(Renumbered) Management Algorithm

       CONFIRMED/SUSPECTED TSC
       (Clinical Criteria +/- Genetic Testing)
                     ↓
       BASELINE ASSESSMENT
       - MRI Brain
       - Renal Imaging (US/MRI)
       - Echocardiogram (Paediatric)
       - Eye Exam
       - Developmental / Neuropsychological
       - Genetic Counselling
                     ↓
       ONGOING SURVEILLANCE (Lifelong)
       - MRI Brain (1-3 yearly, watch for SEGA)
       - Renal Imaging (1-3 yearly)
       - LAM screening (Adult Females)
                     ↓
       MANAGE ORGAN-SPECIFIC COMPLICATIONS
    ┌────────────────┴────────────────┐
 EPILEPSY                      SEGA / ANGIOMYOLIPOMA
    ↓                                  ↓
 ANTI-SEIZURE MEDS               mTOR INHIBITORS
 - Vigabatrin (1st line           (Everolimus / Sirolimus)
   for Infantile Spasms in TSC)   - Shrinks SEGA
 - Other ASMs as needed           - Shrinks Angiomyolipomas
 - Epilepsy Surgery for           - Surgery if mTOR fails
   refractory cases                 or acute haemorrhage
    ↓
 TSC-ASSOCIATED NEUROPSYCHIATRIC DISORDERS (TAND)
 - Screen and manage: Autism, ADHD, Anxiety, Depression, LD

Epilepsy Management

3. Deep Dive: Advanced Epilepsy Management

"The Tuberectomy." TSC epilepsy is often focal (coming from a specific tuber).

• The Concept: If we remove the "Bad Tuber" (Dysplastic tissue), the seizures stop.
• Investigation Phase:
  • Video Telemetry EEG: Capture the seizure onset.
  • MEG (Magnetoencephalography): Pinpoints magnetic source of seizure.
  • PET Scan: Interictal PET shows hypometabolism at the seizure focus.
  • Ictal SPECT: Shows hyperperfusion during a seizure.
• The Surgery: Resection of the tuber and surrounding epileptogenic zone.
• Outcomes: 60-70% seizure freedom if a single focus is identified.

"The VNS (Vagal Nerve Stimulator)."

• Indication: Multifocal epilepsy (multiple active tubers) where resection is impossible.
• Mechanism: Pacemaker for the brain. Stimulates the Lt Vagus nerve to desynchronise cortical activity.
• Efficacy: 50% reduction in seizures in 50% of patients. Palliative, not curative.

"The Ketogenic Diet."

• Indication: Bi-hemispheric epilepsy, drug resistant.
• Mechanism: Shifts brain metabolism from glucose (glycolysis) to ketone bodies. This stabilises neuronal membranes.
• Efficacy: Highly effective in children with TSC.

4. Case Studies: The Variable Phenotype

Case A: The "Lucky" Parent.

• A 30-year-old man presents with a mild kidney bleed. CT shows multiple angiomyolipomas.
• Incidental finding: Calcified subependymal nodules in brain.
• History: Did poorly in school but holds a job. No seizures.
• Diagnosis: Mild TSC.
• Impact: He has a 2-month-old baby. The baby is tested and has TSC. The baby develops infantile spasms. The mutation is the same, but the phenotype is wildly different.

Case B: The De Novo Catastrophe.

• A baby presents with chaotic seizures (West Syndrome) at 4 months.
• MRI: Cortical tubers everywhere.
• Parents: Clinical exam and genetics are normal.
• Diagnosis: De Novo TSC2 Mutation.
• Prognosis: High risk of severe intellectual disability if spasms are not stopped immediately.

SEGA Management (Renumbered)

• Everolimus (mTOR Inhibitor): First-line for growing or symptomatic SEGA. Shrinks tumour.
• Surgery: If hydrocephalus develops (obstructed Foramen of Monro), or if mTOR inhibitor fails/contraindicated.

1. Surgical Atlas: Managing the Major Lesions

A. Subependymal Giant Cell Astrocytoma (SEGA)

• The Problem: These are benign (WHO Grade I) but grow near the Foramen of Monro. Blockage causes obstructive hydrocephalus (headache, vomiting, death).
• Resection:
  • Approach: Transcallosal or Transcortical.
  • Goal: Gross Total Resection is curative.
  • Risk: Hemiparesis, Memory loss (Fornix injury).
  • Role of Medicine: Everolimus (mTOR inhibitor) can shrink SEGA by >50%. Now often the FIRST LINE therapy, especially for bilateral or deep tumours. Surgery is reserved for acute hydrocephalus or drug failure.

B. Renal Angiomyolipoma (AML)

• The Problem: Tumours composed of blood vessels (Angio), muscle (Myo), and fat (Lipoma).
• Risk: Aneurysms form in the tumour vessels. Rupture causes retroperitoneal haemorrhage (Wunderlich Syndrome). Risk is high if >4cm.
• Intervention:
  • Embolisation: Interventional Radiology. Catheter into renal artery -> Selective occlusion of tumour vessels with coils/particles. Kidney sparing.
  • Nephrectomy: Avoid if possible! TSC patients often have CKD. Sparing nephrons is vital.

2. Deep Dive: The mTOR Pathway

"The Cell's Metabolic Switch."

• Normal Physiology:
  • mTOR (mechanistic Target Of Rapamycin) is a protein kinase that senses "plenty".
  • Inputs: Insulin, Growth Factors, Amino Acids, Energy (ATP).
  • On Switch: When times are good, mTOR turns ON -> Cell growth, Protein synthesis, Ribosome biogenesis.
  • The Brake: The TSC1/TSC2 Complex (Hamartin/Tuberin) inhibits mTOR. It keeps growth in check.
• In TSC:
  • The Brake is broken.
  • mTOR is permanently ON (Constitutively active).
  • Result: Cells grow too big (Giant cells), divide too much (Tumours), and migrate poorly (Cortical Tubers).
• Pharmacology: "Rapalogues"
  • Sirolimus (Rapamycin): The original inhibitor. Discovered from bacteria on Easter Island (Rapa Nui).
  • Everolimus: A derivative with better bioavailability.
  • Mechanism: Binds to FKBP12 -> Blocks mTORC1 complex -> Stops cell growth.
  • Impact: These drugs target the molecular root cause of the disease. They are "Disease Modifying".

Renal Angiomyolipoma Management

• Small (less than 3cm), Asymptomatic: Surveillance.
• Large (>3cm) or Growing: Everolimus/Sirolimus to shrink. Reduces haemorrhage risk.
• Acute Haemorrhage (Wunderlich Syndrome): Embolisation (first-line) or Nephrectomy if massive.

LAM Management

• Sirolimus: Stabilises lung function.
• Lung Transplant: For end-stage disease.

Neuropsychiatric (TAND)

• Screening: All patients should be screened for Autism, ADHD, Learning Disability, Anxiety, Depression.
• Multi-disciplinary: Involvement of Psychology, Psychiatry, Special Education.