• Brain metastases occur in 20–40% of all cancer patients during the course of their disease.
• Rising incidence as cancer survival improves ^[1] — this is a key GC lecture point. As systemic therapies improve and patients live longer, the brain (protected by the blood-brain barrier, which many chemotherapy agents cannot cross) becomes a "sanctuary site" where metastases can develop unchecked.
• Estimated incidence: 8.3–14.3 per 100,000 population per year in developed countries, though autopsy series suggest the true figure is higher (~25% of all cancer deaths have brain metastases at autopsy).
• In Hong Kong, the most relevant primaries are lung cancer (the most common cancer in males) ^[3] and breast cancer (the most common cancer in females, lifetime risk 1 in 16 in HK) ^[4], both of which are leading causes of brain metastases.

• Peak age: 50–70 years (reflecting peak cancer incidence).
• No strong sex predilection overall, but sex-specific primaries (breast in females, lung slightly more in males in HK) create different patterns.
• In children, brain metastases are rare; intracranial tumours in children are much more likely to be primary (medulloblastoma, cerebellar astrocytoma, etc.) ^[2].

Brain metastases spread via haematogenous or direct invasion. ^[1]

Common origins: Lung, breast, colon, kidney, melanoma… ^[1]

The most common primary sites for brain metastases, in approximate order of frequency:

Not all cancers metastasise to the brain equally. The "seed and soil" hypothesis (Stephen Paget, 1889) explains this:

1. Seed factors (tumour cell intrinsic):

   • Expression of adhesion molecules that bind to cerebral endothelium (e.g., integrins, selectins)
   • Ability to cross the BBB (via secretion of proteases like MMPs, or by transcytosis)
   • Expression of colonisation factors (e.g., serpins that protect against plasmin-mediated apoptosis in the brain microenvironment)
   • EGFR mutations, ALK rearrangements, HER2 amplification — all associated with higher brain metastasis rates

2. Soil factors (brain microenvironment):

   • Astrocytes can be "co-opted" by tumour cells — they provide growth factors and protect tumour cells from immune attack
   • The brain's unique immune environment (immune privilege, lack of conventional lymphatic drainage until recently discovered meningeal lymphatics) allows tumour cells to evade immune surveillance
   • Rich glucose supply supports metabolically active tumour cells

Understanding the pathophysiology requires walking through the metastatic cascade:

Detailed Steps:

1. Local invasion: Primary tumour cells acquire mesenchymal phenotype (epithelial-mesenchymal transition, EMT), allowing them to invade surrounding tissues and access vasculature.

2. Intravasation: Tumour cells enter the bloodstream. For lung cancer, this is especially efficient because pulmonary veins drain directly into the left heart, giving tumour cells immediate access to the systemic arterial circulation (no first-pass through the liver filter).

3. Survival in circulation: Most circulating tumour cells (CTCs) die due to shear stress, anoikis (apoptosis from loss of cell-matrix attachment), and immune attack. Those that survive often form tumour cell-platelet aggregates that shield them from NK cell killing.

4. Arrest at cerebral microvessels: CTCs arrest at the grey-white matter junction where vessels narrow. They adhere to the cerebral endothelium via adhesion molecules.

5. Extravasation across BBB: Tumour cells secrete proteases (MMPs, cathepsins) and inflammatory mediators that disrupt tight junctions. They may also undergo transcytosis (passing through endothelial cells). Some tumours (especially melanoma) are particularly adept at crossing the BBB.

6. Colonisation: Once in the brain parenchyma, tumour cells must adapt to the unique microenvironment. They co-opt astrocytes (which produce growth factors like IL-6, TGF-β) and interact with microglia. They upregulate pathways for survival in the brain's glucose-rich environment.

7. Angiogenesis: Growing metastases secrete VEGF and other angiogenic factors to develop their own blood supply. This new vasculature is abnormal and leaky.

8. Vasogenic oedema: The abnormal tumour vasculature (lacking normal BBB properties) leaks plasma proteins and fluid into the surrounding white matter, causing disproportionate oedema. This oedema compresses surrounding brain tissue.

9. Mass effect and raised ICP: The combination of tumour mass + oedema + possible obstruction of CSF flow (especially posterior fossa tumours obstructing the 4th ventricle) leads to raised ICP.

• Supratentorial (80–85% in adults): cerebral hemispheres
• Infratentorial (15–20%): cerebellum, brainstem
• Leptomeningeal (carcinomatous meningitis): diffuse involvement of meninges by tumour cells in CSF — a distinct and poor-prognosis entity

(See Etiology section above)

• May present before the primary disease ^[1] — brain metastasis can be the first manifestation of cancer (the primary is discovered after)
• May develop when the primary disease is long in remission and without extraneural metastasis ^[1] — the brain acts as a sanctuary site
• Synchronous: discovered at the same time as the primary
• Metachronous: discovered after initial treatment of the primary

The Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) is used to estimate prognosis in brain metastasis patients based on:

• Age
• Karnofsky Performance Status (KPS)
• Number of brain metastases
• Presence of extracranial metastases
• Primary tumour type and molecular subtype (e.g., HER2 status for breast cancer, EGFR/ALK status for NSCLC)

Median survival ranges from ~3 months (unfavourable GPA score, e.g., multiple brain mets from SCLC with poor KPS) to >24 months (favourable GPA score, e.g., single brain met from HER2+ breast cancer with good KPS treated with surgery + SRS).

The clinical presentation of brain metastases depends on: (a) the location of the metastasis, (b) the size and number of lesions, (c) the degree of oedema, and (d) the rate of growth.

Special Presentations Worth Noting:

• Brain metastases may present before the primary disease is known ^[1]. A patient with no cancer history presenting with new seizures, headache, or focal deficit may have their cancer diagnosed because of the brain metastasis.
• "Silent" metastases: Small metastases in "non-eloquent" brain areas (e.g., right frontal pole, non-dominant temporal) may be asymptomatic and found incidentally on staging imaging.
• Leptomeningeal carcinomatosis: Presents differently from parenchymal metastases — multifocal cranial nerve palsies, radiculopathy, communicating hydrocephalus, headache, cognitive decline. Diagnosis requires CSF cytology or MRI showing leptomeningeal enhancement.

"History & Examination crucial — Look for primary & screen for other foci" ^[1] — GC lecture slide emphasising that clinical assessment must always look for the underlying primary cancer.

• In ~10–15% of brain metastasis cases, the brain lesion is the first manifestation of cancer — the primary is unknown at presentation.
• Most commonly from: lung (especially adenocarcinoma), melanoma, RCC.
• Workup for unknown primary: CT chest/abdomen/pelvis, PET-CT, tumour markers, tissue biopsy of the brain lesion for immunohistochemistry (IHC) to identify the primary.
  • IHC: TTF-1 (lung adenocarcinoma), CK7/CK20 profile (various), HMB-45/S100/Melan-A (melanoma), PAX8 (RCC/thyroid), ER/PR/HER2 (breast)

• Distinct from parenchymal brain metastases.
• Tumour cells coat the leptomeninges (pia + arachnoid) and float in CSF.
• Clinical features: multifocal, involving any level of the neuraxis — cranial neuropathies (especially CN III, VI, VII), radiculopathies, cauda equina syndrome, communicating hydrocephalus, headache, cognitive decline.
• Diagnosis: CSF cytology (may need repeated LPs — sensitivity ~50% per LP, improves to ~90% with 3 LPs), MRI with gadolinium showing leptomeningeal enhancement.
• Prognosis: very poor (median survival 4–6 weeks untreated, 2–4 months with treatment).
• Most common primaries: breast, lung, melanoma, haematological malignancies.

This is the scenario where the GC lecture specifically warns: "Multiple lesions in a cancer patient can be something else" ^[1].

In ~10–15% of brain metastasis cases, the brain lesion is the presenting symptom and no cancer is known. The differential here is broader:

• Uses isotopes like thallium-201 to detect abnormalities in the BBB.
• Functions: (1) Distinguish benign from malignant brain lesions, (2) Predict histological grade of brain tumours, (3) Select areas for biopsy ^[10].
• High uptake in active tumour (metastasis, recurrence) vs. low uptake in radiation necrosis, abscess.
• This is specifically listed on the GC lecture slide as a step in the workup of a solitary brain mass in a cancer patient ^[1].

The GC lecture slide specifically includes an exclamation mark after "serum tumour markers" — emphasising this as high yield. Relevant markers include:

• Histological examination of biopsy specimen remains the most important component of diagnostic evaluation of brain tumours ^[10].
• Stereotactic biopsy for deep-seated or multiple lesions.
• Open surgical resection with intraoperative histology for accessible solitary lesions.
• IHC panel on tissue: TTF-1 (lung/thyroid), CK7/CK20 (various), CDX2 (colorectal), PAX8 (RCC/thyroid/gynae), ER/PR/HER2 (breast), S100/HMB-45/Melan-A (melanoma), PSA/NKX3.1 (prostate) ^[12].

When brain metastasis is the first presentation, or the primary is uncertain:

IHC Panel for Unknown Primary Brain Metastasis [12]

Once brain metastases are confirmed, the systemic extent of disease must be evaluated because it determines prognosis (GPA score) and treatment strategy:

High-dose dexamethasone (for peritumoral vasogenic oedema) ^[3]

Multiple brain metastases / leptomeningeal carcinomatosis — systemic steroid, palliative whole-brain radiotherapy ^[7]

• Drug: Dexamethasone ("dexa" = potent, "methasone" = synthetic corticosteroid — specifically chosen because it has minimal mineralocorticoid effect, so less sodium/water retention, and has a long half-life ~36–54 hours)
• Dose: Loading dose 10 mg IV followed by 4–8 mg every 6 hours (typical high-dose regimen). Taper once definitive treatment initiated and oedema controlled.
• Mechanism: Restores blood-brain barrier (BBB) integrity → reduces vasogenic oedema → decreases mass effect → lowers ICP. It does this by:
  • Reducing expression of VEGF (a key driver of BBB permeability)
  • Stabilising endothelial tight junctions
  • Reducing perivascular inflammation
• Why dexamethasone and not other steroids? Dexamethasone has essentially zero mineralocorticoid activity (no salt and water retention → no worsening of oedema), the longest duration of action among glucocorticoids, and excellent CNS penetration.
• Clinical effect: Dramatic improvement often within 6–24 hours. Patients may go from obtunded to conversant overnight. This is one of the most gratifying interventions in clinical medicine.
• Side effects (important because patients may be on steroids for weeks-months):
  • Hyperglycaemia (steroid-induced diabetes) — monitor glucose
  • Immunosuppression → opportunistic infections (PJP prophylaxis with co-trimoxazole if prolonged use)
  • Proximal myopathy (steroid myopathy) — "paradox: you give steroids to improve function, but long-term use causes weakness"
  • Gastric ulceration → co-prescribe PPI
  • Cushing's syndrome (moon face, central obesity, skin thinning)
  • Insomnia, psychiatric disturbance
  • Osteoporosis
  • Adrenal suppression → must taper, never stop abruptly

• Indication: Only if the patient has had a seizure. Prophylactic anticonvulsants are NOT recommended in brain metastasis patients who have not had seizures (AAN guideline). The evidence shows no benefit of prophylaxis and significant drug interaction risks.
• Drug of choice: Levetiracetam (Keppra) — preferred because:
  • Does not induce hepatic cytochrome P450 enzymes (unlike phenytoin, carbamazepine)
  • Therefore does not interact with chemotherapy drugs, targeted therapies, or dexamethasone
  • Fewer side effects
  • IV and oral formulations available
• Why NOT phenytoin? Phenytoin is a potent CYP450 inducer → accelerates metabolism of dexamethasone, chemotherapy agents (especially temozolomide, irinotecan), and many targeted therapies → reduces their efficacy. It also has a narrow therapeutic window and requires drug level monitoring.

• Cancer patients with brain metastases are at very high VTE risk (Khorana score often elevated; immobility from neurological deficits; hypercoagulable state of malignancy).
• Pharmacological thromboprophylaxis with LMWH is generally recommended post-operatively and during hospitalisation, though the risk of intratumoural haemorrhage (especially melanoma, RCC) must be balanced.
• DOACs are increasingly used in cancer-associated VTE, but evidence in brain metastases is evolving due to haemorrhage concerns.

Single brain met: surgery + stereotactic radiosurgery (SRS) ^[3]

Rationale: Surgical resection provides immediate decompression (reducing mass effect and ICP), obtains tissue for histological diagnosis, and can achieve local control. For a solitary or single accessible metastasis, surgery offers the best chance of durable local control when combined with post-operative SRS.

Indications:

• Solitary or single brain metastasis ^[3] that is surgically accessible (not in eloquent cortex or deep brainstem)
• Lesion causing significant mass effect or obstructive hydrocephalus (urgent decompression needed regardless of number of mets)
• Diagnostic uncertainty — Surgery + histology if in doubt ^[1] (e.g., solitary lesion in cancer patient where metastasis vs. primary brain tumour vs. abscess cannot be distinguished radiologically)
• Large symptomatic lesion (typically > 3 cm) where SRS alone would be less effective (radiation necrosis risk increases with larger volumes)
• Good KPS (≥ 70), controlled or absent extracranial disease, reasonable life expectancy (> 3 months)

Contraindications:

• Multiple brain metastases (> 3) — surgery cannot address all lesions
• Inaccessible location (deep brainstem, thalamus, basal ganglia) — unacceptable surgical morbidity
• Poor KPS (< 70) — high perioperative risk, low benefit
• Uncontrolled widespread extracranial disease — surgery unlikely to change overall trajectory
• Coagulopathy (must correct before surgery)
• Radiosensitive tumours (e.g., SCLC, lymphoma, germ cell tumours) — better treated with radiation/chemotherapy

Technique:

• Craniotomy with image-guided (neuronavigation) resection
• Functional MRI (fMRI) and DTI tractography for pre-operative planning when lesion is near eloquent cortex ^[10]
• Intraoperative techniques: cortical mapping, awake craniotomy (for lesions near speech or motor areas)
• Goal: maximal safe resection — remove entire lesion with a margin while preserving neurological function
• Post-operative: typically followed by SRS to the surgical cavity (rather than WBRT) to reduce local recurrence while preserving neurocognition

Evidence: Landmark RCTs (Patchell 1990, Vecht 1993) demonstrated that surgery + WBRT is superior to WBRT alone for solitary brain metastasis, improving median survival from ~4 months to ~10 months and functional independence.

Stereotactic radiosurgery/radiotherapy for limited brain metastases ^[7][17][18]

"Stereotactic" = "stereo" (three-dimensional) + "tactic" (arrangement) — means precisely targeting a point in 3D space. "Radiosurgery" = using radiation as a surgical tool, delivering a high dose to a small, precisely defined volume in a single fraction (or a few fractions if "stereotactic radiotherapy" / SRT).

Mechanism: Delivers a highly focused, high-dose beam of radiation to the metastasis with rapid dose fall-off at the margins, sparing surrounding normal brain. This causes DNA double-strand breaks in tumour cells → mitotic catastrophe → tumour cell death, while the surrounding brain receives minimal dose.

Types of SRS delivery:

Indications:

• Limited brain metastases ^[7][17][18] — generally 1–4 lesions (some centres now treat up to 10–15 with SRS if total volume is small)
• Each lesion typically ≤ 3–4 cm in maximum diameter (larger lesions → higher risk of radiation necrosis)
• Post-operative SRS to the surgical cavity (replacing post-op WBRT to reduce neurocognitive decline)
• Recurrence after prior WBRT (salvage SRS)
• Any histology (works even for classically "radioresistant" tumours like melanoma and RCC, because the high single-fraction dose overcomes radioresistance)

Contraindications:

• Too many lesions (relative — depends on total volume and institutional protocol)
• Very large lesions ( > 4 cm) — high risk of radiation necrosis; consider surgery instead
• Lesions with significant mass effect requiring urgent surgical decompression
• Leptomeningeal disease (diffuse, cannot be targeted with SRS)
• Poor KPS with limited life expectancy (no benefit from SRS if survival < 1 month)

Advantages over WBRT:

• Preserves neurocognitive function (does not irradiate the entire brain)
• Can be repeated for new metastases
• Single-session or few-session treatment (convenient)
• High local control rates (~80–90% at 1 year for small lesions)

Complications:

• Radiation necrosis (~5–25%): develops 6–24 months post-SRS. Can mimic tumour recurrence on MRI (both enhance). Distinguished by SPECT, MRI perfusion, or biopsy. Managed with corticosteroids, bevacizumab (anti-VEGF — reduces vascular permeability), or surgical resection.
• Peritumoral oedema (acute, usually responsive to dexamethasone)
• Seizures (rare)
• Cranial nerve injury (if lesion near CN, e.g., posterior fossa lesions near CN V, VII, VIII)

Multiple brain met / inoperable: WBRT ^[3]

Palliative whole-brain radiotherapy for multiple brain metastasis not amenable to stereotactic radiosurgery/radiotherapy, or for leptomeningeal metastases ^[7][17][18]

Mechanism: Irradiates the entire brain with a moderate dose of radiation, targeting both visible metastases and microscopic deposits that may not yet be detectable on MRI. Typical dose: 30 Gy in 10 fractions (the classic palliative regimen) or 20 Gy in 5 fractions (shorter, for patients with poor prognosis).

Indications:

• Multiple brain metastases not amenable to SRS ^[7][17][18] — typically ≥ 5 or high total volume
• Leptomeningeal carcinomatosis ^[7][17][18]
• Widely disseminated brain disease with poor KPS where SRS to each lesion is impractical
• Post-operative adjuvant after resection of solitary metastasis (increasingly replaced by SRS in current practice, but still used in some settings)
• Prophylactic cranial irradiation (PCI) in SCLC ^[14] — a specific form of WBRT given to SCLC patients who respond well to initial treatment, to prevent subsequent brain metastases

Contraindications:

• Very poor prognosis (KPS < 50, expected survival < 1 month) — WBRT takes 2–3 weeks to deliver and several more weeks for maximal effect; patients may not survive long enough to benefit → best supportive care more appropriate
• Prior WBRT (re-irradiation with WBRT carries high risk of neurotoxicity; SRS may be used for re-treatment)
• Patient refusal

Complications (the major concern):

• Neurocognitive decline — the most significant long-term toxicity. WBRT damages hippocampal neural stem cells → progressive memory loss, executive dysfunction, personality change. This occurs in ~50–90% of long-term survivors.
  • Mitigation strategies:
    • Hippocampal-avoidance WBRT (HA-WBRT) — uses IMRT to shape the radiation field, sparing the hippocampus. The NRG CC001 trial demonstrated significant preservation of memory with HA-WBRT + memantine vs. standard WBRT.
    • Memantine — NMDA receptor antagonist (same drug used in Alzheimer's disease) given during and after WBRT to reduce neurocognitive decline. "Memantine" → "memory" + "maintain" — the name hints at its purpose.
• Fatigue during treatment
• Alopecia (usually temporary but can be permanent)
• Somnolence syndrome (delayed, 1–6 months post-WBRT: excessive drowsiness, fever, anorexia — self-limiting)
• Leukoencephalopathy (late, especially combined with methotrexate)

Best supportive care ^[7][17][18]

Indication: Patients with very poor prognosis (low KPS, widespread uncontrolled extracranial disease, poor DS-GPA score, expected survival < 1–3 months) where the toxicity and time commitment of active treatment outweighs benefits.

Components:

• Dexamethasone for symptom control (oedema, headache)
• Anticonvulsants if seizures present
• Analgesics (WHO pain ladder)
• Palliative care referral — symptom management, advance care planning, psychosocial support
• End-of-life care — comfort measures, dignity therapy, family support

A critical cross-topic point: known malignant intracranial neoplasm (primary or metastatic) is an ABSOLUTE contraindication to thrombolytic therapy ^[19][20]. This applies to fibrinolytics used for AMI (e.g., tPA, streptokinase) and for acute ischaemic stroke. The reason is the risk of catastrophic intratumoural haemorrhage — the abnormal tumour vasculature can rupture under the hypocoagulable state induced by fibrinolytics.

• Cancer patients are at high risk for VTE (malignancy-associated hypercoagulable state).
• Therapeutic anticoagulation (for DVT/PE) in patients with brain metastases is generally NOT contraindicated, but requires careful risk-benefit assessment:
  • Higher risk of intracranial haemorrhage with melanoma, RCC, choriocarcinoma mets
  • LMWH traditionally preferred over warfarin in cancer-associated VTE
  • DOACs (edoxaban, rivaroxaban) now have evidence in cancer-associated VTE but less data specifically in brain metastases

This is the most feared and immediately life-threatening complication. The cranial vault is a fixed-volume compartment — any increase in its contents (tumour + oedema + obstructed CSF) must be compensated or ICP rises.

• Mechanism: Tumour mass + vasogenic oedema → ↑brain volume. If the metastasis obstructs CSF flow (especially posterior fossa lesions compressing the 4th ventricle or aqueduct of Sylvius), obstructive hydrocephalus develops → ↑CSF volume. Both raise ICP.
• Symptoms: Headache (worse in morning — recumbent position impairs venous drainage, and nocturnal hypoventilation raises pCO₂ → cerebral vasodilatation → ↑ICP), projectile vomiting (medullary vomiting centre stimulation), nausea, progressive drowsiness, blurred vision (transient visual obscurations from papilloedema).
• Signs: Papilloedema (bilateral disc swelling from transmitted ICP along optic nerve sheath → impaired axoplasmic flow → disc oedema) ^[21], CN VI palsy (false localising sign of raised ICP — the long intracranial course of CN VI makes it vulnerable to compression/stretching as the brain shifts) ^[21], Cushing's triad (late: hypertension + bradycardia + irregular respiration — indicates brainstem compression).
• Management: High-dose dexamethasone ^[3], head of bed elevation to 30°, avoid straining/Valsalva, urgent neurosurgical referral. If hydrocephalus: CSF diversion (external ventricular drain or ventriculoperitoneal shunt). Definitive treatment of the metastasis (surgery or radiation).

The most lethal complication — occurs when raised ICP forces brain tissue across rigid dural reflections (falx, tentorium) or through the foramen magnum.

• Clinical significance: Herniation is a neurosurgical emergency. Once tonsillar herniation occurs with brainstem compression, death follows rapidly unless decompressed. Signs of impending herniation (deteriorating GCS, unilateral fixed dilated pupil, Cushing's triad) require immediate action: IV mannitol/hypertonic saline, dexamethasone, and emergency neurosurgical decompression.

• Frequency: 10–20% of patients with brain metastases ^[2]; higher with cortical involvement, melanoma (~67%), haemorrhagic metastases.
• Mechanism: Cortical irritation by tumour cells, peritumoral oedema disrupting electrolyte balance across neuronal membranes, blood products (iron-catalysed free radicals) from haemorrhagic metastases lowering the seizure threshold, and glutamate release from injured neurons.
• Types: Focal seizures (with or without secondary generalisation). Focal seizures have localising value — a right arm jerking seizure localises to the left precentral gyrus.
• Seizures arise only from supratentorial lesions (infratentorial i.e. cerebellar cortex is inhibitory in nature) ^[2].
• Status epilepticus: Continuous or rapidly recurring seizures without recovery of consciousness between episodes. A medical emergency requiring IV benzodiazepines → IV phenytoin/levetiracetam → general anaesthesia if refractory.
• Management: Levetiracetam preferred (no CYP450 interactions with chemotherapy and dexamethasone). Prophylactic anticonvulsants NOT recommended if no seizures have occurred (AAN guideline).

• Which metastases bleed? Melanoma, RCC, choriocarcinoma, thyroid (mnemonic "MR CT") — and also HCC. These tumours develop abnormal, fragile neovasculature and can invade blood vessel walls.
• Presentation: Sudden "stroke-like" onset — acute headache, new focal deficit, rapid ↓consciousness. Can be catastrophic if large. May be the presenting feature of a previously undiagnosed cancer.
• Why it matters clinically: A patient presenting with an apparent spontaneous intracerebral haemorrhage (ICH) who has underlying cancer may actually have a haemorrhagic brain metastasis. Once the acute phase settles, contrast MRI should be performed to look for an underlying enhancing mass within the haematoma.
• Management: Supportive (BP control, reverse anticoagulation if applicable, manage raised ICP). Surgical evacuation if life-threatening and accessible. Definitive treatment of the underlying metastasis once stable.

• Mechanism: Posterior fossa metastases (cerebellar) can compress the 4th ventricle or aqueduct of Sylvius, blocking CSF flow from the 3rd ventricle to the 4th ventricle and onwards to the subarachnoid space.
• Consequence: Upstream dilatation of lateral and 3rd ventricles → rapidly rising ICP → headache, vomiting, drowsiness, papilloedema. Can progress to herniation if untreated.
• Management: Emergency CSF diversion (external ventricular drain), followed by definitive treatment of the posterior fossa metastasis (surgery or SRS).

• Cancer patients have a baseline hypercoagulable state (Trousseau's syndrome). Brain metastases further increase VTE risk through immobility (hemiparesis, bed rest), dehydration, and the prothrombotic effects of dexamethasone.
• Brain metastasis patients have among the highest VTE rates of any cancer subgroup (~20–30% incidence).
• Dilemma: Therapeutic anticoagulation for DVT/PE carries a risk of intratumoral haemorrhage, especially with melanoma/RCC metastases. LMWH is traditionally used; IVC filters considered if anticoagulation is contraindicated.

• Mechanism: Brain metastases (or associated oedema, surgery, or whole-brain radiation) can disrupt the hypothalamic-pituitary axis → inappropriate ADH release → water retention → dilutional hyponatraemia ^[22].
• Clinical: Hyponatraemia presenting as confusion, lethargy, seizures, coma if severe. Must distinguish from cerebral salt wasting (which also causes hyponatraemia but with volume depletion).
• CNS causes of SIADH include: meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP ^[22].
• Management: Fluid restriction (1st line), hypertonic saline if severe/symptomatic, treat the underlying cause.

• Although uncommon, metastases to the pituitary or hypothalamus can cause hormonal dysfunction.
• The posterior pituitary receives its blood supply from the systemic circulation (vertebral artery branches) → systemic metastases are more likely to affect the posterior pituitary first ^[23] → diabetes insipidus (polyuria, polydipsia) may be the presenting feature.
• Anterior pituitary involvement leads to progressive hypopituitarism (GH, ACTH, TSH, LH/FSH deficiency in that order — most sensitive axes fail first).

• Cognitive decline: Progressive deterioration in memory, attention, executive function, and processing speed. Caused by direct tumour destruction of cognitive networks, oedema, and raised ICP. Bilateral frontal metastases → apathy, personality change, loss of social inhibition.
• Depression: Common (~25–40% prevalence in brain tumour patients). Multifactorial: biological (frontal lobe damage, neurochemical disruption), psychological (reaction to diagnosis), and iatrogenic (dexamethasone-induced mood changes).
• Fatigue: Overwhelming exhaustion, unrelated to exertion. Caused by disease burden, raised ICP, medications (dexamethasone, anticonvulsants), and systemic cancer effects.

• Some brain metastases can shed tumour cells into the CSF → leptomeningeal carcinomatosis (LMC).
• Clinical: Multifocal cranial neuropathies, radiculopathies, communicating hydrocephalus, headache, spinal cord dysfunction.
• Prognosis: Very poor (median survival 4–6 weeks untreated, 2–4 months treated).
• Management: systemic steroid + palliative WBRT ^[7]. ± intrathecal chemotherapy.

Since patients with brain metastases often require prolonged dexamethasone, steroid complications are extremely common and clinically significant:

• Local recurrence after surgery or SRS: ~20–30% at 1 year.
• Distant brain recurrence (new metastases elsewhere in the brain): reflects the ongoing metastatic potential of the primary cancer.
• The challenge of distinguishing recurrence from radiation necrosis is a major clinical problem ^[2]. Both present as new/enlarging enhancing lesions. MRI perfusion, SPECT ^[1], and amino acid PET are used. Radiation necrosis typically appears 1–3 years post-RT, with lack of clearly defined T2W lesion and high oedema-to-enhancement volume ratio ^[2]. Treatment: steroids, bevacizumab, or surgical resection.

• Untreated brain metastases: median survival ~1 month ^[2].
• WBRT alone: median survival ~3–6 months.
• Surgery + WBRT: ~10–12 months ^[2].
• Surgery + SRS: ~12–15 months.
• Favourable subtypes with targeted therapy (EGFR-mutant NSCLC, HER2+ breast): can exceed 2 years.
• Cause of death: brain herniation, progressive neurological deterioration, systemic disease progression, or treatment-related complications (pulmonary embolism, infection).