Brain Tumours
Brain tumours are abnormal growths of cells within the brain or central spinal canal, classified as primary or metastatic and benign or malignant, that cause neurological dysfunction through mass effect, infiltration, or increased intracranial pressure.
A brain tumour is any abnormal mass of tissue arising within or adjacent to the brain parenchyma, meninges, cranial nerves, or pituitary region in which cells grow and multiply uncontrollably, unchecked by the mechanisms that normally regulate cell growth. The term encompasses both primary tumours (originating from intracranial structures) and secondary (metastatic) tumours (originating from extracranial malignancies that spread to the brain).
The word "tumour" comes from Latin tumor = swelling. In the context of the brain, even a histologically "benign" lesion can behave lethally because the rigid skull provides no room for expansion — hence the concept of malignancy in brain tumours is not always clear-cut compared to extracranial counterparts [1].
Key Concept — Malignancy in Brain Tumours
The concept of malignancy is different in primary intracranial tumours — it is often NOT clear cut. A histologically benign-looking tumour (e.g., a low-grade glioma) can display aggressive clinical behaviour (widely infiltrating, occupying functionally important areas preventing surgical removal). Conversely, a histologically malignant-looking tumour rarely shows extracranial metastasis because the brain lacks conventional lymphatic drainage. Therefore, TNM staging is not useful for primary brain tumours [1][2].
Epidemiology
- Primary brain tumours are rare: ~6 per 100,000 per year [2].
- Brain tumours account for 1–2% of all malignancies but 13% of all malignancy-related deaths — disproportionately lethal because of the critical, unforgiving location [3].
- Secondary (metastatic) tumours are far more common than primary tumours: secondary tumours are approximately 6–10× more common than primary ones [3]. Metastatic disease complicates ~25% of extracranial malignancies, and incidence is rising as systemic anticancer therapy improves patient lifespan (the brain becomes a "sanctuary site" behind the blood–brain barrier) [1][2].
- Pituitary adenomas account for 6–18% of all brain tumours and are found in 12–22% at autopsy [4][5].
Tumour locations and types depend on age [3]:
| Age Group | Predominant Location | Common Tumour Types |
|---|---|---|
| Adults | 70–85% supratentorial | Metastases, meningioma, gliomas (e.g., GBM) |
| Children (2–12 years) | 70% infratentorial (posterior fossa) | Medulloblastoma, pilocytic astrocytoma, ependymoma, germ cell tumours |
| < 2 years or 12–18 years | ~50% supra- and infratentorial | Variable |
High Yield — Age & Location Rule
Think of it this way: in adults, the cerebral hemispheres are the biggest target for blood-borne metastases and degenerative glial change. In children, the posterior fossa (cerebellum, brainstem, 4th ventricle) is disproportionately affected by embryonal and developmental tumours.
- Meningiomas: Female > Male (~2:1), due to progesterone/oestrogen receptor expression on tumour cells.
- Glioblastoma (GBM): Male > Female (~1.6:1).
- Medulloblastoma: Male > Female in children.
The only proven environmental risk factor for brain tumours is high-dose ionising radiation → meningiomas and gliomas [3].
| Category | Risk Factor | Associated Tumour(s) |
|---|---|---|
| Environmental | High-dose ionising radiation | Meningiomas, gliomas |
| Infectious | EBV, immunosuppression (HIV/AIDS, post-transplant) | Primary CNS lymphoma |
| Familial/Genetic syndromes | NF1 (neurofibromatosis type 1) | Optic pathway glioma, pilocytic astrocytoma, neurofibroma |
| NF2 (neurofibromatosis type 2) | Bilateral vestibular schwannomas, meningiomas, ependymomas | |
| VHL (von Hippel-Lindau) | Haemangioblastoma (cerebellar, retinal) | |
| Tuberous sclerosis complex (TSC) | Subependymal giant cell astrocytoma (SEGA), cortical tubers | |
| Li-Fraumeni syndrome (TP53) | Gliomas, medulloblastoma, choroid plexus carcinoma | |
| Turcot syndrome | Medulloblastoma (APC mutation) or GBM (MMR mutation) | |
| MEN1 | Pituitary adenomas |
Exam Favourite — NF2 Mnemonic
NF2 = "22": Think of 2 vestibular schwannomas (bilateral), chromosome 22, and multiple meningiomas/ependymomas. NF2 features include: meningioma, ependymoma, acoustic schwannoma [6].
Anatomy and Relevant Functional Neuroanatomy
Understanding which brain region is affected by a tumour is the key to predicting clinical features. Let's walk through the critical anatomy.
The brain is enclosed in the rigid skull (Monro-Kellie doctrine: total intracranial volume of brain + CSF + blood is fixed). Any added mass must displace one of these components or intracranial pressure (ICP) rises.
Supratentorial compartment (above tentorium cerebelli):
- Cerebral hemispheres (frontal, parietal, temporal, occipital lobes)
- Basal ganglia, thalamus
- Lateral and 3rd ventricles
- Sellar/parasellar region (pituitary, optic chiasm, cavernous sinus)
Infratentorial compartment / Posterior fossa (below tentorium cerebelli):
- Cerebellum
- Brainstem (midbrain, pons, medulla)
- 4th ventricle
- Cerebellopontine angle (CPA)
Key Anatomical Relationships for Brain Tumours
The pituitary gland sits within the sella turcica (Latin: "Turkish saddle") of the sphenoid bone [4]:
- Superior: Diaphragma sellae → optic chiasm (suprasellar extension compresses chiasm → bitemporal hemianopia)
- Lateral: Cavernous sinus containing CN III, IV, V1, V2, VI and the internal carotid artery → lateral extension causes diplopia and cranial nerve palsies [4][5]
- Inferior: Sphenoid sinus → the transsphenoidal surgical approach exploits this anatomical relationship
- Superior and posterior: 3rd ventricle → large tumours can obstruct CSF flow → hydrocephalus
The CPA is the junction between cerebellum, pons, and petrous temporal bone. CN VII (facial) and CN VIII (vestibulocochlear) traverse this space. Vestibular schwannomas arise here and expand the internal acoustic meatus [1].
Posterior to the 3rd ventricle and superior to the tectum (quadrigeminal plate). Tumours here compress the cerebral aqueduct → obstructive hydrocephalus, and compress the superior colliculi → Parinaud's syndrome (vertical gaze palsy, light-near dissociation, convergence-retraction nystagmus, lid retraction = Collier sign) [2].
| Region | Function | Deficit from Tumour |
|---|---|---|
| Frontal lobe (precentral gyrus) | Primary motor cortex | Contralateral UMN weakness |
| Prefrontal cortex | Executive function, personality, judgement | Cognitive/personality change [1] |
| Broca's area (dominant inferior frontal gyrus) | Expressive speech | Expressive (non-fluent) aphasia |
| Temporal lobe (superior temporal gyrus, dominant) | Wernicke's area — receptive language | Receptive (fluent) aphasia |
| Temporal lobe (mesial) | Memory (hippocampus) | Memory impairment, seizures |
| Parietal lobe (postcentral gyrus) | Primary sensory cortex | Contralateral cortical sensory loss |
| Non-dominant parietal lobe | Spatial awareness | Hemispatial neglect |
| Occipital lobe | Primary visual cortex | Contralateral homonymous hemianopia |
| Cerebellum | Coordination, balance | Truncal ataxia, limb ataxia, dysmetria [1] |
| Brainstem | CN nuclei, long tracts, consciousness | CN palsies, hemiplegia, altered consciousness |
Aetiology (with Focus on Hong Kong)
Pathology: Secondary tumours are 6–10× more common than primary tumours [3].
A. Primary Brain Tumours
Primary brain tumours are classified by cellular origin [1]:
| Cellular Origin | Tumour Types |
|---|---|
| Meninges | Meningioma |
| Neuroepithelial tissue | Astrocytoma, GBM, oligodendroglioma, ependymoma |
| Sellar region | Pituitary adenoma |
| Nerve sheath cells | Schwannoma, neurofibroma |
| Neuronal | Gangliocytoma |
| Embryonal | Medulloblastoma |
| Lymphoid cells | Lymphoma |
| Germ cells | Germinoma, teratoma |
| Malformative tumour | Craniopharyngioma |
"Details vary with study methodology, country, ethnic group…!" [1] — The exact proportions differ between Western and Asian (including Hong Kong) populations.
| Tumour | Approximate % of Intra-axial |
|---|---|
| Glioblastoma (WHO Grade IV) | ~47% |
| Anaplastic astrocytoma (WHO Grade III) | ~24% |
| Diffuse astrocytoma (WHO Grade II) | ~15% |
| Oligodendroglioma (WHO Grade II) | ~5% |
| Primary CNS lymphoma | ~3% |
| Other | ~7% |
| Tumour | Approximate % of Extra-axial |
|---|---|
| Meningioma | ~80% |
| Vestibular schwannoma | ~10% |
| Pituitary adenoma | ~7% |
| Other | ~3% |
Intra-axial vs Extra-axial — this is the single most important distinction on imaging [7]:
- Intra-axial ("within the axis/brain"): the mass is within the brain parenchyma itself. Look for the claw sign (parenchyma wrapping around the mass) and perilesional oedema.
- Extra-axial ("outside the axis/brain"): the mass is outside the parenchyma (meninges, skull base, etc.). Look for the CSF cleft (rim of CSF between lesion and brain), widening of adjacent CSF spaces, intervening pial vessels, and dural tail sign (in meningioma).
Commonest intracranial tumour in adults [2]. Key points:
| Primary Site | Approximate % | Notes |
|---|---|---|
| Lung | 37–49% (or 16–20% in some series) | Most common primary in Hong Kong (high rates of lung cancer due to smoking + high EGFR mutation rates in non-smokers) |
| Breast | 16–19% | Second most common in females |
| Melanoma | ~16% (has highest propensity per tumour) | Uncommon in Hong Kong/this locality [2] |
| Colorectal | ~9% | Common in Hong Kong (high colorectal cancer incidence) |
| Renal cell carcinoma (RCC) | ~7–10% | Classically hypervascular metastases |
Route of spread: Haematogenous or direct invasion — NOT lymphatic, because the brain does not have conventional lymphatic drainage [2].
Sites of metastasis: ~80% cerebral hemisphere, ~15% cerebellum, ~5% brainstem [2]. The commonest location is the watershed area between major arterial supplies and the grey-white junction — because blood vessel diameter decreases at this point, acting as a "trap" for tumour cell clumps [2].
- Nasopharyngeal carcinoma (NPC): endemic in Hong Kong, can invade the skull base directly (through foramen lacerum) and cause cranial nerve palsies. While not a "brain tumour" per se, NPC with intracranial extension is a common differential in the Hong Kong context [8].
- Lung cancer: the leading cause of brain metastases in Hong Kong due to high incidence of both smoking-related and EGFR-mutant lung cancers.
- Hepatocellular carcinoma (HCC): while the most common primary cancer in Hong Kong, brain metastases from HCC are relatively uncommon but do occur [9].
- Primary CNS lymphoma: increasingly recognised, especially with immunosuppressed patients (post-transplant, HIV). EBV-driven.
Pathophysiology
Brain tumours produce symptoms through several distinct pathophysiological mechanisms. Understanding these is essential because different mechanisms respond to different treatments.
High-grade diseases tend to present with subacute onset of signs and symptoms of raised ICP [2].
The Monro-Kellie doctrine states that the cranial vault is a fixed-volume container. ICP rises when the total volume of brain + CSF + blood exceeds the compensatory capacity of the system.
Mechanisms of raised ICP in brain tumours [3]:
| Mechanism | Explanation |
|---|---|
| Increased brain volume: mass effect | The tumour itself occupies space. Large tumours directly compress and displace brain tissue. |
| Vasogenic oedema | Disrupted blood–brain barrier (BBB) + tumour-secreting VEGF (vascular endothelial growth factor) → plasma proteins leak into extracellular space → osmotic gradient draws water out of vessels → oedema. Most apparent on FLAIR MRI [3]. This is the component most amenable to dexamethasone therapy. |
| Hydrocephalus | Obstructive (tumour blocks CSF pathway, e.g., aqueduct compression by pineal tumour, 4th ventricle compression by posterior fossa tumour) or communicating (leptomeningeal carcinomatosis impairs CSF absorption at arachnoid granulations) [3]. |
| Obstruction of cerebral venous drainage | E.g., midline meningioma pressing on superior sagittal sinus → venous congestion → increased intracranial blood volume → raised ICP [3]. |
| Ischaemia | Large tumours can compress arterial supply → ischaemic oedema (cytotoxic). |
Low-grade diseases tend to present with slowly progressive focal neurological symptoms [2].
Focal deficits arise from [1][2]:
- Neuronal destruction — direct tumour infiltration kills neurons (irreversible)
- Pressure effect — compression displaces but does not yet kill neurons (partially reversible with surgery)
- Oedema — vasogenic oedema compresses surrounding tissue (reversible with steroids — this is why dexamethasone can dramatically improve neurological deficits in brain tumours) [1]
- Loss of neuronal function — disconnection syndromes (white matter tract disruption)
The focal deficit is location-specific, which enables clinical localisation of the lesion [1]. If clinical deficits do not correlate with neuroimaging, consider the possibility of other concomitant pathologies [2].
Epilepsy affects 50–80% of primary tumours and 10–20% of secondary tumours [2].
Why are brain tumours epileptogenic?
- Peri-tumoural cortex is irritated by oedema, ischaemia, neurotransmitter imbalances (excess glutamate released by glioma cells), altered local ion concentrations, and blood products (from micro-haemorrhages).
- The irritated cortex fires abnormally → seizure.
Key points about tumour-related epilepsy [2]:
- Site: always supratentorial — infratentorial (cerebellar) cortex is inhibitory in nature and does not generate seizures.
- Types: typically repetitive and stereotyped in a given patient — focal seizures (simple or complex) ± secondary generalisation.
- Low-grade gliomas (especially oligodendrogliomas and WHO grade II astrocytomas) have the highest seizure rates because they infiltrate cortex without destroying it, creating a large area of peri-tumoural irritation.
When ICP rises asymmetrically, brain tissue shifts from high-pressure to low-pressure compartments [1]:
| Herniation Type | Structure Involved | Clinical Consequence |
|---|---|---|
| Subfalcine (cingulate) | Cingulate gyrus herniates under falx cerebri | Compression of anterior cerebral artery → contralateral leg weakness |
| Transtentorial (uncal) | Medial temporal lobe (uncus) herniates through tentorial notch | Ipsilateral CN III palsy (dilated pupil, "down and out"), contralateral hemiparesis, decreased consciousness (reticular activating system compression) |
| Central (downward) | Diencephalon herniates downward | Progressive deterioration: small reactive pupils → fixed dilated pupils → decerebrate posturing → death |
| Tonsillar | Cerebellar tonsils herniate through foramen magnum | Medullary compression → cardiorespiratory arrest (Cushing's triad: hypertension, bradycardia, irregular respiration) |
| Upward (cerebellar) | Cerebellum herniates upward through tentorial notch | Midbrain compression |
- Hypersecretion: Functioning pituitary adenomas autonomously secrete hormones (prolactin, GH, ACTH, TSH) [4][5].
- Hyposecretion: Non-functioning adenomas or craniopharyngiomas compress normal pituitary tissue and/or the pituitary stalk, causing hypopituitarism. The classical order of hormone loss reflects differential sensitivity: GH → FSH/LH → ACTH → TSH [4][5]. (GH-producing cells are the most abundant and peripherally located, hence most vulnerable to compression.)
- Stalk effect: Compression of the pituitary stalk interrupts dopamine delivery from the hypothalamus → loss of tonic inhibition of prolactin secretion → mild hyperprolactinaemia (typically < 100 ng/mL, unlike true prolactinomas where prolactin is usually > 200 ng/mL).
Classification
The current WHO classification (5th edition, 2021) integrates both histological features and molecular markers — a paradigm shift from the purely morphological classifications used previously. Key grading parameters include:
- Mitotic activity
- Invasiveness (infiltration into surrounding brain)
- Microvascular proliferation
- Necrosis (especially pseudopalisading necrosis in GBM)
WHO Grading: Grades I–IV (applicable to gliomas):
| Grade | Behaviour | Example |
|---|---|---|
| I | Benign, slow-growing, often curable with surgery alone | Pilocytic astrocytoma, meningioma (most) |
| II | Low-grade but infiltrative, tendency to recur or dedifferentiate | Diffuse astrocytoma, oligodendroglioma |
| III | Anaplastic/malignant features | Anaplastic astrocytoma, anaplastic oligodendroglioma |
| IV | Highly malignant, aggressive | Glioblastoma (GBM), diffuse midline glioma H3K27M-altered |
Key Molecular Markers (WHO CNS5, 2021)
- IDH mutation: Diffuse gliomas are now classified primarily by IDH status. IDH-mutant gliomas have a significantly better prognosis than IDH-wildtype.
- 1p/19q co-deletion: Defines oligodendroglioma (IDH-mutant + 1p/19q co-deleted).
- MGMT promoter methylation: Predicts response to temozolomide in GBM.
- H3K27M mutation: Defines diffuse midline glioma (previously called DIPG in the brainstem).
- TERT promoter mutation: Associated with GBM.
Distinguishing "benign" vs "malignant" (metastasises outside CNS) is less important for brain tumours [3]. Instead, classification by the following three parameters is more clinically useful:
As discussed above under Aetiology, this is the most important imaging distinction:
- Intra-axial: Gliomas, metastases, primary CNS lymphoma
- Extra-axial: Meningiomas, schwannomas, pituitary adenomas, craniopharyngiomas
Tumour-Specific Subclassifications
- By size: Microadenoma ( < 1 cm) vs Macroadenoma ( > 1 cm)
- By function: Functioning (70–80%) vs Non-functioning
- By secretory subtype (descending frequency): Prolactinoma (25%) > Non-functioning (50% of total) > GH-producing (12%) > ACTH-producing (5–10%) > Glycoprotein-secreting (1%)
- WHO Grade I (benign, ~80%), Grade II (atypical, ~15–20%), Grade III (malignant/anaplastic, ~2%)
- Adamantinomatous (children, often calcified and cystic)
- Papillary (adults, rarely calcified)
Clinical Features
Brain tumours present through three cardinal mechanisms [1][2]:
- Raised ICP — subacute onset headache, vomiting, papilloedema (high-grade tumours)
- Focal neurological deficits — slowly progressive, location-specific (low-grade tumours)
- Epilepsy — supratentorial tumours, especially low-grade gliomas
Additionally: 4. Hormonal dysfunction — pituitary adenomas, craniopharyngiomas 5. Incidental finding — increasingly common with widespread CT/MRI use 6. Pituitary apoplexy — neurosurgical emergency
A. Symptoms
Headache is the presenting symptom in 40–50% of brain tumour patients [2].
- Character: Generalised, dull, constant [2]
- Timing: Worse in the morning — why? Because during sleep, the supine position impairs venous drainage from the brain (venous return relies on gravity when upright), and REM-associated hypoventilation causes hypercapnia → cerebral vasodilation → further ICP elevation. On waking, the ICP is at its peak.
- Aggravating factors: Coughing, straining, bending forward (all increase intrathoracic pressure → impede jugular venous drainage → worsen ICP).
- Progression: Increases in severity and frequency over weeks to months.
Red Flags for Headache Suggesting Brain Tumour
- New-onset headache in someone > 50 years old or < 5 years old
- Progressive worsening headache
- Headache worse in the morning or waking from sleep
- Headache aggravated by coughing/straining/Valsalva
- Associated with vomiting (especially "projectile" vomiting without preceding nausea)
- Associated with new focal neurological deficits or seizures
- Personality/behaviour change
- Due to raised ICP → direct stimulation of the vomiting centre in the area postrema (floor of the 4th ventricle), which lies outside the BBB.
- Can be "projectile" — i.e., sudden-onset vomiting without much preceding nausea. This is classically associated with posterior fossa tumours in children, where rapid 4th ventricle obstruction causes acute ICP rise.
These are negative symptoms (loss of function) and their nature depends on the location of the tumour [1][2]:
| Location | Symptoms | Pathophysiology |
|---|---|---|
| Frontal lobe | Cognitive/personality change, apathy, disinhibition, executive dysfunction; contralateral weakness (UMN pattern) [1] | Prefrontal cortex handles personality/executive function; precentral gyrus is primary motor cortex |
| Temporal lobe (dominant) | Aphasia (word-finding difficulty, word substitution → receptive aphasia), memory problems [2] | Wernicke's area in posterior superior temporal gyrus; hippocampus for memory |
| Temporal lobe (non-dominant) | Visuospatial dysfunction, emotional changes | Non-dominant temporal lobe handles non-verbal perception |
| Parietal lobe | Cortical sensory loss (contralateral), dyspraxia, acalculia, agraphia; hemispatial neglect (non-dominant) [2] | Postcentral gyrus = primary sensory cortex; non-dominant parietal = spatial awareness |
| Occipital lobe | Contralateral homonymous hemianopia | Primary visual cortex |
| Cerebellum | Truncal ataxia (midline lesions), limb ataxia + dysmetria (hemispheric lesions), nystagmus, scanning speech [1] | Cerebellum coordinates movement and balance |
| Brainstem | Cranial nerve palsies, long-tract signs (hemiplegia, sensory loss), altered consciousness | CN nuclei + ascending/descending tracts + reticular activating system |
| Sellar/parasellar | Visual field defects (classically bitemporal hemianopia), hormonal disturbances, headache | Optic chiasm compression (nasal fibres cross → loss of temporal fields bilaterally) |
| Cerebellopontine angle | Unilateral sensorineural hearing loss, tinnitus, unsteadiness, facial numbness [1] | CN VIII → hearing/vestibular; CN V → facial sensation |
Types of focal deficit [2]:
- Weakness: UMN type (in upper limb: extensors weaker than flexors; in lower limb: flexors weaker than extensors — this is the "pyramidal pattern" of weakness), typically responsive to steroids (due to oedema) [2]
- Sensory loss: cortical deficits if involving primary sensory cortex, usually do NOT respect dermatomal or peripheral nerve distribution [2]
- Aphasia: word-finding hesitation, word substitution, severe expressive/receptive aphasia [2]
- Visuospatial dysfunction and cognitive dysfunction (e.g., memory problems, mood/personality changes) [2]
Epilepsy: affects 50–80% of primary tumours and 10–20% of secondary tumours [2].
- Always supratentorial [2].
- Character: Typically repetitive and stereotyped in a given patient — i.e., the same seizure type recurs [2].
- Types: Focal seizures (simple partial, complex partial) ± with secondary generalisation [2].
- Why? The peri-tumoural cortex is irritated (glutamate excitotoxicity from glioma cells, ionic imbalances, oedema) and fires abnormally.
- Clinical pearl: Any adult presenting with a new-onset seizure should be investigated for an intracranial lesion (tumour, vascular malformation, etc.) until proven otherwise.
| Tumour Type | Hormone | Clinical Syndrome |
|---|---|---|
| Prolactinoma | ↑Prolactin | Galactorrhoea (breast secretion) + hypogonadotropic hypogonadism → amenorrhoea (F), impotence (M) |
| GH-producing adenoma | ↑GH/IGF-1 | Acromegaly (adults) / Gigantism (children, before epiphyseal closure) |
| ACTH-producing adenoma | ↑ACTH → ↑Cortisol | Cushing's disease |
| TSH-producing adenoma | ↑TSH | Secondary hyperthyroidism (rare) |
| Non-functioning adenoma | None (no hormonal hypersecretion) | Hypopituitarism (stalk compression / normal tissue compression) + local symptoms (headache, visual loss) |
Order of hormone loss in hypopituitarism: GH → FSH/LH → ACTH → TSH [4][5].
- Classically bitemporal hemianopia (optic chiasm compression) [5]
- Unilateral visual loss (optic nerve compression) or homonymous hemianopia (optic tract compression) [5]
- Optic atrophy may be evident on fundoscopy [5]
- Diplopia (lateral extension of tumour into cavernous sinus → CN III, IV, or VI palsy) [5]
- Due to raised ICP affecting the reticular activating system in the brainstem.
- Can be acute (pituitary apoplexy, acute hydrocephalus from posterior fossa tumour) or gradual (progressive herniation).
| Location | CNs Affected | Symptoms |
|---|---|---|
| Anterior cranial fossa | CN I | Anosmia (olfactory groove meningioma) |
| Middle cranial fossa / Cavernous sinus | CN III, IV, V1, V2, VI | Diplopia, facial numbness, ptosis |
| Posterior cranial fossa / CPA | CN V, VII, VIII, IX, X, XII | Hearing loss, facial palsy, dysphagia, hoarseness, tongue atrophy |
| Foramen magnum | CN IX, X, XI, XII + long tracts | Dysphagia, dysarthria, weakness |
- Cranial diabetes insipidus: Stalk compression or hypothalamic infiltration → loss of ADH secretion → polyuria, polydipsia (especially with craniopharyngioma or germinoma) [5].
- Hypothalamic damage (from craniopharyngioma): Hyperphagia, obesity, loss of thirst sensation, disturbance of temperature regulation [5].
B. Signs
- Papilloedema: Swelling of the optic disc on fundoscopy — caused by increased CSF pressure transmitted along the optic nerve sheath, compressing the central retinal vein → impaired venous drainage → disc swelling. This is a late sign [2].
- Cushing's triad (a late, ominous sign of brainstem compression): Hypertension + Bradycardia + Irregular respiration [2]. The pathophysiology: brainstem ischaemia (due to herniation) triggers a massive sympathetic surge (hypertension) → baroreceptor reflex causes vagal-mediated bradycardia → medullary respiratory centre dysfunction causes irregular breathing.
- Decreased consciousness: GCS drop.
- Sixth nerve palsy (false localising sign): CN VI has the longest intracranial course and is stretched over the petrous ridge when ICP rises diffusely, regardless of tumour location.
- UMN signs: Hyperreflexia, clonus, upgoing plantars (Babinski), spasticity — contralateral to the hemisphere lesion.
- Cortical sensory signs: Two-point discrimination loss, agraphaesthesia, astereognosis.
- Aphasia signs: Assessed by spontaneous speech, naming, repetition, comprehension.
- Visual field defects: Bitemporal hemianopia, homonymous hemianopia (detected by confrontation testing).
- Cerebellar signs: Finger-nose-finger dysmetria, heel-shin ataxia, dysdiadochokinesia, broad-based gait, Romberg test (falls to affected side with eyes open in cerebellar lesions).
Ipsilateral optic atrophy + contralateral papilloedema — classically associated with large olfactory groove meningioma [3].
- Why? The tumour directly compresses the ipsilateral optic nerve → optic atrophy (the nerve dies, so it cannot swell). Meanwhile, the mass raises ICP generally → the contralateral optic disc swells (papilloedema).
Vestibular Schwannoma (Acoustic Neuroma) [1][2]:
- Sensorineural hearing loss (95%) — cochlear nerve compression
- Unsteadiness, mild vertigo (61%) — vestibular nerve. Typically NOT severe spinning vertigo due to gradual onset → central compensation [2]
- Facial numbness, hyperaesthesia, pain (17%) — trigeminal nerve compression
- NO facial nerve involvement — the facial nerve bundle is thick and resilient; usually only stretched over the slowly growing tumour [2]
Pineal Region Tumours [2]:
- Parinaud's syndrome (dorsal midbrain syndrome) with the mnemonic LLVV:
- Light-near dissociation (pupils constrict to accommodation but not to light)
- Lid retraction (Collier sign)
- Vertical gaze palsy (upward gaze palsy = "sunset eye sign")
- Vergence abnormalities (convergence-retraction nystagmus)
Craniopharyngioma [5]:
- Growth retardation (children — GH deficiency)
- Cranial diabetes insipidus (stalk compression → ADH loss)
- Visual field defects (chiasmal compression)
- Signs of raised ICP (3rd ventricle compression → hydrocephalus)
- Hypothalamic signs (obesity, temperature dysregulation)
Pituitary apoplexy: a neurosurgical emergency! [2]
Due to haemorrhagic infarction of a pituitary tumour [2]:
- Sudden onset of excruciating headache (stretching of sella turcica)
- Diplopia (pressure on CN III)
- Hypopituitarism (especially adrenal crisis — most immediately life-threatening)
- ± Visual defects, vertigo, altered consciousness [2]
| Location | Clinical Presentation | Common Pathologies |
|---|---|---|
| Anterior cranial fossa | Asymptomatic; Raised ICP (headache, N/V); Seizure; Anosmia; Visual complaints; Foster-Kennedy syndrome | Meningioma; Olfactory groove neuroblastoma |
| Middle cranial fossa | Visual disturbance (optic nerve/chiasm compression); CN palsy (III, IV, V, VI); Hormonal disturbances | Meningioma; Schwannoma; Pituitary adenoma; Craniopharyngioma |
| Posterior cranial fossa | CN palsy (facial palsy, hearing loss, dysphagia, hoarseness of voice, tongue atrophy); Obstructive hydrocephalus; Brainstem compression (hemiplegia, sensory loss) | Meningioma; Vestibular schwannoma |
Pituitary tumours may present as incidental findings on:
- Skull X-ray: double-flooring of sella turcica (due to asymmetrical enlargement of the pituitary fossa)
- CT/MRI brain performed for other reasons (e.g., head injury, headache work-up)
| Tumour | WHO Grade | Peak Age | Location | Key Features |
|---|---|---|---|---|
| Glioblastoma (GBM) | IV | Middle-aged or above [1] | Cerebral hemispheres | Infiltrative, rapid growth, invasive; almost always recurs; life expectancy ~14 months [1]; butterfly lesion crossing corpus callosum |
| Meningioma | I (90%) | Middle-aged, F > M | Convexity, parasagittal, skull base | Extra-axial, dural tail, homogenous enhancement, slow-growing but potentially lethal [2] |
| Pituitary adenoma | I | Adults 30–60 | Sella turcica | Hormonal syndromes, bitemporal hemianopia |
| Vestibular schwannoma | I | 40–60 (bilateral in NF2) | CPA | SNHL, tinnitus, unsteadiness |
| Medulloblastoma | IV | Children < 10 | Posterior fossa (4th ventricle) | Embryonal, can disseminate via CSF ("drop metastases") |
| Craniopharyngioma | I | Bimodal (children + 50–70y) | Suprasellar | Cystic, calcified, hypothalamic/pituitary dysfunction |
| Primary CNS lymphoma | High-grade | 50–70 (younger if HIV) | Periventricular, deep grey | EBV-associated, dramatic steroid response ("ghost tumour"), prominent DWI restriction |
| Brain metastases | N/A | Adults | Grey-white junction, watershed | Multiple, well-circumscribed, large oedema:size ratio |
High Yield Summary
- Brain tumours present with raised ICP, focal neurological deficits, and/or epilepsy — the exact combination depends on tumour grade, speed of growth, and location.
- Secondary (metastatic) tumours are the commonest intracranial tumours in adults (6–10× more common than primary). Most common primaries: lung, breast, melanoma, colorectal, RCC.
- The concept of malignancy in brain tumours is NOT clear-cut — even "benign" tumours can be lethal due to location. TNM staging is not used because extracranial metastasis is rare (no lymphatic drainage).
- In adults, 70–85% of tumours are supratentorial; in children, 70% are infratentorial.
- The only proven environmental risk factor is high-dose ionising radiation (→ meningiomas, gliomas). EBV/immunosuppression → primary CNS lymphoma.
- Intra-axial vs extra-axial is the key imaging distinction: look for claw sign vs CSF cleft and dural tail.
- Vasogenic oedema (from BBB disruption + VEGF) is the most steroid-responsive component of tumour-related symptoms.
- Epilepsy from brain tumours is always supratentorial — cerebellar cortex is inhibitory.
- Pituitary adenomas: order of hypopituitarism = GH → FSH/LH → ACTH → TSH. Prolactinoma is the most common functioning adenoma.
- Pituitary apoplexy = sudden haemorrhage into adenoma → excruciating headache + CN III palsy + adrenal crisis = neurosurgical emergency.
- Foster-Kennedy syndrome = ipsilateral optic atrophy + contralateral papilloedema → olfactory groove meningioma.
- Acoustic neuroma = vestibular schwannoma → progressive SNHL, tinnitus, unsteadiness but typically NO facial nerve palsy (nerve is only stretched).
- GBM (WHO Grade IV): most common malignant primary brain tumour, heterogeneous enhancement, butterfly lesion, life expectancy ~14 months.
- Craniopharyngioma: from Rathke's pouch, cystic + calcified, presents with growth retardation in children, hypothalamic damage, visual field defects, cranial DI.
Active Recall — Brain Tumours (Definition, Epidemiology, Risk Factors, Anatomy, Aetiology, Pathophysiology, Classification, Clinical Features)
[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf [2] Senior notes: Ryan Ho Neurology.pdf (Section 8.3 Intracranial Tumours, pp. 161–170) [3] Senior notes: maxim.md (Section 5.5 Brain tumours) [4] Senior notes: Ryan Ho Endocrine.pdf (p. 107 — Pituitary adenoma) [5] Senior notes: Ryan Ho Fundamentals.pdf (pp. 441–442 — Pituitary Tumour) [6] Senior notes: Ryan Ho Rheumatology.pdf (p. 170 — Neurofibroma, NF2 features) [7] Senior notes: Ryan Ho Radiology.pdf (p. 23 — Intracranial Tumours, intra vs extra-axial) [8] Lecture slides: GC 219. Infections and tumours in pharynx and oral cavity.pdf (NPC context) [9] Lecture slides: WCS 064 - A large liver - by Prof R Poon.pdf (HCC context)
Differential Diagnosis of Brain Tumours
When you see a mass on brain imaging, your immediate reflex might be to call it a tumour — but not every intracranial mass is neoplastic. The differential diagnosis of an intracranial space-occupying lesion (SOL) is broad, and getting it wrong has serious consequences: you would not want to start someone on temozolomide chemoradiation for what turns out to be a brain abscess, nor would you want to perform a craniotomy on a primary CNS lymphoma (which responds dramatically to steroids and chemotherapy, not surgery). The approach to differential diagnosis depends on three key axes:
- Is the lesion truly a tumour, or is it a non-neoplastic mimic?
- If it is a tumour, is it primary or secondary (metastatic)?
- If primary, what specific tumour type?
The differential diagnosis of intracranial tumours includes both neoplastic and non-neoplastic lesions [2]:
| Category | Differential | Why It Mimics a Tumour | Key Distinguishing Features |
|---|---|---|---|
| Vascular | Haematoma (intracerebral, subdural) | Mass effect, focal deficit, headache | Acute onset, history of trauma/anticoagulation, hyperdense on CT (acute blood) |
| Giant aneurysm | Can appear as a round mass with mass effect | Pulsatile on angiography, peripheral calcification, flow void on MRI | |
| AVM (arteriovenous malformation) | Heterogeneous signal, surrounding oedema possible | Flow voids ("bag of worms"), history of seizures or haemorrhage, DSA diagnostic | |
| Infarct with oedema | Early infarction can cause mass effect mimicking tumour | Sudden onset fitting vascular territory, restricted diffusion on DWI, no enhancement initially | |
| Venous thrombosis (e.g., CVST) | Haemorrhagic infarction with oedema | Does not respect arterial territory, "empty delta sign" on CT venogram, headache with raised ICP | |
| Infective | Brain abscess | Ring-enhancing lesion mimicking GBM or metastasis [2] | Restricted diffusion on DWI (bright centre — pus restricts water movement), fever, raised inflammatory markers, smooth thin ring wall |
| Tuberculoma | Enhancing lesion ± surrounding oedema | Endemic area, TB risk factors, other systemic TB features, "target sign" | |
| Sarcoidosis (neurosarcoidosis) | Enhancing meningeal or parenchymal lesion | Systemic features (bilateral hilar lymphadenopathy, skin, eyes), elevated ACE | |
| Encephalitis (viral, especially herpes) | Temporal lobe swelling and signal change | Acute febrile onset, temporal predilection (HSV), restricted diffusion in cortex | |
| Traumatic | Haematoma | As above | History of trauma |
| Contusion | Haemorrhagic cortical lesion with oedema | Coup-contrecoup pattern, history of trauma | |
| Cystic | Arachnoid cyst | CSF-density non-enhancing mass | Follows CSF signal on all MRI sequences, no enhancement, no surrounding oedema, usually incidental |
| Parasitic cyst (neurocysticercosis) | Cystic lesion with surrounding oedema ± enhancement | Endemic exposure, scolex visible within cyst, calcification in chronic stage | |
| Demyelination | Tumefactive MS | Large enhancing white matter lesion mimicking glioma | Open-ring enhancement (incomplete ring with opening towards cortex), young patient with relapsing neurological episodes |
| Other | Radionecrosis | Enhancing lesion mimicking tumour recurrence post-RT | History of prior radiotherapy, typically 1–3 years after RT, high oedema-to-enhancement ratio [2] |
High Yield — Brain Abscess vs GBM vs Metastasis
All three can present as ring-enhancing lesions. The key discriminator on MRI is DWI (diffusion-weighted imaging):
- Brain abscess: Restricted diffusion in the centre (bright on DWI, dark on ADC) — because pus is viscous and restricts water molecule movement [3].
- GBM: Central necrosis typically shows facilitated diffusion (dark on DWI) — necrotic fluid is less viscous than pus.
- Metastasis: Variable DWI signal, but typically no restricted diffusion in the centre. This is a must-know imaging distinction for exams [2][3].
This is the single most important branch in the differential. The approach differs fundamentally:
| Feature | Primary Brain Tumour | Brain Metastasis |
|---|---|---|
| Number of lesions | Usually solitary | Multiple lesions (though 30–50% present as solitary) [2] |
| Location | Variable (gliomas: white matter; meningiomas: dural-based) | Grey-white junction, watershed areas [2] |
| Margin | Infiltrative (gliomas) or well-defined (meningiomas) | Well-circumscribed [2] |
| Oedema | Proportional to tumour grade | Large volume of vasogenic oedema compared to size of lesion ("disproportionate oedema") [2] |
| History | No known malignancy | Pre-existing cancer (but 10–15% of solitary cerebral mass lesions in patients with pre-existing cancer are NOT metastases!) [2] |
| Enhancement | Variable by type | Round, well-circumscribed, enhancing |
| Age | Gliomas: any age; Meningiomas: middle-aged | Typically adults with known cancer |
| Involvement of multiple compartments | Unusual for a single primary | Suggestive of metastatic disease [2] |
"10–15% of solitary cerebral mass lesions in a patient with pre-existing cancer are NOT metastases" — always consider primary brain tumour and brain abscess in the differential [2].
C. Differential Diagnosis by Location
Location is one of the most powerful tools for narrowing the differential. Different tumour types have strong predilections for specific anatomical sites [3].
| Specific Location | Top Differentials | Reasoning |
|---|---|---|
| Cerebral hemisphere (intra-axial) | GBM, anaplastic astrocytoma, oligodendroglioma, metastases, primary CNS lymphoma [3] | These are the commonest intra-axial tumours in adults. GBM and metastases together account for the vast majority. |
| Corpus callosum | GBM ("butterfly lesion"), oligodendroglioma, lipoma [3] | GBM crosses midline via corpus callosum white matter tracts — the bilateral enhancing mass with a "butterfly" pattern is classic [1]. |
| Convexity/parasagittal (extra-axial) | Meningioma [2] | Arises from arachnoid granulations along the dural surface. Dural tail sign and homogeneous enhancement are hallmarks. |
| Sellar/suprasellar | Pituitary adenoma, craniopharyngioma, meningioma, Rathke's cleft cyst, germ cell tumour, metastasis (CA breast/lung) [4][5][10] | Pituitary adenoma is by far the most common sellar mass in adults from the 3rd decade onward [10]. |
| Lateral ventricle | Ependymoma, meningioma, subependymoma, choroid plexus papilloma [3] | Tumours that grow within or adjacent to ventricular lining. |
| Third ventricle | Colloid cyst, ependymoma [3] | A colloid cyst at the foramen of Monro can cause acute intermittent obstructive hydrocephalus → sudden death. |
| Pineal region | Germ cell tumours (children), pineal parenchymal tumours, gliomas (adults) [2] | The pineal gland contains remnant germ cells; in children, these are the most common tumours here. |
| Optic chiasm/nerve | Meningioma, pilocytic astrocytoma (especially in NF1) [3] | Optic pathway gliomas in children with NF1 are a classic association. |
| Specific Location | Top Differentials (Adults) | Top Differentials (Children) | Reasoning |
|---|---|---|---|
| Cerebellum | Metastasis, haemangioblastoma (especially VHL) [3] | Pilocytic astrocytoma (cystic with mural nodule), medulloblastoma [3] | Medulloblastoma is the most common malignant posterior fossa tumour in children, arising from the vermis/4th ventricle roof. |
| 4th ventricle | Ependymoma | Ependymoma, choroid plexus papilloma, medulloblastoma [3] | Ependymoma arises from ependymal lining of ventricles; in children, most are infratentorial. |
| Cerebellopontine angle (CPA) | Vestibular schwannoma (acoustic neuroma, ~80% of CPA tumours), meningioma, epidermoid cyst [2][3] | Rare in children unless NF2 | The CPA is a classic exam location. Vestibular schwannoma expands the internal acoustic meatus — a pathognomonic finding. |
| Brainstem | Diffuse midline glioma (H3K27M-mutant) | Diffuse intrinsic pontine glioma (DIPG, now classified as diffuse midline glioma) | Brainstem tumours are largely inoperable — biopsy only ± chemoRT. |
| Foramen magnum | Meningioma, schwannoma, neurofibroma [3] | Rare | These present with progressive myelopathy + lower CN palsies. |
This deserves special attention as a common exam topic [4][5][10]:
| Category | Differentials |
|---|---|
| Pituitary hyperplasia (physiological/reactive) | Lactotroph hyperplasia (pregnancy), thyrotroph hyperplasia (longstanding primary hypothyroidism), gonadotroph hyperplasia (longstanding primary hypogonadism), somatotroph hyperplasia (ectopic GHRH secretion) [10] |
| Benign tumours | Pituitary adenoma (most common in adults), craniopharyngioma (most common in children/young adults), meningioma, pituicytoma [4][10] |
| Malignant tumours | Pituitary carcinoma (very rare), germ cell tumours, chordomas, CNS lymphoma [4][10] |
| Secondary tumours | CA lung (males), CA breast (females) [4][10] |
| Cysts | Rathke's cleft cyst, arachnoid cyst, dermoid cyst [10] |
| Inflammatory/infectious | Lymphocytic hypophysitis, pituitary abscess [4][10] |
| Vascular | Carotid-cavernous fistula [4][10] |
Exam Pearl — Craniopharyngioma vs Pituitary Adenoma
Both present with visual field defects and hormonal dysfunction, but:
- Craniopharyngioma: Often in children/young adults, cystic, 50% calcified (visible on XR/CT), causes cranial DI (stalk compression) and hypothalamic damage (obesity, hyperphagia, thermoregulatory dysfunction) [5].
- Pituitary adenoma: Adults 30–60, within sella, rarely calcified, DI is uncommon (DI suggests stalk or hypothalamic involvement — think craniopharyngioma, germinoma, or metastasis instead).
- CT is better for detecting calcification (meningioma, craniopharyngioma) while MRI with contrast is the modality of choice for sellar lesions overall [4][5].
| Age Group | Most Common Tumour Types | Key Reasoning |
|---|---|---|
| Adults ( > 18y) | Metastases > GBM > meningioma > pituitary adenoma | Metastases are 6–10× more common than primary tumours. GBM is the most common malignant primary brain tumour. |
| Children (2–12y) | Pilocytic astrocytoma > medulloblastoma > ependymoma > craniopharyngioma > germ cell tumours | 70% infratentorial. Embryonal and developmental tumours predominate [2][3]. |
| Infants ( < 2y) | Choroid plexus papilloma/carcinoma, teratoma, ATRT | Extremely rare tumours; congenital or embryonal. |
| MRI Pattern | Differential Diagnosis | Why This Pattern |
|---|---|---|
| Heterogeneous enhancement with central necrosis [2] | GBM, brain abscess, metastasis | GBM outgrows its blood supply → central necrosis. Abscess centre is pus. |
| Homogeneous enhancement, dural-based, extra-axial [2] | Meningioma | Arises from arachnoid cells on dural surface. Rich blood supply → uniform enhancement. Dural tail = reactive dural thickening. |
| Non-enhancing, T2-hyperintense, expansile [2] | Low-grade glioma | Intact BBB (low-grade tumour does not disrupt BBB significantly → no contrast leak → no enhancement). |
| Periventricular, T2-iso/hypointense with restricted diffusion on DWI [2] | Primary CNS lymphoma | Densely cellular tumour → restricts water diffusion. Deep grey matter/periventricular predilection. C/I: steroids before biopsy (causes acute lymphocyte lysis → "ghost tumour" → ↓ diagnostic yield) [2] |
| Multiple ring-enhancing lesions at grey-white junction | Brain metastases | Haematogenous spread → tumour cell clumps trapped at grey-white junction where vessel calibre narrows [2]. |
| Extra-axial CPA mass expanding the IAM | Vestibular schwannoma | Arises from Schwann cells within internal acoustic meatus → expands the canal [2]. |
| Sellar mass with calcification + cystic component | Craniopharyngioma [5] | Develops from Rathke's pouch remnant cells; often cystic and 50% calcified. |
| Ring enhancement with restricted diffusion in centre | Brain abscess | Pus is viscous → restricts water molecule diffusion (unlike necrotic tumour fluid) [2][3]. |
H. Special Differential Diagnosis Scenarios
CN VI palsy is a famous "false localising sign" of raised ICP — it does not localise the tumour itself. CN VI has the longest intracranial course and is stretched over the clivus/petrous ridge when ICP rises diffusely. Therefore, a posterior fossa tumour can cause bilateral CN VI palsies even though the tumour is nowhere near CN VI.
Other causes of CN VI palsy that may overlap with brain tumour presentations [11]:
- Pontine lesion (infarction, demyelination, tumour)
- Microvascular disease (most common overall cause in adults with vascular risk factors)
- Petrous bone pathology (petrositis — Gradenigo syndrome)
- Cavernous sinus pathology (infection, ICA aneurysm, CST)
- Orbital pathology (tumours, cellulitis)
In Hong Kong, NPC (nasopharyngeal carcinoma) with skull base invasion is an important cause of CN VI palsy in young patients [11]. Always consider this in the local context.
Slowly growing tumours (especially frontal meningiomas, low-grade gliomas) can present insidiously with personality change, cognitive decline, and apathy — mimicking neurodegenerative dementia (especially frontotemporal dementia). Conversely, FTD can be mistaken for a tumour. Neuroimaging is essential to distinguish these.
High Yield Summary — Differential Diagnosis
- Non-neoplastic mimics: brain abscess, haematoma, AVM, giant aneurysm, infarct with oedema, CVST, tuberculoma, neurocysticercosis, tumefactive MS, radionecrosis.
- Abscess vs GBM vs metastasis: all can be ring-enhancing. Use DWI — restricted diffusion in centre = abscess (pus).
- Primary CNS lymphoma: periventricular, DWI restriction, T2-iso/hypointense, DO NOT give steroids before biopsy (ghost tumour).
- Multiple enhancing lesions at grey-white junction = brain metastases until proven otherwise.
- Sellar mass differential: pituitary adenoma (adults) vs craniopharyngioma (children/young adults, calcified, cystic, DI).
- 10–15% of solitary brain masses in cancer patients are NOT metastases — consider primary tumour and abscess.
- Location, age, and imaging pattern are the three pillars of narrowing the differential.
- CN VI palsy = false localising sign of raised ICP (longest intracranial course); in Hong Kong, always consider NPC.
Active Recall — Differential Diagnosis of Brain Tumours
References
[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf [2] Senior notes: Ryan Ho Neurology.pdf (Section 8.3 Intracranial Tumours, pp. 161–167) [3] Senior notes: maxim.md (Section 5.5 Brain tumours) [4] Senior notes: Ryan Ho Endocrine.pdf (p. 106–107 — Pituitary Tumour) [5] Senior notes: Ryan Ho Fundamentals.pdf (pp. 441–442 — Pituitary Tumour, Craniopharyngioma) [7] Senior notes: Ryan Ho Radiology.pdf (p. 23 — Intracranial Tumours) [10] Senior notes: felixlai.md (Pituitary adenoma — Differential diagnosis of sellar mass) [11] Senior notes: Ryan Ho Opthalmology.pdf (p. 85 — Sixth Nerve Palsy) [12] Senior notes: Ryan Ho Psychiatry.pdf (p. 94 — Frontotemporal Dementia differential)
Diagnostic Approach to Brain Tumours
Unlike many medical conditions (e.g., rheumatoid arthritis, SLE) where validated diagnostic criteria exist, brain tumours do not have a single set of criteria analogous to ACR/EULAR criteria. The reason is straightforward: brain tumours are an extraordinarily heterogeneous group of diseases — over 100 distinct entities in the WHO CNS5 classification — and the definitive diagnosis is histopathological (and increasingly molecular). What we do have is a systematic diagnostic algorithm that integrates:
- Clinical suspicion (history + examination → "Could this be a brain tumour?")
- Neuroimaging (CT ± contrast → MRI with contrast → characterise and localise)
- Tissue diagnosis (biopsy or surgical resection → histology + molecular profiling)
- Staging/systemic work-up (for metastatic disease or to guide treatment planning)
The diagnosis of a brain tumour is therefore never purely clinical or purely radiological — it requires tissue confirmation for definitive diagnosis and grading (with the exception of certain scenarios where imaging is considered diagnostic, such as classic brainstem DIPG in children where biopsy carries unacceptable risk).
Diagnostic Algorithm — Step-by-Step
The clinical approach proceeds in a logical sequence. Think of it as answering a series of questions, each one narrowing the differential.
The clinical presentation raises suspicion. The three cardinal presentations from the previous section are:
- Raised ICP: Subacute progressive headache (worse in morning), vomiting, papilloedema
- Focal neurological deficit: Progressive, location-specific
- Seizures: New-onset in an adult, especially focal with secondary generalisation
Red flags that should trigger urgent neuroimaging:
- New-onset seizure in an adult
- Progressive focal neurological deficit
- Headache with features of raised ICP (morning headache, vomiting, papilloedema)
- Personality/cognitive change with no other explanation
- Known cancer patient with new neurological symptoms
CT brain ± contrast is often the first-line imaging in the acute or emergency setting [2][5][7][13][14]:
Why CT first?
- Widely available, fast (seconds), no sedation needed
- Detects acute blood (hyperdense), calcification, mass effect, hydrocephalus
- Adequate to detect large lesions and guide emergency management (e.g., herniation requiring urgent intervention)
What to look for on CT [5][13]:
| CT Finding | What It Tells You | Examples |
|---|---|---|
| Site and multiplicity | Single vs multiple lesions; supratentorial vs infratentorial | Multiple lesions → think metastases or abscess or lymphoma [5] |
| Mass effect | Midline shift, ventricular compression, sulcal effacement, obliteration of basal cisterns | Indicates significant space-occupying effect; basal cistern obliteration is very suggestive of raised ICP [5] |
| Density | Hyperdense = acute blood or calcification; Hypodense = oedema, infarction, low-grade tumour; Mixed = tumour with haemorrhage/necrosis [5] | Calcification suggests meningioma or craniopharyngioma [4] |
| Contrast enhancement | Normal brain tissue does NOT enhance (due to intact BBB) [2] | Enhancement means either the lesion is outside the BBB (e.g., meningioma — homogenously enhancing) or there is disruption of the BBB (e.g., high-grade tumours, inflammation, stroke) [2] |
| Ring enhancement | Ring of peripheral enhancement with non-enhancing centre | Abscess, metastasis, glioblastoma, dermoid cyst [5] |
CT Interpretation Pearl
Contrast enhancement = BBB disruption or extra-BBB location. A non-enhancing lesion suggests an intact BBB — typically a low-grade glioma. A homogeneously enhancing extra-axial lesion is classic for meningioma. Ring enhancement is the hallmark of GBM, abscess, and metastases.
Step 3: Definitive Neuroimaging — MRI Brain with Gadolinium Contrast
MRI with contrast is generally preferred over CT for brain tumour diagnosis [2][3]:
Why MRI is superior:
- Allows better soft tissue delineation [2]
- Especially useful at skull base, craniocervical junction, brainstem [2] — areas where CT suffers from beam-hardening artefact from dense bone
- Multi-sequence capability provides complementary information (see below)
- No ionising radiation
- Gadolinium contrast-enhanced MRI is the gold standard for brain tumour characterisation [3]
Limitations of MRI:
- Time-consuming (~30–60 min), loud, requires patient cooperation
- Contraindicated in certain metallic implants, pacemakers
- Less sensitive than CT for acute blood ( < 24 hours) and calcification
| Sequence | Physics Principle | What It Shows | Role in Brain Tumours |
|---|---|---|---|
| T1-weighted (T1W) | Short TR/TE; fat is bright, water is dark | Anatomical detail; tumour usually hypointense (dark) | Structural anatomy; detect fat-containing lesions (lipoma, dermoid), subacute blood (bright due to methaemoglobin) |
| T1W + Gadolinium (Gd) | Gd shortens T1 → enhancing tissue becomes bright | Enhancement = BBB disruption or extra-BBB structure | Most important sequence for tumour characterisation — delineates enhancing tumour, ring enhancement, dural tail |
| T2-weighted (T2W) | Long TR/TE; water is bright, fat is dark | Oedema and tumour (both bright) | Detect oedema surrounding tumour; low-grade gliomas are T2-bright |
| FLAIR | T2W with CSF signal suppressed | Oedema stands out (bright) without being obscured by CSF | Vasogenic oedema is most apparent on FLAIR [3]; periventricular lesions easier to see |
| DWI (Diffusion-Weighted Imaging) | Measures Brownian motion of water molecules | Restricted diffusion = bright (water molecules cannot move freely) | Differentiate abscess (restricted) vs cystic tumour/necrotic GBM (facilitated) [3]; primary CNS lymphoma shows prominent diffusion restriction [2] |
| ADC map | Quantitative map derived from DWI | Confirms restricted diffusion (dark on ADC if truly restricted) | Confirms DWI findings; low ADC = high cellularity or pus |
| GRE / SWI | Susceptibility to magnetic field inhomogeneity | Blood products (haemosiderin), calcification — appear as signal dropout | Detect microhaemorrhages within tumour, calcification |
| MRS (MR Spectroscopy) | Measures metabolite concentrations | Choline (cell membrane turnover), NAA (neuronal marker), lactate, lipid | Elevated choline + decreased NAA = tumour. Lipid/lactate peak = necrosis (high-grade). Can help differentiate tumour from non-neoplastic lesion. |
| Perfusion MRI (pMRI) | Measures cerebral blood volume (CBV) | High CBV = high vascularity | High-grade gliomas have elevated rCBV (due to neoangiogenesis); helps grade gliomas non-invasively |
| DTI (Diffusion Tensor Imaging / Tractography) | Measures directionality of water diffusion along white matter tracts | Identify important white matter tracts | Pre-operative planning: identify important tracts to guide surgical resection [2] |
This is extremely high yield for exams [2]:
| Tumour | MRI Appearance | Why It Looks This Way |
|---|---|---|
| High-grade glioma (GBM) | ↓T1W, heterogeneous enhancement with surrounding vasogenic oedema (↑T2W) ± central necrosis [2]; heterogeneous enhancement, butterfly lesion [1] | Rapid growth outstrips blood supply → central necrosis. BBB is severely disrupted → intense but irregular enhancement. VEGF secretion → florid vasogenic oedema. Crosses corpus callosum via white matter tracts → butterfly pattern. |
| Low-grade glioma | ↑T2W, non-enhancing expansile lesion without surrounding vasogenic oedema [2] | BBB remains largely intact → no contrast leak → no enhancement. Slow growth means minimal oedema. |
| Primary CNS lymphoma | Solitary or multifocal T2W-iso/hypointense, contrast-enhancing lesions in subcortical/periventricular regions, classically with prominent diffusion restriction on DWI [2] | Extremely cellular tumour (densely packed lymphocytes) → restricts water diffusion. T2-iso/hypointense because of high nuclear-to-cytoplasmic ratio (less water content than typical tumours). |
| Brain metastases | Round, well-circumscribed contrast-enhancing lesion with variable signal on T1/2W ± surrounding oedema (if large), involving multiple regions esp if multiple intracranial compartments [2] | Haematogenous spread → well-circumscribed (pushing rather than infiltrating). BBB disrupted → enhancement. Disproportionate oedema relative to lesion size. |
| Meningioma | Extra-axial, dura-based T1W-hypo/isointense, T2W-iso/hyperintense lesion with strong homogeneous enhancement [2]; well-circumscribed dural-based lesion with "dural tail" and homogeneous enhancement [2] | Arises from arachnoid cap cells — outside BBB entirely → enhances uniformly. "Dural tail" = reactive dural thickening adjacent to tumour. |
| Vestibular schwannoma | Enhancing CPA mass expanding internal acoustic meatus [2] | Schwann cell tumour within IAM → expands the bony canal as it grows. |
| Craniopharyngioma | Cystic + solid, calcification, suprasellar, T1-bright cyst content (due to cholesterol) [4][5] | Develops from Rathke's pouch remnants; cystic degeneration common; cholesterol crystals in cyst fluid → bright on T1W. 50% calcified (visible on XR/CT) [4][5]. |
Exam Must-Know — MRI Patterns
Students commonly confuse the MRI appearances. Remember these three anchor patterns:
- Enhancing = BBB broken or outside BBB → high-grade tumour, meningioma, metastasis, lymphoma
- Non-enhancing + T2-bright = intact BBB → low-grade glioma
- Ring-enhancing = GBM (irregular thick ring), metastasis (thin smooth ring), abscess (thin smooth ring + DWI restriction centrally)
Functional imaging is used for pre-operative planning [2]:
| Modality | Purpose | Mechanism |
|---|---|---|
| Functional MRI (fMRI) | Identify important cortical areas to guide surgical resection [2] | Detects BOLD (blood-oxygen-level-dependent) signal changes when the patient performs tasks (e.g., finger tapping → motor cortex; naming → Broca's area). Maps eloquent cortex relative to the tumour. |
| MRI DTI / Tractography | Identify important white matter tracts to guide surgical resection [2] | Maps the course of major tracts (e.g., corticospinal tract, arcuate fasciculus) relative to the tumour. If the tumour displaces but does not infiltrate the tract, resection may be safer. |
| DSA (Digital Subtraction Angiography) | Shows tumour vascularity, "tumour brush" due to angiogenesis [2] | Only occasionally required [2] — mainly for pre-operative embolisation of hypervascular tumours (e.g., meningioma, haemangioblastoma) or to map vascular anatomy. |
The definitive diagnosis of a brain tumour requires tissue — obtained by either surgical resection or stereotactic biopsy [1][2].
Principles of brain tumour surgery [1]:
- Obtain histological diagnosis
- Maximal safe removal
- Preserve life
- Preserve function
- "Resection margin" is difficult in neurosurgery
Surgical approaches [2]:
- Craniotomy: Flap of bone cut and reflected — for resection of accessible tumours
- Burr hole: Often for stereotactic biopsy
- Craniectomy: Burr hole + removal of surrounding bone — for decompression
- Transsphenoidal (transnasal or sublabial): For pituitary tumours [2]
- Transoral: For anterior foramen magnum/upper cervical lesions
Stereotactic biopsy [2]:
- Usually for non-resectable tumours (e.g., pontine gliomas) or lymphoma (which is not treated by surgery — biopsy only) [1][2]
- Uses frameless stereotaxy or frame-based systems with image guidance to precisely target lesion
Tissue is processed for [2]:
- Histopathology: H&E staining → assess mitosis, necrosis, microvascular proliferation, cellular atypia
- Immunohistochemistry: GFAP (astrocytic marker), synaptophysin (neuronal), EMA (meningioma), Ki-67 (proliferation index), CD20 (B-cell lymphoma)
- Molecular pathology (essential in WHO CNS5, 2021):
- IDH1/2 mutation status (most important prognostic marker in diffuse gliomas)
- 1p/19q co-deletion (defines oligodendroglioma)
- MGMT promoter methylation (predicts temozolomide response in GBM)
- H3K27M mutation (defines diffuse midline glioma)
- ATRX loss (associated with IDH-mutant astrocytoma)
- BRAF V600E (seen in pleomorphic xanthoastrocytoma, some paediatric gliomas — actionable target)
- TERT promoter mutation (associated with GBM)
Exam Pearl — When NOT to Biopsy/Resect First
CNS lymphoma: biopsy only — do NOT attempt resection. Surgery does not improve outcome and delays definitive chemotherapy. And critically, do NOT give steroids before biopsy — steroids cause acute lysis of lymphocytes → the tumour may "disappear" (ghost tumour) → markedly reduced diagnostic yield on biopsy [2].
A systemic malignancy screen should be performed if the clinical or radiological picture suggests metastatic disease [2]:
| Investigation | Purpose |
|---|---|
| CT chest / abdomen / pelvis with contrast | Detect primary malignancy (lung, colorectal, renal, etc.) |
| PET-CT (FDG-PET/CT) | Detect occult primary if unknown; staging of known cancer; distinguish tumour recurrence from radionecrosis |
| Tumour markers | PSA (prostate), AFP/β-hCG (germ cell tumours — especially for pineal region masses), CA-125, CEA, etc. depending on clinical context |
| Bone scan | If suspecting bony metastatic disease |
| Biopsy if diagnosis in doubt ± PET-CT if unknown primary [2] |
Step 7: Additional Investigations for Specific Scenarios
Hormonal investigation is mandatory for any sellar mass [4][5]:
| Suspected Tumour | Hormonal Investigation | Diagnostic Finding |
|---|---|---|
| Prolactinoma | Serum prolactin | ↑Serum prolactin > 200 ng/mL (usually > 10× ULN) [4][5] |
| GH-secreting adenoma (acromegaly) | Serum IGF-1 + OGTT with GH | ↑Serum IGF-1; GH NOT suppressible on OGTT (nadir > 1 ng/mL) [4][5] |
| ACTH-secreting adenoma (Cushing's disease) | 24-hour urinary free cortisol, late-night salivary cortisol, overnight dexamethasone suppression test | ↑ACTH + ↑cortisol; confirmed by ≥2 diagnostic tests [4][5] |
| TSH-secreting adenoma | TSH + free T4 | ↑TSH with ↑fT4 (inappropriate TSH secretion) [4][5] |
| Gonadotroph tumour | FSH, LH, α-subunit | Seldom hypersecretes clinically; α-subunit may be elevated [4][5][10] |
| Non-functioning adenoma | Pituitary axis function panel (GH, IGF-1, cortisol, ACTH, TSH, fT4, FSH, LH, prolactin, testosterone/oestradiol) | Hypopituitarism: GH → FSH/LH → ACTH → TSH (order of loss) [4][5] |
Radiological diagnosis of pituitary tumours [4][5]:
- Contrast MRI: modality of choice — thin-cut coronal and sagittal T1W with gadolinium through the sella
- CT: better for calcified tumours (meningioma, craniopharyngioma) [4][5]
Stalk effect vs prolactinoma: If prolactin is mildly elevated ( < 100 ng/mL) with a large sellar mass, this likely represents "stalk effect" (loss of dopaminergic inhibition) rather than a true prolactinoma (where prolactin is usually > 200 ng/mL and correlates with tumour size).
Visual assessment: Formal visual field testing (Humphrey or Goldmann perimetry) should be performed for any sellar mass near the optic chiasm to document visual field defects and guide treatment urgency.
- Imaging: hyperdensity (acute blood) in pituitary region on CT [2]; MRI shows haemorrhage in the sella
- Emergency hormonal assessment: cortisol (adrenal crisis is the immediate threat to life)
| Tumour Type | Key Investigations | Key Findings |
|---|---|---|
| GBM | MRI (T1 + Gd, T2, FLAIR, DWI), fMRI/DTI pre-op, histology + molecular (IDH, MGMT) | Heterogeneous enhancement ± central necrosis, butterfly lesion, IDH-wildtype, MGMT methylation predicts TMZ response |
| Low-grade glioma | MRI (T2, FLAIR), consider MRS, histology + molecular (IDH, 1p/19q) | Non-enhancing T2-bright, IDH-mutant = better prognosis, 1p/19q co-deleted = oligodendroglioma |
| Primary CNS lymphoma | MRI (DWI — restricted), stereotactic biopsy (NO steroids before biopsy) [2], HIV test, slit-lamp exam | Periventricular, DWI restriction, homogeneous enhancement, CD20+, may be EBV-driven |
| Brain metastases | MRI brain, CT CAP, PET-CT, tumour markers, biopsy if diagnosis in doubt [2] | Multiple enhancing lesions at grey-white junction, large oedema relative to size |
| Meningioma | CT (calcification, hyperostosis), MRI (dural tail, homogeneous enhancement) | Extra-axial, dural-based, well-circumscribed, homogeneous enhancement, dural tail [2][7] |
| Pituitary adenoma | Contrast MRI (modality of choice), pituitary hormone panel, visual fields [4][5] | Enhancement on MRI; prolactinoma: PRL > 200 ng/mL; acromegaly: ↑IGF-1, non-suppressible GH on OGTT; Cushing's: ↑ACTH + ↑cortisol [4][5] |
| Craniopharyngioma | CT (calcification visible in 50%), MRI, hormone panel, visual fields [4][5] | Cystic + solid, calcified, suprasellar, T1-bright cyst fluid |
| Vestibular schwannoma | Pure tone audiometry (95% abnormal), MRI with Gd [2] | CPA mass expanding IAM, enhancement, asymmetric SNHL |
| Pineal tumour | MRI, serum AFP/β-hCG/PLAP, CSF markers, biopsy only (resection dangerous) [2] | Obstructive hydrocephalus, Parinaud's syndrome, elevated germ cell markers |
This distinction is one of the most important skills in neuroradiology [7]:
| Feature | Intra-axial | Extra-axial |
|---|---|---|
| Definition | Within the brain parenchyma | Outside the brain parenchyma (meninges, skull, etc.) |
| Key sign | Claw sign: parenchyma extends around the mass [7] | CSF cleft: rim of CSF between lesion and brain [7] |
| Oedema | Perilesional oedema common [7] | Less oedema (unless very large) |
| Other features | May be demonstrated by multiplanar reformatting [7] | Widening of adjacent CSF spaces; intervening pial vessels; intervening cortex between mass and white matter; dural tail sign and hyperostosis (meningioma) [7] |
| Examples | Glioma, metastasis, lymphoma, abscess | Meningioma, schwannoma, epidermoid cyst |
A systematic approach to reading a CT brain in the context of a suspected brain tumour:
| Structure | What to Look For | Significance |
|---|---|---|
| Ventricular system | Size, position, compression of horns (frontal, temporal, occipital) [5] | Hydrocephalus (dilated) or compression (effaced) |
| Skull | Hyperostosis, osteolytic lesions, fractures [5] | Hyperostosis → meningioma invasion; osteolytic → metastasis or myeloma |
| Signs of raised ICP | Brain swelling (effacement of sulci, Sylvian fissures), obliteration of basal cisterns (very suggestive), mass effect (midline shift, ventricular compression) [5] | Urgent intervention may be needed |
| Tissue density | Hyperdensity (acute blood, calcification), hypodensity (oedema, infarct, tumour), mixed density (tumour with haemorrhage/necrosis) [5] | Guides differential |
| Enhancement pattern | Homogeneous, ring, heterogeneous, non-enhancing | Narrows tumour differential (see table above) |
| Multiplicity | Single vs multiple | Multiple → metastases, lymphoma, abscess, granuloma [5] |
Skull X-ray is seldom done nowadays due to low sensitivity and specificity [2], but findings that may appear on exams include:
- Pituitary fossa erosion (focal bone erosion) → pituitary adenoma [2]
- Hyperostosis (focal bone thickening) → meningioma invasion [2]
- Abnormal calcification → meningioma, craniopharyngioma, aneurysm wall [2]
- Midline shift evident by displacement of calcified pineal gland [2]
- Signs of raised ICP showing erosion of posterior clinoids [2]
- Expansion of internal acoustic meatus → vestibular schwannoma
- Double-flooring of sella turcica → asymmetrical pituitary adenoma [4][5]
High Yield Summary — Diagnosis of Brain Tumours
- There are no formal diagnostic criteria for brain tumours — diagnosis is based on clinical suspicion → neuroimaging → tissue diagnosis.
- CT brain ± contrast is first-line in the acute/emergency setting; MRI with gadolinium is the gold standard for characterisation.
- Normal brain does NOT enhance on CT/MRI — enhancement means BBB disruption (high-grade tumour, inflammation) or extra-BBB location (meningioma).
- MRI pattern recognition is essential: GBM = heterogeneous enhancement + necrosis; low-grade glioma = non-enhancing T2-bright; lymphoma = periventricular + DWI restriction; meningioma = dural-based + dural tail + homogeneous enhancement; metastasis = multiple, grey-white junction, disproportionate oedema.
- DWI is the key differentiator between abscess (restricted) and necrotic tumour (facilitated).
- Tissue diagnosis is mandatory — by stereotactic biopsy or surgical resection. WHO CNS5 requires molecular profiling (IDH, 1p/19q, MGMT, H3K27M).
- CNS lymphoma: biopsy only, NO steroids before biopsy (ghost tumour phenomenon).
- Pituitary tumours: contrast MRI is modality of choice; CT better for calcification; full hormone panel + visual fields mandatory.
- fMRI and DTI are for pre-operative planning — mapping eloquent cortex and white matter tracts.
- Systemic malignancy screen (CT CAP, PET-CT) if metastatic disease suspected.
Active Recall — Diagnostic Criteria, Algorithm, and Investigations for Brain Tumours
References
[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf [2] Senior notes: Ryan Ho Neurology.pdf (Section 8.3 Intracranial Tumours, pp. 161–167) [3] Senior notes: maxim.md (Section 5.5 Brain tumours — Investigations) [4] Senior notes: Ryan Ho Endocrine.pdf (pp. 106–107 — Pituitary Tumour) [5] Senior notes: Ryan Ho Fundamentals.pdf (pp. 441–442, 472 — Pituitary Tumour, CT Brain) [7] Senior notes: Ryan Ho Radiology.pdf (p. 23 — Intracranial Tumours, intra vs extra-axial) [10] Senior notes: felixlai.md (Pituitary adenoma — Classification, Differential diagnosis of sellar mass) [13] Senior notes: Ryan Ho Diagnostic Radiology.pdf (pp. 39–40 — CT interpretation) [14] Senior notes: Ryan Ho Radiology.pdf (p. 17 — Choice of Modality)
Management of Brain Tumours
Before diving into specific treatment modalities, let's establish the overarching philosophy. Managing brain tumours is fundamentally different from managing extracranial malignancies because:
- The brain is an unforgiving organ — even small amounts of collateral damage during treatment can produce devastating, permanent neurological deficits.
- "Resection margin" as understood in general surgery (achieving clear margins with 1–2 cm of normal tissue) is difficult in neurosurgery [1] — you cannot simply cut away 2 cm of normal brain around a tumour in the motor cortex.
- Some tumours are better treated without surgery at all (e.g., CNS lymphoma → biopsy only; prolactinoma → medical therapy first).
Principles of brain tumour management [1]:
- Aim at cure if feasible
- Preserve life
- Preserve function
- Preserve personhood
- Maximise quality of life
- Do not treat the scan — i.e., the presence of an abnormality on imaging alone does not mandate intervention; clinical context matters
Treatment options for brain tumours [1][2]:
- General medication therapy
- Surgical biopsy and resection
- Radiation therapy
- Chemotherapy
- Target therapy
- Immunotherapy
A. Medical Therapy
Medical therapy in brain tumours serves two main roles: (1) symptom control (oedema, seizures) and (2) definitive treatment (in specific tumour types like prolactinoma and CNS lymphoma).
Steroids (e.g., dexamethasone) [1][2]:
Mechanism: Dexamethasone reduces vasogenic oedema by restoring blood–brain barrier (BBB) integrity. It decreases capillary permeability and reduces VEGF expression by tumour cells. The result is a rapid decrease in peri-tumoural oedema → reduction in mass effect → improvement in neurological symptoms, sometimes dramatically within hours.
Why dexamethasone specifically? Dexamethasone is preferred over other corticosteroids because:
- It has minimal mineralocorticoid activity (does not cause salt/water retention → less cerebral oedema exacerbation)
- Long half-life (~36 hours) → convenient dosing
- High glucocorticoid potency
Dosing [2]:
- PO (or IV if severe) dexamethasone 10 mg loading then 4 mg Q4h or 8 mg BD
Indications [1]:
- ↓ Cerebral oedema and relieve symptoms
- Peri-operative use (to reduce surgical swelling)
- Palliation (in inoperable tumours)
- Raised ICP due to CNS infections and brain tumours [15]
Contraindications/Cautions [1][2]:
- Exclude infection first — steroids will immunosuppress and worsen CNS infections (e.g., abscess, TB) [1]
- C/I: suspected CNS lymphoma → steroid causes acute lysis of lymphocytes → ↓ diagnostic yield on biopsy (the "ghost tumour" phenomenon) [2]
- Avoid in cerebral infarction or haemorrhage — steroids worsen outcomes in stroke [15]
- DM (diabetes mellitus) — glucocorticoid-induced hyperglycaemia
- Immunosuppression — increased infection risk
- Peptic ulcer — need PPI prophylaxis
- Proximal myopathy (chronic use), osteoporosis, Cushingoid features, psychosis
Clinical Pearl — Dexamethasone and Brain Tumours
Think of dexamethasone as a "bridge therapy" — it buys time by reducing oedema and improving symptoms while you plan definitive treatment (surgery, chemoRT). It does NOT treat the tumour itself (except in lymphoma, where it paradoxically destroys the tumour cells — which is exactly why you must NOT give it before biopsy in suspected lymphoma).
Anticonvulsants (e.g., phenytoin, levetiracetam) [1][2]:
Mechanism: Brain tumours cause seizures via peri-tumoural cortical irritation (glutamate excitotoxicity, ionic imbalances, oedema). Anticonvulsants stabilise neuronal membranes or modulate neurotransmitter activity.
Levetiracetam (Keppra) is the most commonly used in the brain tumour setting [2]:
- Favourable drug interaction profile (does not induce hepatic CYP450 enzymes, unlike phenytoin or carbamazepine — important because chemotherapy agents like temozolomide are hepatically metabolised)
- Fewer side effects than older agents
- No need for therapeutic drug monitoring
- Prophylaxis or treatment (if patient has already had a seizure)
- Not for infratentorial lesions [1] — because the cerebellar cortex is inhibitory and does not generate seizures [2]
- Usually not for primary prophylaxis in patients who have never had a seizure [2] — evidence does not support routine prophylactic AEDs in brain tumour patients without prior seizures (AAN guidelines)
Exceptions where primary prophylaxis may be considered:
- Peri-operative period (perioperative seizure prophylaxis for supratentorial craniotomy — typically for 7 days post-op)
- Melanoma brain metastases (higher seizure risk)
Tranexamic acid — perioperatively to reduce bleeding [1].
Tranexamic acid (from Latin trans = across + amine + acid) is an antifibrinolytic — it inhibits plasminogen activation, preventing the breakdown of fibrin clots. Used during craniotomy to reduce intraoperative blood loss.
For acute raised ICP due to brain tumour with mass effect [15]:
| Agent | Mechanism | Key Points |
|---|---|---|
| Mannitol | Osmotic diuretic — draws free water from brain tissue into circulation | Onset 15 min, duration 6 hours. Needs Foley catheter. Avoid in renal failure, hypernatraemia, serum osmolality > 320 mOsm/L [15] |
| Hypertonic saline (3% NaCl) | Similar osmotic mechanism to mannitol | Alternative to mannitol; may be preferred in hypovolaemic patients |
| Hyperventilation | Lowers PaCO₂ → cerebral vasoconstriction → ↓ intracranial blood volume → ↓ ICP | Target PaCO₂ 3.0–3.5 kPa (26–30 mmHg). Only as emergency temporising measure — rebound effect if prolonged [15] |
B. Surgery
Surgery is the cornerstone of brain tumour management for most tumour types — it provides both tissue diagnosis and cytoreduction.
Principles of brain tumour surgery [1]:
- Obtain histological diagnosis
- Maximal safe removal — remove as much tumour as possible without causing new neurological deficits
- Preserve life
- Preserve function
- "Resection margin" is difficult in neurosurgery — unlike extracranial surgery, you cannot take wide margins around brain tumours because surrounding tissue is functional [1]
Key surgical decisions [1]:
- Whether/When to resect?
- How to resect?
- How much to resect?
Spectrum of surgical intervention by tumour type [1]:
| Tumour Type | Surgical Approach | Rationale |
|---|---|---|
| CNS lymphoma | Biopsy only [1] | Surgery does not improve survival; definitive treatment is chemotherapy (high-dose methotrexate) |
| Meningioma | Total resection [1] | Well-circumscribed, extra-axial; complete resection is often curative |
| Glioma in eloquent area | Subtotal removal [1] | Complete resection would cause unacceptable neurological deficit; debulk what is safely possible |
| Non-functioning incidentaloma | Observe [1] | Small, asymptomatic, not causing mass effect — serial imaging surveillance |
| Approach | Description | Main Use |
|---|---|---|
| Craniotomy | Flap of bone cut and reflected, then replaced after surgery | Main approach for tumour resection (convexity, parasagittal) |
| Burr hole | Small hole drilled in skull | Often for stereotactic biopsy (e.g., deep-seated tumours, lymphoma) |
| Craniectomy | Bone is removed and NOT replaced | Decompressive craniectomy for severe brain swelling |
| Transsphenoidal (transnasal or sublabial) | Access through sphenoid sinus to sella turcica | Pituitary adenomas — route of choice [4][5] |
| Transoral | Access through mouth | Anterior foramen magnum/upper cervical lesions |
Modern neurosurgery employs several adjunctive technologies to maximise safe resection:
| Technique | How It Works | Why It Helps |
|---|---|---|
| Frameless stereotaxy (image-guided surgery) | Small skull markers allow intraoperative localisation of a handheld probe relative to pre-operative imaging [2] | Surgeon can see in real-time where the probe tip is relative to the tumour and critical structures (mapped by fMRI/DTI) |
| Evoked potentials | Detect cortical electrical response to sensory stimuli, or peripheral motor response to cortical electrical stimulation [2] | Real-time functional monitoring — warns the surgeon if the resection approaches a functionally important tract |
| Awake craniotomy | Patient is awake during part of the surgery; intraoperative electrical stimulation of cortex → observe speech/motor response [2] | Maps speech cortex → guides resection to avoid affecting speech [2]. Used when tumour is in or near Broca's/Wernicke's area |
| 5-ALA-guided resection | 5-aminolevulinic acid (5-ALA) is a precursor in haeme/porphyrin biosynthesis that accumulates in tumour cells → intraoperative UV light → tumour fluoresces a different colour [2] | Allows visual distinction between tumour (fluorescent pink) and normal brain (blue) → more complete resection |
Surgical Indications by Tumour Type
Surgery ± adjuvant radiotherapy if [2]:
- Solitary operable lesion (esp if large, symptomatic, oedematous)
- Young patient with good function and reasonable life expectancy
- Stable systemic disease, esp if effective systemic Tx available (e.g., hormonal Tx in Ca breast, EGFR/ALK TKI in NSCLC, immunotherapy in melanoma)
Indications for resecting brain metastasis [1] — this is essential knowledge:
- Tissue diagnosis needed (especially if solitary lesion and no known primary)
- Large symptomatic lesion causing significant mass effect
- Accessible location with acceptable surgical risk
Surgery — indication: all functioning tumours (except prolactinoma) and all macroadenomas [4]:
Surgical approach [4]:
- Trans-sphenoidal (route of choice): transnasal endoscopic or sublabial
- Unresectable if tumour compresses/abuts optic pathway or invades cavernous sinus → maximal debulking instead [4]
- Transfrontal if very large suprasellar extension or severe chiasmal compression [4]
Advantages [4]:
- Rapid ↓ secretion and ↓ size → remission > 85% for microadenomas, 40–50% for macroadenomas
Disadvantages / Complications [4][10]:
- Residual or recurrence esp if macroadenomas (2–8%) [4]
- Hypopituitarism — may require lifelong hormone replacement
- Diabetes insipidus (DI) — due to surgical injury to stalk or posterior pituitary (may be transient) [4]
- CSF leakage (rhinorrhoea) — occurs in 0.5–4%; failure to stop increases risk of meningitis [10]
- Vision loss — if optic nerve/chiasm damaged during surgery
- Vascular injury and CVA — internal carotid artery is immediately lateral in the cavernous sinus
- Intracranial haemorrhage
- ENT symptoms — nasal congestion, crusting (transsphenoidal approach goes through nasal cavity)
- Meningitis — if CSF leak not controlled
- Mortality — very rare in experienced centres
Follow-up [4]:
- Monitor pituitary function for 4–6 weeks for hypopituitarism
- Post-op imaging at 1 year, 2 years, 5 years, 10 years for any recurrence
Exam Essential — Complications of Transsphenoidal Surgery
Essential knowledge: treatment principles for pituitary adenoma and complications of transsphenoidal surgery [1]. The three most commonly tested complications are: (1) Diabetes insipidus (stalk injury → loss of ADH), (2) CSF leak/meningitis (breach of sellar floor/dura), and (3) Hypopituitarism (damage to normal pituitary tissue). Always remember that DI can be transient (stalk bruising) or permanent (stalk transection).
| Complication | Mechanism |
|---|---|
| Haemorrhage | Intraoperative or post-operative bleeding into tumour bed |
| Brain swelling | Reactive oedema, manipulation injury |
| Hydrocephalus | CSF pathway disruption, post-operative blood in ventricles |
| Seizure | Cortical irritation from surgical manipulation |
| New neurological deficit | Damage to eloquent cortex or tracts during resection |
| Infections | Wound infection, meningitis, abscess |
Rehabilitation is a critical component of post-operative care [2]:
- Physiotherapy, occupational therapy, speech therapy, clinical psychology
C. Radiotherapy
Radiation therapy for brain tumours aims to deliver a high treatment dose to the tumour bed while minimising radiation to normal tissue — a balance between treatment efficacy and side effects [1].
| Modality | Mechanism | Key Features |
|---|---|---|
| External beam radiotherapy (ERT/EBRT) | Standard radiotherapy with parallel rays [2] | Delivered in fractionated doses (e.g., 30 fractions over 6 weeks). Used for gliomas, post-operative adjuvant treatment. |
| Stereotactic radiosurgery (SRS) | Focused radiation beams converge onto tumour [1] | Single high-dose fraction (or hypofractionated). Extremely precise targeting. Key modalities: X-knife (linear accelerator), Gamma knife (gamma source) [1][2]. |
| Cyberknife | Uses real-time imaging and moves to adjust to movement [1] | Allows treatment of moving targets (e.g., lung, liver metastases) — less relevant for brain (brain doesn't move) but conceptually important. |
| Interstitial brachytherapy | Radioactive source placed directly within brain tissue [2] | Rarely used. |
| Whole brain radiotherapy (WBRT) | Treats the entire brain | Historically used for brain metastases to treat micrometastases. Falling out of favour due to severe neurocognitive side effects. |
| Tumour | RT Role | Specific Details |
|---|---|---|
| Brain metastases | Adjuvant after surgery (SRS preferred) or primary for inoperable | SRS: as alternative to surgery if small/inoperable; WBRT: if not eligible to SRS/surgery, e.g., multiple bulky tumours [2] |
| Malignant glioma (WHO III–IV) | Chemoirradiation with temozolomide (TMZ) — standard therapy [1] | Concomitant TMZ + ERT, then adjuvant TMZ (Stupp protocol) [1][2] |
| Meningioma | Adjuvant after subtotal resection, or primary if inoperable | Radiosurgery or wide-field external RT as adjunct [2] |
| Pituitary adenoma | Usually as adjunct to surgery (for residual tumours) [4] | Conventional EBRT or SRS by gamma/X-knife [4]. NOT used if < 5 mm from optic chiasm (risk of optic neuropathy) [4]. Delayed effect on secretion → not used acutely [4]. Higher incidence of hypopituitarism (up to 80%) [4]. |
| Vestibular schwannoma | Alternative to surgery | Surgery/Radiosurgery [1] — SRS increasingly used for small-to-medium tumours |
| Pineal tumours | Chemo or radiotherapy (mainstay) [2] | Surgical resection is dangerous → biopsy only; germ cell tumours are exquisitely radiosensitive |
| Medulloblastoma | Craniospinal irradiation + chemotherapy | Mandatory post-surgical adjuvant due to high CSF dissemination risk |
| Acute Complications | Chronic Complications |
|---|---|
| Fatigue, loss of appetite (very common) | Radionecrosis: typically 1–3 years after RT — S/S: focal deficit near original tumour site, raised ICP. Mx: steroids. |
| Headache: typically mild (cf severe headache in tumour progression) | Neurocognitive deficits — WBRT: ↓ learning, memory 3 months – 1 year, long-term ↓↓ QoL [2]. Partial brain RT: significantly less risk. |
| Nausea/vomiting | Vasculopathy and ischaemic stroke |
| Initial worsening of prior neurological S/S — due to reactive swelling → should pre-treat with steroids | Hypopituitarism: up to 80% — low threshold to screen post-RT [2] |
| Radiation dermatitis and alopecia | Ocular toxicity: cataract, optic neuropathy, dry eye |
| Acute encephalopathy (uncommon but severe) — S/S: severe headache, nausea, drowsiness, fever, focal neuro. Uncommon except at very high dose. | Ototoxicity (SN hearing loss) |
| Secondary brain tumours (long-term risk) |
WBRT vs SRS — The Paradigm Shift
The trend in 2025–2026 is to avoid WBRT whenever possible due to devastating neurocognitive toxicity. SRS is now more preferred [2] — it can treat multiple lesions without the diffuse brain damage of WBRT. WBRT is reserved for patients with numerous bulky metastases who are not candidates for SRS or surgery, or as prophylactic cranial irradiation (PCI) in SCLC [16].
D. Chemotherapy and Systemic Therapy
Treatment for malignant glioma (WHO III or IV) [1]:
- Maximal safe surgical removal where feasible
- Chemoirradiation with temozolomide (TMZ)
- Standard therapy
- TMZ is an alkylating agent — it adds alkyl groups to DNA bases (particularly O6-guanine), causing DNA mismatch → triggers apoptosis in tumour cells
- Concomitant TMZ + ERT, then adjuvant TMZ [1] — this is the Stupp protocol (TMZ given daily during 6 weeks of RT, then 6 cycles of adjuvant TMZ, 5 days per 28-day cycle) [2]
- Anti-angiogenesis agents — e.g., bevacizumab [1] — a monoclonal antibody against VEGF (vascular endothelial growth factor). By blocking VEGF, it reduces tumour angiogenesis and vasogenic oedema. Used as second-line therapy or at recurrence.
- Tumour Treating Fields (TTF) [1] — a novel modality using alternating electric fields delivered via adhesive transducer arrays on the shaved scalp. The electric fields disrupt mitotic spindle formation in dividing tumour cells, selectively inhibiting rapidly dividing cells. Approved as adjuvant treatment alongside TMZ.
MGMT promoter methylation — a critical molecular biomarker:
- MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that removes alkyl groups from O6-guanine — directly reversing the damage caused by TMZ.
- If the MGMT promoter is methylated (silenced), the tumour cannot repair TMZ-induced DNA damage → better response to TMZ and improved survival.
- If MGMT is unmethylated → the tumour repairs TMZ damage efficiently → poorer response.
Primary CNS lymphoma is treated with high-dose methotrexate (HD-MTX)-based chemotherapy (typically ≥ 3.5 g/m²) ± whole brain RT:
- Methotrexate at standard doses does not cross the BBB — high doses are required to achieve therapeutic CNS concentrations.
- RT alone leads to high relapse rates and neurocognitive toxicity — combination chemo-RT improves outcomes.
- In elderly patients, HD-MTX alone (without RT) may be preferred to avoid RT-induced cognitive decline.
| Tumour | Chemotherapy | Key Points |
|---|---|---|
| Medulloblastoma | Cisplatin/carboplatin + vincristine + cyclophosphamide ± lomustine | Standard post-surgical adjuvant combined with craniospinal irradiation |
| Oligodendroglioma | PCV (procarbazine, lomustine/CCNU, vincristine) or TMZ | 1p/19q co-deleted oligodendrogliomas are chemosensitive → excellent prognosis with combined RT + PCV |
| Germ cell tumours | Cisplatin-based regimens | Highly chemo- and radiosensitive |
Target therapy and immunotherapy are increasingly used in brain tumours [1]:
| Agent | Target | Tumour Type | Mechanism |
|---|---|---|---|
| Bevacizumab | VEGF | GBM (second-line) [1] | Anti-angiogenesis → reduces tumour vasculature and oedema |
| EGFR TKIs (erlotinib, osimertinib) | EGFR | Brain metastases from EGFR-mutant NSCLC | BBB-penetrant TKIs target driver mutation; important in Hong Kong where EGFR-mutant NSCLC is common |
| ALK inhibitors (alectinib, lorlatinib) | ALK | Brain metastases from ALK-rearranged NSCLC | Excellent CNS penetration |
| Immune checkpoint inhibitors (nivolumab, pembrolizumab) | PD-1/PD-L1 | Brain metastases from melanoma, NSCLC | Activate anti-tumour immune response; less effective in primary brain tumours due to immunosuppressive tumour microenvironment |
| Everolimus | mTOR | SEGA in tuberous sclerosis | Directly targets mTOR pathway upregulated in TSC-related tumours |
Approach to management [4][5]:
- Observe if non-functional microadenoma [4][5]
- Treat if functional or macroadenoma or mass effect [4][5]
| Adenoma Type | First-line Treatment | Rationale |
|---|---|---|
| Prolactinoma | Medical Tx: dopamine agonist (first-line only for prolactinoma) [4][5] | Dopamine tonically inhibits prolactin secretion. Dopamine agonists (cabergoline > bromocriptine) shrink the tumour and normalise prolactin in 70–100% of cases [10]. Cabergoline preferred due to higher efficacy (70–100% success rate) and favourable side effect profile [10]. |
| GH-secreting adenoma | Surgery first-line: transsphenoidal [4] | Medical therapy (somatostatin analogues — octreotide, lanreotide; GH receptor antagonist — pegvisomant) used if surgery fails or as bridge |
| ACTH-secreting adenoma | Surgery first-line: transsphenoidal [4] | Medical therapy (ketoconazole, osilodrostat, pasireotide) as second-line |
| TSH-secreting adenoma | Surgery first-line [4] | Somatostatin analogues (octreotide) as adjunct |
| Non-functioning microadenoma | Observe [4][5] | No mass effect, no hormonal hypersecretion → serial MRI and hormone panels |
| Non-functioning macroadenoma / mass effect | Surgery [4][5] | Causing visual loss, hypopituitarism, or progressive growth |
Radiotherapy for pituitary adenomas [4]:
- Usually as adjunct to surgery (for residual tumours)
- May be primary therapy for macroprolactinoma (if refractory to medical therapy and surgery)
- Modalities: conventional EBRT or stereotactic radiosurgery (SRS) by gamma/X-knife [4]
- Advantages: restrains tumour growth
- Disadvantages:
Surgery/Radiosurgery [1]:
| Scenario | Management |
|---|---|
| Small tumour, elderly patient, minimal symptoms, limited hearing loss | Observation with serial MRI [2] |
| Symptomatic, growing, or large tumour | Surgery (microsurgical excision via retrosigmoid, translabyrinthine, or middle fossa approach) |
| Small-to-medium tumour, patient preference or surgical risk | Radiosurgery (SRS) — effective tumour control rates > 90% |
| Bilateral vestibular schwannomas (NF2) [1] | Requires MDT approach; hearing preservation surgery or radiosurgery; consider bevacizumab |
G. Management of Specific Emergencies
Pituitary apoplexy — acute visual loss, hormonal crisis, SAH [1]:
Management [2]:
- Steroid cover — hydrocortisone 100 mg IV stat then 50 mg Q8h (adrenal crisis is the immediate life-threat)
- Urgent surgical decompression (transsphenoidal) if:
- Signs of raised ICP
- Change in conscious state
- Evidence of compression on neighbouring structures (progressive visual loss, CN III palsy)
- If haemodynamically stable with mild symptoms → conservative management with close monitoring may be acceptable
- External ventricular drain (EVD): Catheter placed into lateral ventricle → drains CSF externally → immediate ICP reduction [15]
- CSF shunting (VP shunt): Long-term solution for chronic hydrocephalus [2]
- Endoscopic third ventriculostomy (ETV): Puncture floor of 3rd ventricle → bypasses obstruction → particularly useful for obstructive hydrocephalus from pineal region or posterior fossa tumours [2]
- ABC assessment and stabilisation
- Dexamethasone IV + mannitol/hypertonic saline
- Emergency craniotomy/craniectomy for decompression
- EVD if hydrocephalus contributing
Management choice for brain metastases is based on prognosis as brain met often implies poor prognosis (survival ≤ 6 months) [2]:
- Dexamethasone + AED for symptomatic relief [2]
- Supportive care if poor functional status [2]
- Prognosis:
Supportive care encompasses:
- Pain management (WHO analgesic ladder)
- Antiemetics for tumour-related nausea/vomiting
- Physiotherapy, occupational therapy, speech therapy
- Clinical psychology and psychiatric support
- End-of-life care planning and hospice involvement
| Tumour | Surgery | Radiotherapy | Chemotherapy/Systemic | Other |
|---|---|---|---|---|
| Brain metastases | Solitary, operable, good prognosis | SRS (preferred) or WBRT | Systemic therapy based on primary (EGFR TKI, immunotherapy) | Dexamethasone + AED |
| GBM (WHO IV) | Maximal safe resection | ERT (concomitant with TMZ) | TMZ (Stupp protocol); bevacizumab 2nd line | TTF |
| Low-grade glioma | Resection if symptomatic/progressive | ± Adjuvant | ± TMZ/PCV (esp. 1p/19q co-deleted) | Watchful waiting if asymptomatic |
| Meningioma | Total resection (first-line) | SRS or EBRT as adjunct | Not standard | |
| CNS lymphoma | Biopsy only | ± WBRT | HD-MTX-based chemotherapy | No steroids before biopsy |
| Prolactinoma | Second-line (if refractory) | Adjunct | Dopamine agonist (cabergoline) = first-line | |
| Other pituitary adenomas | Transsphenoidal = first-line | Adjunct for residual | Medical therapy as second-line | |
| Vestibular schwannoma | Microsurgery if large/symptomatic | SRS | Bevacizumab (NF2) | Observation if small |
| Pineal tumours | Biopsy only | ChemoRT = mainstay | Cisplatin-based (germ cell) | ETV for hydrocephalus |
| Medulloblastoma | Maximal resection | Craniospinal irradiation | Adjuvant multi-agent chemo |
High Yield Summary — Management of Brain Tumours
- Treatment options: medical therapy, surgical biopsy/resection, radiation, chemotherapy, targeted therapy, immunotherapy [1].
- Principles: aim at cure if feasible; preserve life, function, personhood; maximise QoL; do not treat the scan [1].
- Dexamethasone: reduces vasogenic oedema via BBB restoration. C/I in suspected CNS lymphoma (ghost tumour) [1][2].
- Anticonvulsants: for treatment/secondary prophylaxis of seizures in supratentorial tumours. Not for infratentorial lesions. Usually NOT for primary prophylaxis [1][2].
- Surgery: maximal safe removal; resection margin concept does not apply. CNS lymphoma = biopsy only; meningioma = total resection; glioma in eloquent area = subtotal removal [1].
- Transsphenoidal surgery: route of choice for pituitary adenomas. Key complications: DI, CSF leak/meningitis, hypopituitarism [1][4].
- Radiosurgery (SRS): focused converging beams; size limit ~2.5–3 cm; now preferred over WBRT for metastases [1][2].
- Malignant glioma (Stupp protocol): maximal safe resection → concomitant TMZ + ERT → adjuvant TMZ [1][2].
- Prolactinoma: the ONLY pituitary adenoma where medical therapy (dopamine agonist) is first-line [4][5].
- MGMT methylation: predicts TMZ response in GBM — methylated = better prognosis.
- Pituitary apoplexy: steroid cover + urgent surgical decompression if deteriorating vision/consciousness [1][2].
- Brain metastases prognosis: untreated = 1 month; surgery + WBRT = 10–12 months [2].
Active Recall — Management of Brain Tumours
References
[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf [2] Senior notes: Ryan Ho Neurology.pdf (Section 8.3 Intracranial Tumours, pp. 163–167) [4] Senior notes: Ryan Ho Endocrine.pdf (pp. 107–108 — Pituitary adenoma management, surgery, RT) [5] Senior notes: Ryan Ho Fundamentals.pdf (pp. 441–442 — Pituitary Tumour management) [10] Senior notes: felixlai.md (Pituitary adenoma — surgical treatment, dopamine agonists) [15] Senior notes: felixlai.md (Treatment of increased ICP — mannitol, corticosteroids, hyperventilation, AEDs) [16] Senior notes: Ryan Ho Respiratory.pdf (p. 150 — Prophylactic cranial irradiation in SCLC)
Complications of Brain Tumours
Complications of brain tumours arise from three broad sources: the tumour itself (direct effects of mass expansion and invasion), the treatment (surgery, radiotherapy, chemotherapy), and secondary systemic effects (paraneoplastic phenomena, immobility-related complications). Let's work through each systematically, always tying the complication back to its underlying pathophysiology.
A. Complications of the Tumour Itself
This is the most feared complication of brain tumours and the most common cause of death.
Brain herniation due to tumour [1] — when a growing tumour creates an asymmetric pressure gradient, brain tissue shifts from a high-pressure compartment to a low-pressure one through rigid anatomical openings:
| Herniation Type | Mechanism | Clinical Consequence |
|---|---|---|
| Subfalcine (cingulate) | Cingulate gyrus herniates under falx cerebri | ACA compression → contralateral leg weakness; may kink ACA → infarction |
| Transtentorial (uncal) | Medial temporal lobe (uncus) herniates through tentorial notch | Ipsilateral CN III palsy (dilated fixed pupil), contralateral hemiparesis (cerebral peduncle compression), decreased consciousness (reticular activating system) |
| Central (downward) | Diencephalon descends through the tentorial notch symmetrically | Progressive: small reactive pupils → fixed dilated pupils → decerebrate posturing → death |
| Tonsillar | Cerebellar tonsils herniate through foramen magnum | Medullary compression → Cushing's triad (hypertension, bradycardia, irregular respiration) → cardiorespiratory arrest [2] |
| Upward (reverse) | Posterior fossa tumour pushes cerebellum upward through tentorial notch | Midbrain compression, aqueduct obstruction → worsening hydrocephalus |
Why is tonsillar herniation immediately lethal? The medulla contains the cardiovascular and respiratory centres. Compression or ischaemia of the medulla knocks out these vital centres, leading to apnoea and cardiac arrest within minutes.
Tumours in certain locations physically block CSF flow:
- Posterior fossa tumours (medulloblastoma, ependymoma, cerebellar astrocytoma) → block the 4th ventricle or cerebral aqueduct
- Pineal region tumours → compress the cerebral aqueduct → hydrocephalus with raised ICP [2]
- Colloid cyst of the 3rd ventricle → intermittent ball-valve obstruction of the foramen of Monro → sudden hydrocephalus → can cause sudden death
- Large suprasellar tumours (craniopharyngioma, pituitary macroadenoma) → may compress the 3rd ventricle from below
Communicating hydrocephalus can also occur from leptomeningeal carcinomatosis — tumour cells coating the meninges impair CSF absorption at the arachnoid granulations [3].
Seizures affect 50–80% of primary tumours and 10–20% of secondary tumours [2]. Seizures can occur as a presenting feature but also as a complication during the disease course:
- Status epilepticus — prolonged or recurrent seizure activity without recovery of consciousness between episodes. This is a medical emergency because sustained seizure activity causes excitotoxic neuronal death, hyperthermia, rhabdomyolysis, metabolic acidosis, and can be fatal.
- Post-ictal Todd's paralysis — transient focal weakness following a seizure that can be confused with tumour progression or stroke [3].
- Seizures are usually associated with slow-growing tumours that involve cortex (e.g., meningioma, low-grade glioma) [3] — because these tumours create a large penumbra of irritated but functioning cortex.
Tumour haemorrhage [1]:
Some brain tumours are prone to spontaneous haemorrhage, presenting acutely mimicking a stroke:
- Bleeding glioblastoma mimicking haemorrhagic stroke [1] — GBM has abnormal, fragile neovasculature (formed in response to VEGF) that is prone to rupture. The resulting intracerebral haemorrhage can be the first presentation of the tumour.
- Other tumours prone to haemorrhage: metastatic melanoma (characteristically haemorrhagic), choriocarcinoma, renal cell carcinoma metastases, oligodendroglioma (cortical location + fine branching capillary network).
- Pituitary apoplexy — acute haemorrhagic infarction ± SAH [1] — discussed below.
Clinical Pearl — Tumour Bleed vs Stroke
If a middle-aged patient presents with acute intracerebral haemorrhage in an atypical location (not the classic hypertensive sites of basal ganglia, thalamus, pons, cerebellum), or if the haematoma has unusual features on imaging (surrounding enhancing tissue, disproportionate oedema), always consider an underlying tumour as the cause. Follow-up contrast MRI after the haematoma has partially resolved is essential to unmask an occult tumour.
Pituitary apoplexy — an emergency!! [1][2]
Acute haemorrhagic infarction ± SAH [1]:
- Typically occurs in a pre-existing pituitary adenoma (often undiagnosed)
- Pathophysiology: The adenoma outgrows its blood supply → infarction → haemorrhagic transformation → sudden expansion of the sella contents
- Headache — excruciating, sudden onset (stretching of diaphragma sellae + meningeal irritation if SAH)
- Visual loss — acute compression of optic chiasm and/or optic nerves
- Diplopia — CN III palsy (lateral extension into cavernous sinus)
- Acute cortisol insufficiency requiring replacement [1] — this is the immediate threat to life. The haemorrhagic infarction destroys corticotroph cells → acute hypocortisolism → adrenal crisis (hypotension, shock, death if untreated)
- Coma — if severe
Critical management point [1]:
- Give cortisol before T4 — if you replace thyroid hormone before cortisol in a patient with pan-hypopituitarism, the increased metabolic rate from T4 accelerates cortisol catabolism → precipitates life-threatening adrenal crisis. Always replace cortisol first.
- Which can predispose to DI — once cortisol is replaced, previously masked diabetes insipidus may become apparent (cortisol is needed for free water excretion; without it, water retention masks DI) [1]
- Papilloedema from chronically raised ICP → if untreated, chronic papilloedema can cause permanent optic nerve damage [17]. The mechanism: sustained raised ICP → transmitted along optic nerve sheath → "tourniquet effect" on optic nerve axons → progressive axonal damage → optic atrophy → irreversible visual loss.
- Bitemporal hemianopia from chiasmal compression (pituitary adenoma, craniopharyngioma) — if not addressed, leads to progressive visual field loss and eventually blindness.
Tumours in the sellar/suprasellar region can cause:
- Hypopituitarism — classically GH → FSH/LH → ACTH → TSH (order of loss) [4][5] — the most vulnerable cells are compressed first as the tumour expands
- Cranial diabetes insipidus — stalk compression or hypothalamic infiltration → loss of ADH → polyuria, polydipsia. Classic association: craniopharyngioma, germinoma [5]
- Hypothalamic damage — from craniopharyngioma: hyperphagia, obesity, loss of thirst sensation, disturbance of temperature regulation [5]
Brain tumour patients (especially those with high-grade gliomas) have a markedly elevated risk of VTE:
- Deep vein thrombosis (DVT) and pulmonary embolism (PE)
- Mechanisms: (1) Tumour cells release tissue factor and other procoagulants → hypercoagulable state; (2) Immobility (from neurological deficits or post-operative bed rest); (3) Surgery and dexamethasone further increase VTE risk; (4) Brain tumours can directly cause DIC (release of procoagulant factors) [18]
- GBM patients have one of the highest VTE rates of any cancer — up to 20–30% over the disease course
- Management: Mechanical prophylaxis (TED stockings, intermittent pneumatic compression) for all; pharmacological prophylaxis (LMWH) post-operatively once haemostasis is secure
Certain tumours have a propensity to seed through the CSF pathways — "drop metastases":
- Medulloblastoma — the classic example; craniospinal irradiation is given to address this risk
- Ependymoma — can seed along ventricular system
- Pineoblastoma and intracranial germ cell tumours
- Leptomeningeal carcinomatosis — from brain metastases (especially breast, lung, melanoma) or primary CNS tumours spreading along the meninges → communicating hydrocephalus, multiple cranial nerve palsies, radiculopathies
- Extradural spinal metastases from primary brain tumours are rare (brain tumours rarely metastasise outside the CNS), but spinal cord compression from haematogenous metastases of the same primary cancer (e.g., lung CA) is very common [2].
- Sphincter dysfunction is a point of no return [19] — once established, neurological recovery after decompression is poor. This underscores the need for urgent investigation and treatment.
B. Complications of Treatment
Post-operative complications of craniotomy for brain tumour [2]:
| Complication | Mechanism | Clinical Features |
|---|---|---|
| Haemorrhage | Bleeding from tumour bed, disrupted vessels, or coagulopathy | Acute neurological deterioration post-op; requires urgent CT and may need re-operation |
| Brain swelling | Reactive oedema, manipulation of brain tissue, reperfusion injury | Worsening neurological function; managed with dexamethasone, elevation of head, mannitol |
| Hydrocephalus | Blood in ventricles blocking CSF flow, disruption of CSF pathways during surgery | Headache, drowsiness, vomiting; may require EVD or VP shunt |
| Seizure | Cortical irritation from surgical manipulation, blood products on cortex | New-onset seizure post-op; treat with anticonvulsants |
| New neurological deficit | Damage to eloquent cortex or white matter tracts during resection | Weakness, speech deficit, visual field loss (depends on location) |
| Infections | Wound infection, subdural empyema, meningitis, brain abscess | Fever, wound erythema/discharge, meningism, focal signs |
Rehabilitation is a critical part of post-operative care [2]:
- Physiotherapy, occupational therapy, speech therapy, clinical psychology
Complications of transsphenoidal surgery [1][2]:
This is essential knowledge as highlighted in the lecture slides [1]:
| Complication | Mechanism | Clinical Features and Key Points |
|---|---|---|
| Mortality | — | Very rare in experienced centres [1] |
| Hypopituitarism | Damage to normal pituitary tissue during adenoma removal | Can cause shock (cortisol deficiency) [1] — adrenal crisis is the most dangerous immediate endocrine complication. Monitor pituitary function for 4–6 weeks post-op [4] |
| Diabetes insipidus | Injury to the pituitary stalk or posterior pituitary → loss of ADH secretion | Polyuria, haemoconcentration [1]; may be transient (stalk bruising/oedema → recovers in days to weeks) or permanent (stalk transection). Triphasic response: DI → SIADH → permanent DI (reflects release of stored ADH from dying neurons) |
| CSF leakage and meningitis | Breach of sellar floor/dura creates a fistula between the subarachnoid space and the sphenoid sinus/nasal cavity | Beta-2-transferrin positive (in nasal fluid, confirming CSF origin), pneumocephalus (air enters cranial cavity through the fistula) [1]. If leak does not resolve with lumbar drainage, re-operation for repacking of the adenoma bed is needed. Failure to stop CSF leakage increases risk of meningitis [10] |
| Visual loss | Inadvertent damage to optic nerve/chiasm during surgery | Close monitoring post-op [1] — serial visual field testing in the first 24–48 hours |
| ENT symptoms | Transsphenoidal route traverses the nasal cavity and sphenoid sinus | Epistaxis (nosebleed), anosmia (loss of smell), sinusitis [1] |
| Vascular injury | Internal carotid artery lies immediately lateral in the cavernous sinus | Can cause catastrophic haemorrhage or CVA |
| Intracranial haemorrhage | Residual tumour bed bleeding or vascular injury | Headache, neurological deterioration |
Must-Know for Exams — Transsphenoidal Surgery Complications
The lecture explicitly lists these as essential knowledge [1]. For the exam, remember the mnemonic "MHD-CVE-I": Mortality (very rare), Hypopituitarism (can cause shock), Diabetes insipidus (polyuria, haemoconcentration), CSF leakage and meningitis (beta-2-transferrin, pneumocephalus), Visual loss (close monitoring), ENT symptoms (epistaxis, anosmia, sinusitis), Vascular Injury, Intracranial haemorrhage.
Complications of cranial irradiation [2]:
| Acute Complications | Chronic Complications |
|---|---|
| Fatigue, loss of appetite (very common) | Radionecrosis: typically 1–3 years after RT |
| Headache: typically mild (cf severe headache = tumour progression) | → S/S: focal neuro deficit near original tumour site, raised ICP |
| Nausea/vomiting | → Dx: very similar to high-grade tumour recurrence; MRI shows high oedema-to-enhancement ratio, improves spontaneously over time |
| Initial worsening of prior neurological S/S — due to reactive swelling → should pre-treat with steroids [2] | → Mx: symptomatic by steroids |
| Radiation dermatitis and alopecia | Neurocognitive deficits — WBRT: ↓ learning, memory 3 months – 1 year, long-term ↓↓ QoL [2]; partial brain RT: significantly less risk |
| Acute encephalopathy (uncommon but severe) — S/S: severe headache, nausea, drowsiness, fever, focal neuro; uncommon except at very high dose | Vasculopathy and ischaemic stroke |
| Hypopituitarism: up to 80% — low threshold to screen post-RT [2] | |
| Ocular toxicity: cataract, optic neuropathy, dry eye | |
| Ototoxicity (sensorineural hearing loss) | |
| Secondary brain tumours (long-term risk — typically meningiomas or gliomas developing years to decades later, especially in children) |
Radiation necrosis deserves special emphasis [1][2]:
- Radiation necrosis can occur after radiosurgery for brain metastases [1]
- It is the most diagnostically challenging chronic complication because it mimics tumour recurrence on imaging
- Distinguishing features on MRI: high oedema-to-enhancement volume ratio (more oedema than expected for the amount of enhancement), lack of clearly defined T2W lesion, improvement over time without treatment
- Advanced imaging: MR perfusion (low rCBV in necrosis vs high in tumour), MR spectroscopy (high lipid/lactate without elevated choline in necrosis), FDG-PET (hypometabolic in necrosis)
| Agent | Key Side Effects | Mechanism |
|---|---|---|
| Temozolomide | Myelosuppression (thrombocytopenia, lymphopenia), nausea, fatigue, hepatotoxicity | Alkylating agent damages DNA in all rapidly dividing cells (not just tumour cells) — bone marrow is especially vulnerable |
| High-dose methotrexate | Renal toxicity (crystalluria), mucositis, hepatotoxicity, myelosuppression, delayed leukoencephalopathy | MTX precipitates in renal tubules at acidic pH → aggressive hydration and urine alkalinisation required. Leukoencephalopathy is a chronic complication, especially when combined with WBRT |
| Bevacizumab | Hypertension, proteinuria, impaired wound healing, GI perforation, haemorrhage, thromboembolic events | Anti-VEGF → inhibits normal vascular maintenance → endothelial dysfunction |
| PCV regimen | Myelosuppression, peripheral neuropathy (vincristine), pulmonary fibrosis (lomustine) | Multiple agents, each with distinct toxicity profile |
When VP shunts or EVDs are placed for tumour-related hydrocephalus:
| Complication | Details |
|---|---|
| Shunt blockage (most common mechanical failure) | 80% proximal block, 10% valve, 10% distal block. Causes: choroid plexus, brain parenchyma, protein, tumour cells [3] |
| Shunt infection (most serious) | Pathogens: S. epidermidis, S. aureus. S/S: fever, lethargy, meningism, signs of raised ICP [3] |
| Overshunting | Postural headache (worsened standing/sitting, relieved lying down). Can lead to subdural haematoma (stretching of bridging veins) [3] |
| Distal catheter complications | Inguinal hernia, perforated abdominal viscus/peritonitis, intraperitoneal CSF-filled pseudocyst, tumour seeding [3] |
The last point — tumour seeding via VP shunt — is a unique and devastating complication. Tumour cells (especially from medulloblastoma, ependymoma, or germ cell tumours) can travel through the shunt catheter and seed the peritoneal cavity, creating extracranial metastases. This is one of the rare circumstances where brain tumours spread outside the CNS.
C. Electrolyte and Systemic Complications
Both can complicate brain tumours, brain surgery, and SAH (from pituitary apoplexy):
| Feature | SIADH | CSWS |
|---|---|---|
| Mechanism | Non-physiological ↑ADH → inappropriate water retention → dilutional hyponatraemia [18] | Idiopathic natriuresis + diuresis secondary to cerebral disorder [18] |
| Volume status | Euvolaemic hyponatraemia | Hypovolaemic hyponatraemia |
| Urine Na | > 20 mmol/L | > 20 mmol/L (both show inappropriate natriuresis) |
| Treatment | Fluid restriction (± hypertonic saline if severe) | Volume repletion with isotonic saline (opposite of SIADH!) |
CSWS is an important differential diagnosis of SIADH [18]:
- Both can follow head pathologies (cerebral surgery, head injury, SAH, cerebral tumour)
- CSWS results in renal Na loss → hypovolaemic hyponatraemia vs SIADH results in renal water retention → euvolaemic hyponatraemia (different treatment!) [18]
Clinical Pearl — SIADH vs CSWS
Getting the volume status wrong is dangerous: treating CSWS (hypovolaemic) with fluid restriction (the SIADH protocol) will worsen dehydration and potentially cause cerebral vasospasm. Always assess volume status clinically (JVP, skin turgor, mucous membranes, urine output trend, haematocrit) before deciding on treatment.
Brain tumours are a recognised cause of DIC [18] — tumour cells (especially GBM and other high-grade gliomas) release tissue factor and other procoagulant substances, activating the coagulation cascade systemically. This can present as:
- Bleeding tendency (consumption of clotting factors and platelets)
- Microangiopathic haemolytic anaemia (MAHA)
- Multi-organ dysfunction
Patients with brain tumours often have significant neurological deficits and reduced mobility:
- DVT and PE (as discussed above)
- Aspiration pneumonia — from dysphagia (bulbar palsy from brainstem tumours, reduced consciousness)
- Pressure sores — from immobility
- Urinary tract infections — from catheterisation or neurogenic bladder
- Contractures — from prolonged immobility + spasticity
- Depression and anxiety — very common in brain tumour patients (prevalence ~20–40%). Driven by both biological factors (tumour location, particularly frontal and temporal) and reactive factors (diagnosis of cancer, loss of function, fear of death).
- Cognitive decline — from the tumour itself, post-surgical deficits, and especially from WBRT (which causes progressive white matter damage → executive dysfunction, memory impairment, processing speed decline — WBRT: ↓ learning, memory 3 months – 1 year, long-term ↓↓ QoL [2]).
- Personality change — particularly with frontal lobe tumours (apathy, disinhibition, loss of social awareness). Can be mistaken for frontotemporal dementia [20].
Children treated for brain tumours face a unique burden of late effects:
- Neurocognitive deficits — from surgery + radiotherapy (especially craniospinal irradiation for medulloblastoma)
- Endocrine dysfunction — hypopituitarism: up to 80% after cranial irradiation [2]; growth hormone deficiency is the earliest and most common → short stature
- Secondary malignancies — radiation-induced meningiomas and gliomas can develop years to decades later
- Psychosocial impact — educational difficulties, employment challenges, social isolation
| Tumour | Prognosis |
|---|---|
| GBM (WHO Grade IV) | Life expectancy ~14 months with maximal treatment (Stupp protocol) [1]; median overall survival ~15–18 months; 5-year survival < 10% |
| Low-grade glioma (WHO Grade II, IDH-mutant) | Median survival 10–15 years; but risk of malignant transformation to higher grade |
| Meningioma (WHO Grade I) | Excellent prognosis after complete resection; recurrence affected by extent of resection and histology [2] |
| Vestibular schwannoma | Benign; excellent prognosis with surgery or radiosurgery; hearing preservation is the main concern |
| Brain metastases | Untreated: 1 month; Surgery + WBRT: ~10–12 months [2]; improving with targeted therapy and immunotherapy |
| Medulloblastoma | 5-year survival ~70–80% with multimodal treatment (surgery + craniospinal irradiation + chemotherapy); but significant long-term morbidity |
| Primary CNS lymphoma | Improving with HD-MTX-based regimens; median survival 3–5 years; immunocompromised patients have worse outcomes |
| Craniopharyngioma | Benign but significant morbidity from hypothalamic damage; recurrence common after subtotal resection [5] |
High Yield Summary — Complications of Brain Tumours
- Brain herniation is the most feared complication — tonsillar herniation causes immediate cardiorespiratory arrest via medullary compression.
- Tumour haemorrhage: GBM can mimic haemorrhagic stroke; melanoma, RCC, and choriocarcinoma metastases are characteristically haemorrhagic.
- Pituitary apoplexy: emergency — acute headache + visual loss + hormonal crisis (adrenal crisis is the immediate killer). Give cortisol before T4 to avoid precipitating adrenal crisis.
- Transsphenoidal surgery complications [1]: Mortality (very rare), Hypopituitarism (can cause shock), DI (polyuria, haemoconcentration), CSF leak and meningitis (beta-2-transferrin +ve, pneumocephalus), Visual loss, ENT symptoms, Vascular injury, ICH.
- Radionecrosis: mimics tumour recurrence 1–3 years post-RT; distinguish with perfusion MRI and spectroscopy; treat with steroids.
- WBRT causes devastating neurocognitive decline — SRS is now preferred to minimise this.
- Hypopituitarism after cranial irradiation: up to 80% — screen all patients.
- SIADH vs CSWS: both cause hyponatraemia after brain surgery/tumours, but SIADH = euvolaemic (fluid restrict) vs CSWS = hypovolaemic (volume replete). Getting it wrong is dangerous.
- DIC can complicate brain tumours (especially GBM) due to release of tissue factor.
- VP shunt complications: blockage (most common), infection (S. epidermidis, most serious), overshunting (subdural haematoma), tumour seeding (rare but devastating).
Active Recall — Complications of Brain Tumours
References
[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf [2] Senior notes: Ryan Ho Neurology.pdf (Section 8.3 Intracranial Tumours, pp. 161–167) [3] Senior notes: maxim.md (Section 5.5 Brain tumours — Complications of CSF shunt; Seizures) [4] Senior notes: Ryan Ho Endocrine.pdf (pp. 107–108 — Pituitary adenoma, surgery, follow-up) [5] Senior notes: Ryan Ho Fundamentals.pdf (pp. 441–442 — Craniopharyngioma, pituitary tumour) [10] Senior notes: felixlai.md (Pituitary adenoma — surgical complications, CSF leakage) [17] Senior notes: Ryan Ho Opthalmology.pdf (p. 90 — Papilloedema) [18] Senior notes: Ryan Ho Chemical Path.pdf (p. 10 — SIADH, CSWS); Ryan Ho Haemtology.pdf (p. 137 — DIC causes including brain tumours) [19] Lecture slides: GC 110. Paraplegia Spinal cord compression Transverse myelitis Spinal dysraphism Neuroimaging III Spinal Cord.pdf [20] Senior notes: Ryan Ho Psychiatry.pdf (p. 94 — FTD differential diagnosis including brain tumour)
High Yield Summary — Etiology & epidemiology
Primary vs metastatic: Metastases most common parenchymal brain tumours in adults — lung, breast, melanoma, kidney, colon, etc.
Age & site: Adults — mostly supratentorial (glioma, meningioma, mets). Children — posterior fossa (medulloblastoma, pilocytic astrocytoma, ependymoma).
WHO grade matters: Low-grade glioma vs high-grade (GBM IDH-wildtype aggressive) — guides resection, RT, chemo.
Clinical: Progressive neuro deficit, seizures, signs of ↑ICP, endocrine (sellar), cranial nerve (CPA).
Emergencies: Obstructive hydrocephalus, herniation, pituitary apoplexy — steroids + CSF diversion / surgical decompression as indicated.
High Yield Summary — Differential diagnosis
Ring-enhancing lesion DDx: High-grade glioma, metastasis, abscess (restricted diffusion often ↑), toxoplasma (immunosuppressed), demyelination (open ring — context).
Extra-axial: Meningioma (dural tail), vestibular schwannoma (IAC, CN VIII), pituitary adenoma (sella).
Posterior fossa DDx (child): Medulloblastoma (midline vermis), pilocytic astrocytoma (cyst with nodule), ependymoma (4th ventricle floor — extrudes through foramina classic teaching).
Pineal region: Germ cell tumour vs pineal parenchymal — markers (AFP, β-hCG); biopsy over aggressive resection if dangerous anatomy; ETV for hydrocephalus.
CNS lymphoma: Stereotactic biopsy + high-dose methotrexate regimen — do not standard surgical debulk like glioma.
High Yield Summary — Diagnosis
MRI with contrast is cornerstone; spectroscopy / perfusion adjuncts.
Dexamethasone reduces vasogenic oedema around tumour — symptomatic mass effect / perioperative — not cytotoxic therapy.
Biopsy vs resection: Goal = safe maximum resection when eloquent area permits; eloquent high-grade glioma may be debulking + chemoradiation; lymphoma = biopsy + chemo.
Metastases: SRS vs WBRT vs surgery based on number, size (typically ≤3 cm in oligometastatic selection), systemic status, pathology if solitary unknown primary.
Pituitary: Hormone panel, vision fields; prolactinoma — dopamine agonist first-line (no immediate surgery for many microprolactinomas).
Seizure prophylaxis: Often for presenting seizure or perioperative — not indefinite blanket if no seizures (follow guideline nuance).
High Yield Summary — Management themes
GBM (IDH-wildtype high-grade): Max safe resection → radiotherapy + temozolomide → adjuvant TMZ; options include TTFields, bevacizumab for recurrence (context).
Low-grade glioma: Surgery for progressive/symptomatic; observe some stable incidental small lesions.
Meningioma: Simpson grade resection goal; residual/atypical → radiosurgery/RT.
Vestibular schwannoma: Conservative if small elderly; microsurgery vs SRS if growing/symptomatic.
Mets: SRS, WBRT, surgical resection solitary good performer + controlled systemic disease; dexamethasone for oedema; anti-seizure as needed.
Paediatric medulloblastoma: Max safe resection + CSI + chemo regimen per protocol (high-level centre).
High Yield Summary — Complications
Surgery: Neurological deficit, bleeding, CSF leak, infection, venous thromboembolism.
Radiotherapy: Cognitive decline, radiation necrosis (can mimic recurrence), endocrine failure if skull base included.
Chemo: Myelosuppression, infection; PCP prophylaxis when indicated; lymphoma regimens — tumour lysis monitoring.
Tumour progression: Remote recurrence, leptomeningeal spread, hydrocephalus.
Immunosuppression on prolonged steroids: Infections, hyperglycaemia, proximal myopathy, psychosis.