrupted.
• 2-hit hypothesis Hypothesis A hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis. Statistical Tests and Data Representation:
  • Tumor Tumor Inflammation suppressor:
    • The tumor-suppressor proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis ensure that the cell remains in the resting phase Resting phase Skin: Structure and Functions of a cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle.
    • Loss of function Loss of Function Inflammation → inhibitory signal is lifted → cells spend less time in G1 phase G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle
  • mTOR mTOR Peutz-Jeghers Syndrome pathway:
    • A posttranslational modification that results in up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle.
    • Normally controlled by the tuberin–hamartin complex
    • Loss of the complex results in continuous up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics and growth of cells.

Clinical Presentation

Dermatologic features (95%)

• Ash leaf spots:
  • Hypopigmented macules (> 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma)
  • Located on trunks/extremities
  • Present from birth
  • ≥ 3 usually the earliest sign of tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor complex (TSC)
• Shagreen patches Patches Vitiligo:
  • Flesh-colored nodules
  • Irregularly shaped, thickened skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions (leather-like)
  • Usually located on the lower back
• Angiofibroma:
  • Red spots or small cutaneous bumps
  • Appear around 3–5 years of age and increase over time
  • Butterfly pattern on the face (malar region)
  • Ungual fibromas: smooth, firm, flesh-colored lumps that emerge from the nail folds.
• Confetti lesions:
  • Hypopigmented macules (< 3 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma)
  • Multiple
  • Dispersed throughout the body

CNS features (70%)

• Cortical tubers
• Glioneuronal hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer
• Subependymal giant-cell astrocytomas (SEGAs)
• Subependymal nodules
• Present with:
  • Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy
  • Infantile spasm
  • Cognitive impairment
  • Behavioral issues
  • Symptoms of increased cranial pressure:
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Diplopia Diplopia A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. Myasthenia Gravis

Cardiopulmonary features (40%)

• Cardiac rhabdomyomas: maybe detected in utero
• Coarctation of the aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy
• Lymphangioleiomyomatosis Lymphangioleiomyomatosis A disease characterized by the progressive invasion of smooth muscle cells into the lymphatic vessels, and the blood vessels. The majority of the cases occur in the lungs of women of childbearing age, eventually blocking the flow of air, blood, and lymph. The common symptom is shortness of breath (dyspnea). Interstitial Lung Diseases (LAM) of the lung (similar to diffuse pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans): present with dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea or pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax

Renal features

• Angiomyolipomas 
• Renal cysts Renal Cysts Imaging of the Urinary System
• Present with:
  • Hemorrhage
  • Flank pain Flank pain Pain emanating from below the ribs and above the ilium. Renal Cell Carcinoma
  • Hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
  • Tender abdominal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast

Ophthalmic features (30%)

• Retinal hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer
• Retinal achromic patches Patches Vitiligo (hypopigmented spots)

Diagnosis

No single clinical presentation of TSC is considered diagnostic. 

• Detailed history and physical
• Thorough full-body skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions examination is crucial.
• Imaging studies to rule out cardiac or renal manifestations:
  • Ultrasonography
  • CT
  • MRI 
• Diagnostic criteria for TSC: 
  • 2 major clinical features OR
  • 1 major and ≥ 2 minor clinical features
• Probable TSC:
  • 1 major clinical feature OR
  • ≥ 2 minor clinical features

Diagnostic criteria for TSC

• Genetic criteria: presence of TSC1 or TSC2 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
• Clinical criteria:
  • Major features:
    • Ash leaf spots
    • Shagreen patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes
    • Angiofibroma
    • Ungual fibroma
    • Multiple retinal hamartomas Retinal Hamartomas Neurofibromatosis Type 2
    • CNS features
    • Cardiac rhabdomyoma
    • Lymphangioleiomyomatosis Lymphangioleiomyomatosis A disease characterized by the progressive invasion of smooth muscle cells into the lymphatic vessels, and the blood vessels. The majority of the cases occur in the lungs of women of childbearing age, eventually blocking the flow of air, blood, and lymph. The common symptom is shortness of breath (dyspnea). Interstitial Lung Diseases (LAM)
    • Angiomyolipoma
  • Minor features:
    • Dental enamel Enamel A hard thin translucent layer of calcified substance which envelops and protects the dentin of the crown of the tooth. It is the hardest substance in the body and is almost entirely composed of calcium salts. Under the microscope, it is composed of thin rods (enamel prisms) held together by cementing substance, and surrounded by an enamel sheath. Teeth: Anatomy pits
    • Intraoral fibromas
    • Retinal achromic patches Patches Vitiligo
    • Multiple renal cysts Renal Cysts Imaging of the Urinary System
    • Nonrenal hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer

Management

• A multidisciplinary approach aims to monitor and treat clinical manifestations of the disease.
• Counseling regarding genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies and mode of inheritance must be discussed.

CNS manifestations

• Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy:
  • Educate parents on infantile spasm.
  • EEG EEG Seizures done routinely
  • Treatment of spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy/ seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures:
    • Vigabatrin Vigabatrin An analogue of gamma-aminobutyric acid. It is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for the catabolism of gamma-aminobutyric acid and is used as an anticonvulsant. Second-Generation Anticonvulsant Drugs for infantile spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy
    • Antiepileptics
    • Surgical tumor Tumor Inflammation resection for treatment-resistant cases
• Tumors:
  • MRI done every 1–3 years
  • Treatment:
    • Surgical resection
    • mTOR mTOR Peutz-Jeghers Syndrome inhibitor: everolimus Everolimus A derivative of sirolimus and an inhibitor of tor serine-threonine kinases. It is used to prevent graft rejection in heart and kidney transplant patients by blocking cell proliferation signals. It is also an antineoplastic agent. Immunosuppressants
• Neuropsychiatric:
  • Monitor skills and mood at each visit.
  • Intervene with support and early intervention as needed.

Cardiac manifestations

• Asymptomatic cases: 
  • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) and ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) are done at baseline and every 3 years until regression Regression Corneal Abrasions, Erosion, and Ulcers of rhabdomyoma occurs.
• Symptomatic cases:
  • Need closer assessments, especially of conduction pathways, using ambulatory ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) tests.

Renal manifestations

• Abdominal MRI done every 3 years
• GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests and blood pressure monitoring yearly
• Treatment:
  • Angiomyolipoma:
    • Artery embolization Embolization A method of hemostasis utilizing various agents such as gelfoam, silastic, metal, glass, or plastic pellets, autologous clot, fat, and muscle as emboli. It has been used in the treatment of spinal cord and intracranial arteriovenous malformations, renal arteriovenous fistulas, gastrointestinal bleeding, epistaxis, hypersplenism, certain highly vascular tumors, traumatic rupture of blood vessels, and control of operative hemorrhage. Gastrointestinal Bleeding
    • mTOR mTOR Peutz-Jeghers Syndrome inhibitor
    • Surgical resection
  • Renal cysts Renal Cysts Imaging of the Urinary System: manage hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions manifestations

• Annual detailed skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions exam
• Counseling regarding sun protection 
• Counseling against use of over-the-counter treatments
• Treat disfiguring lesions using laser therapy Laser Therapy The use of photothermal effects of lasers to coagulate, incise, vaporize, resect, dissect, or resurface tissue. Glaucoma

Eyes and dental manifestations

• Complete eye exam annually.
• Dental checkups annually

Respiratory manifestations

• Counseling against smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases and the use of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy in women
• High-resolution CT High-resolution CT Imaging of the Lungs and Pleura done every 5–10 years (more frequently if cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change are detected)
• Treatment:
  • mTOR mTOR Peutz-Jeghers Syndrome inhibitors: sirolimus Sirolimus A macrolide compound obtained from streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. Immunosuppressants (1st-line), everolimus Everolimus A derivative of sirolimus and an inhibitor of tor serine-threonine kinases. It is used to prevent graft rejection in heart and kidney transplant patients by blocking cell proliferation signals. It is also an antineoplastic agent. Immunosuppressants
  • Lung transplantation Lung transplantation The transference of either one or both of the lungs from one human or animal to another. Organ Transplantation

Differential Diagnosis

• Vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo: most common depigmenting disorder; caused by the destruction of melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions. The etiology of vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo is unknown, but genetic and autoimmune factors may play a role. Presentation is with hypopigmented or depigmented macules or patches Patches Vitiligo. The ash leaf spots and confetti spots may initially be confused with the hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi noted in vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo. However, the mucosa is spared in TSC, and the lesions are not usually found around the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions covering the joints. Vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo doesn’t present with epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy or hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer. 
• Multiple endocrine neoplasia Multiple endocrine neoplasia Multiple endocrine neoplasia syndromes are autosomal dominant inherited conditions characterized by 2 or more hormone-producing tumors involving the endocrine organs. There are different types of MEN, namely MEN1-4. Multiple Endocrine Neoplasia (MEN): autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inherited conditions characterized by ≥ 2 hormone-producing tumors involving endocrine organs. MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia may present with angiofibroma in a similar malar, butterfly pattern as seen in TSC; however, other endocrine abnormalities, especially involvement of the parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy gland is not noted in TSC and can differentiate the 2 conditions.
• Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy: chronic brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification disorder marked by recurrent and unprovoked seizures Unprovoked Seizures Seizures. These seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures can be classified as focal or generalized and idiopathic Idiopathic Dermatomyositis or secondary to another condition such as tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor. Clinical presentation correlates to the classification of the epileptic disorder. Diagnosis is confirmed with EEG EEG Seizures. Some epileptic disorders resolve over time, but many require lifelong antiepileptic medication for management; in some refractory cases, surgical procedures may be needed.