• Primary brain tumours are rare: approximately 6/100,000 per year ^[2]
• Diffuse gliomas collectively account for ~25–30% of all primary brain tumours and ~80% of malignant primary brain tumours
• Astrocytoma, IDH-mutant specifically accounts for approximately 5–10% of all diffuse gliomas (far less common than IDH-wildtype glioblastoma)
• Peak incidence: 30–45 years — significantly younger than IDH-wildtype GBM (median ~65 years)
• Slight male predominance (M:F ≈ 1.2–1.4:1)
• IDH-mutant astrocytomas carry a significantly better prognosis than IDH-wildtype counterparts at every histological grade

• Brain tumours rank among the top 10 cancers in Hong Kong by incidence but are relatively uncommon overall
• The Hong Kong Cancer Registry does not sub-classify gliomas by IDH status at population level, but institutional data from Queen Mary Hospital and Prince of Wales Hospital increasingly use molecular classification
• No specific ethnic/geographic predisposition for IDH-mutant astrocytoma, though the IDH1 R132H mutation frequency is similar across ethnicities

• Grade 2 IDH-mutant astrocytoma: median age ~35–40 years
• Grade 3: median age ~38–45 years
• Grade 4: median age ~40–50 years
• Contrast with IDH-wildtype GBM: median age ~64 years

The younger age at presentation is partly because IDH mutations are thought to be early, "trunk" events in gliomagenesis — they arise in neural progenitor cells during a window of vulnerability in younger patients.

1. Ionising radiation exposure — the only firmly established environmental risk factor for gliomas

   • Prior cranial radiotherapy (e.g., for childhood leukaemia, tinea capitis) increases glioma risk 2–7× with a latency of 10–30 years
   • Mechanism: radiation induces DNA double-strand breaks → genomic instability → TP53 loss, IDH mutations, etc.

2. Hereditary/genetic cancer syndromes (rare, < 5% of cases):

"Turcot syndrome = familial colon cancer + brain tumours" ^[3]

3. Immune factors: immunosuppression (e.g., post-transplant, HIV) is associated with CNS lymphoma rather than astrocytoma — but is worth mentioning as a brain tumour risk factor broadly.

• Mobile phone use: extensive studies (INTERPHONE, Danish cohort, Million Women Study) have NOT demonstrated a convincing association
• Head trauma: no proven association
• Diet, smoking, alcohol: no consistent evidence for glioma

Astrocytes are the most abundant glial cells in the CNS. Understanding their normal function explains several features of astrocytomas:

• IDH-mutant astrocytomas preferentially arise in the frontal lobe (most common), followed by temporal and insular cortex
• They tend to involve the cerebral cortex and subcortical white matter diffusely
• They have a propensity for midline structures (e.g., corpus callosum, thalamus) in higher-grade disease

Focal neurological deficits depend on tumour location: ^[1][2]

• Frontal lobe: motor disturbances (convulsions, hemiparesis, aphasia), cognitive impairment (especially corpus callosum gliomas), impaired initiation and spontaneity, personality changes (apathy = dorsolateral PFC; disinhibition = orbitofrontal cortex), urinary incontinence, anosmia
• Temporal lobe: receptive dysphasia, contralateral superior homonymous quadrantanopia, complex partial seizures, impaired working memory
• Parietal lobe: sensory disturbances, contralateral inferior homonymous quadrantanopia, Gerstmann's syndrome (dominant side: agraphia, acalculia, finger agnosia, left-right disorientation), apraxia and contralateral hemineglect (non-dominant side)
• Occipital lobe: contralateral hemianopia (macular-sparing), visual hallucinations, cortical blindness if bilateral
• Cerebellum: projective vomiting (area postrema), obstructive hydrocephalus (S/S of raised ICP, CN 6 palsy), cerebellar signs (nystagmus, ataxia), CN 7 palsy

This is the single most important concept to understand for this condition.

What is IDH?

• Isocitrate dehydrogenase is a metabolic enzyme in the citric acid (Krebs/TCA) cycle
• Normal function: catalyses the oxidative decarboxylation of isocitrate → α-ketoglutarate (α-KG) + CO₂, generating NADPH
• Three isoforms exist: IDH1 (cytoplasmic/peroxisomal), IDH2 and IDH3 (mitochondrial)

What does the mutation do?

• The most common mutation is IDH1 R132H (~90% of IDH-mutant gliomas) — a missense mutation at codon 132 replacing arginine with histidine
• This is a gain-of-function (neomorphic) mutation: the mutant enzyme acquires a NEW enzymatic activity
• Instead of converting isocitrate → α-KG, mutant IDH converts α-KG → 2-hydroxyglutarate (2-HG), an "oncometabolite"

Why is 2-HG oncogenic? 2-HG is structurally similar to α-KG and acts as a competitive inhibitor of α-KG-dependent dioxygenases:

1. TET2 inhibition → DNA hypermethylation (the "CpG island methylator phenotype" or G-CIMP) → silencing of tumour suppressor genes and differentiation genes → cells remain in a progenitor-like, proliferative state
2. Histone demethylase (KDM) inhibition → histone hypermethylation → chromatin remodelling → altered gene expression
3. Prolyl hydroxylase domain (PHD) enzyme inhibition → stabilisation of HIF-1α → upregulation of angiogenesis and glycolysis (though this effect is debated in gliomas)
4. Collagen prolyl-4-hydroxylase inhibition → altered extracellular matrix → facilitates tumour invasion

The current model of IDH-mutant astrocytoma pathogenesis follows a sequential, multi-step process:

The concept of "driver" vs "passenger" mutations is critical here. IDH mutation is the driver — it is the initiating event. Subsequent TP53 and ATRX mutations are co-drivers that cooperate. Many other mutations are passengers. ^[4]

• ATRX = Alpha-Thalassemia/mental Retardation syndrome, X-linked
• Normal function: ATRX is a chromatin remodelling protein that helps maintain telomere structure and incorporates histone variant H3.3 at telomeres
• When ATRX is lost → telomeres become unstable → the cell activates Alternative Lengthening of Telomeres (ALT), a recombination-based mechanism to maintain telomere length
• This allows indefinite replication (one of the hallmarks of cancer)
• ATRX loss is mutually exclusive with 1p/19q codeletion — this is the molecular basis for distinguishing astrocytoma (ATRX lost, 1p/19q intact) from oligodendroglioma (ATRX retained, 1p/19q codeleted)

Under WHO CNS5:

• CDKN2A/B homozygous deletion automatically upgrades an IDH-mutant astrocytoma to Grade 4, even if the histology looks low-grade
• CDKN2A encodes p16^INK4a (inhibits CDK4/6 → blocks G1→S transition) and p14^ARF (stabilises p53 by inhibiting MDM2)
• CDKN2B encodes p15^INK4b (also inhibits CDK4/6)
• Homozygous deletion → loss of both cell cycle brake mechanisms → uncontrolled proliferation

Increased ICP due to: ^[1]

• Tumour mass effect
• Vasogenic oedema (most apparent on FLAIR MRI): disrupted BBB, tumour-secreting VEGF
• Hydrocephalus: obstructive / communicating (leptomeningeal carcinomatosis)
• Obstruction of cerebral venous drainage (e.g., superior sagittal sinus thrombosis)

Why vasogenic oedema?

• Tumour cells secrete VEGF (vascular endothelial growth factor) → disrupts tight junctions between endothelial cells of the BBB → plasma proteins leak into the interstitial space → oncotic gradient pulls water out → vasogenic oedema
• This is distinct from cytotoxic oedema (cell swelling, as in stroke)
• Vasogenic oedema responds to dexamethasone (reduces VEGF expression and restores tight junction proteins)
• Best seen on FLAIR MRI (Fluid-Attenuated Inversion Recovery — suppresses CSF signal so that perilesional oedema "lights up")

Seizures — 50% present as status epilepticus / post-ictal Todd's paralysis ^[1] Usually associated with slow-growing tumours that involve cortex, e.g., meningioma, low-grade glioma ^[1]

Why are seizures so common in IDH-mutant astrocytomas?

1. Cortical involvement: these tumours infiltrate the cerebral cortex, directly irritating neurons
2. 2-HG is a glutamate analogue: 2-HG structurally resembles glutamate → binds and activates NMDA receptors → excitotoxicity and neuronal hyperexcitability → lowers seizure threshold
3. Disrupted potassium buffering: loss of normal astrocyte function impairs K⁺ homeostasis → elevated extracellular K⁺ → neuronal depolarisation
4. Slow growth: gives the brain time to develop abnormal excitatory circuits around the tumour (faster-growing tumours tend to destroy cortex rather than irritate it)
5. Peritumoral glutamate release: tumour cells release excess glutamate via the system Xc⁻ cystine/glutamate antiporter

Under the WHO CNS5 classification, astrocytoma, IDH-mutant is graded 2–4 based on a combination of histological features AND molecular markers:

WHO 2016 classification of gliomas (WHO grading): further classified based on IDH status ^[2] — this was the transitional step toward the current CNS5 system.

An important distinction:

Localized astrocytomas (pilocytic astrocytoma Grade 1, subependymal giant cell astrocytoma Grade 1, pleomorphic xanthoastrocytoma Grade 2/3) vs. Diffuse astrocytomas (astrocytoma IDH-mutant Grade 2–4) ^[2]

• Pilocytic astrocytoma (Grade 1): typically IDH-wildtype, well-circumscribed, curable with surgery alone — most common brain tumour in children
• Astrocytoma, IDH-mutant (Grade 2–4): diffusely infiltrative — the condition we are discussing
• These are fundamentally different diseases with different biology, treatment, and prognosis

Why does 1p/19q codeletion confer better prognosis? The codeletion results from an unbalanced translocation t(1;19)(q10;p10). The retained alleles on 1p and 19q harbour fewer deleterious mutations, and loss of certain genes on these chromosome arms may reduce tumour aggressiveness. Additionally, 1p/19q-codeleted tumours are highly chemosensitive — the exact mechanism is incompletely understood but may relate to impaired DNA repair pathways.

"High-grade glioma: ↓T1W, heterogeneous enhancement with surrounding vasogenic oedema (↑T2W) ± central necrosis" ^[5] "Low-grade glioma: ↑T2W, non-enhancing expansile lesion without surrounding vasogenic oedema" ^[5]

Why is IDH-wildtype GBM so much more aggressive? IDH-wildtype GBM arises de novo (primary GBM) without a low-grade precursor. It accumulates highly aggressive molecular alterations: TERT promoter mutation → unlimited telomerase-driven replication; EGFR amplification → constitutive growth factor signalling; chromosome 7 gain/chromosome 10 loss (+7/−10) → loss of PTEN tumour suppressor; extensive microvascular proliferation driven by VEGF. This molecular cocktail creates a highly proliferative, angiogenic, and treatment-resistant tumour.

"Grade IV (glioblastoma multiforme): very malignant → mean lifespan 14m" ^[5]

"Pilocytic astrocytoma (PA) is the most common astrocytoma in children and is classified as Grade 1 (WHO). Classical site is cerebellum but can occur anywhere in CNS including hypothalamus, optic nerve and chiasmal region. Rarely invasive and rarely undergoes malignant transformation" ^[6][7]

Why the different biology? Pilocytic astrocytoma is a localised astrocytoma — it does not diffusely infiltrate brain parenchyma, unlike IDH-mutant astrocytoma which is a diffuse glioma. At the molecular level, pilocytic astrocytoma is driven by MAPK pathway activation (typically BRAF fusions) rather than IDH mutation → 2-HG → epigenetic reprogramming. This fundamental difference in molecular pathogenesis explains the dramatically different clinical behaviour.

"Primary CNS lymphoma: solitary/multifocal T2W-iso/hypointense, contrast-enhancing lesions in subcortical regions, classically associated with prominent diffusion restriction on DWI" ^[5]

Why is PCNSL T2-hypointense while gliomas are T2-hyperintense? PCNSL is extremely cellular — tightly packed lymphoma cells with high nuclear-to-cytoplasmic ratio and minimal extracellular water → short T2 relaxation time → dark on T2. Gliomas have more extracellular water (oedema, loose architecture) → long T2 → bright on T2.

Why does PCNSL show restricted diffusion on DWI? The extremely high cellularity restricts water molecule movement → restricted diffusion → bright on DWI, dark on ADC. This helps distinguish PCNSL from gliomas, which typically show facilitated diffusion.

"Meningioma: extra-axial, dura-based T1W-hypo/isointense, T2W-iso/hyperintense lesion with strong homogeneous enhancement" ^[5]

The distinction between intra-axial and extra-axial is usually straightforward on MRI — an extra-axial mass has a CSF cleft between tumour and brain parenchyma and displaces rather than infiltrates the cortex. This is a fundamental radiological distinction.

"MOST common type of malignant CNS tumours of childhood consistent with embryonal origin" ^[6][7] "Occurs exclusively in the cerebellum in midline cerebellar vermis. Males predominance with median age of diagnosis = 5–7 years. High propensity to disseminate through subarachnoid space (leptomeningeal dissemination). Presents with signs and symptoms of increased ICP (extension into 4th ventricles causing obstructive hydrocephalus) and cerebellar signs" ^[6][7]

This differential is largely resolved by patient age and tumour location — medulloblastoma is a paediatric posterior fossa tumour, while IDH-mutant astrocytoma is an adult supratentorial tumour. However, rare cases of adult medulloblastoma and paediatric supratentorial gliomas exist.

"DWI: differentiate cystic intra-axial tumour (facilitated diffusion) vs brain abscess (restricted diffusion)" ^[1]

Why does an abscess restrict diffusion? The pus within an abscess cavity is viscous — it contains proteins, cellular debris, and bacteria, all of which physically impede the free movement of water molecules → restricted diffusion (bright on DWI, dark on ADC map). A tumour cyst, by contrast, contains serous fluid with free water movement → facilitated diffusion.

This is one of the trickiest differentials in neuroradiology because both conditions affect young adults and produce white matter lesions. The "open ring" enhancement pattern (enhancement on the leading demyelinating edge only) is a classic distinguishing feature of tumefactive MS.

To diagnose astrocytoma, IDH-mutant, ALL of the following must be met:

In essence, the diagnosis is a molecular one: IDH-mutant + no 1p/19q codeletion = astrocytoma, IDH-mutant.

Once the diagnosis of astrocytoma, IDH-mutant is established, grading uses both histological and molecular features:

"Dexamethasone + AED for symptomatic relief" ^[2] "IV dexamethasone 4mg Q6h: reduce oedema around the lesion" ^[10]

Why are seizures so important to control? Beyond the obvious (injury risk, status epilepticus), uncontrolled seizures impair quality of life, impair rehabilitation, and may confound neurological assessment during follow-up.

"Temozolomide is an alkylating agent" ^[5] "Temozolomide-based chemoradiation: concomitant use with external RT then adjuvant chemo for 6 cycles (5d each, Q1m)" ^[2][5]

Key Trials:

This is the most significant recent advance (2023–2025) in the management of IDH-mutant gliomas:

"Watchful waiting may be adopted in low-grade astrocytomas" ^[2][5]

This watchful waiting approach was historically standard but is now evolving. The rationale was that early treatment (RT/chemo) did not improve OS in low-risk patients and exposed them to toxicity. However, with vorasidenib now available (well-tolerated, targeted), the threshold for early adjuvant treatment is lowering.

"Grade II/III: treatable but incurable → almost ALL will recur in ~10y with ↑grading (recur < 3y if IDH-wildtype)" ^[2][5]

This is the single most important complication in astrocytoma, IDH-mutant and is virtually inevitable.

• What happens: Over time, additional genetic hits accumulate (CDKN2A/B homozygous deletion, RB1 loss, PI3K/mTOR pathway activation, PDGFRA amplification) → the tumour evolves from a slower-growing entity to a more aggressive, higher-grade one
• Timeline: Grade 2 → Grade 3 in approximately 5–7 years; Grade 3 → Grade 4 in approximately 2–3 years (though highly variable)
• Clinical manifestation: New or worsening neurological deficits, new seizure pattern, increasing headache, reduced consciousness, new contrast enhancement on previously non-enhancing MRI
• Why does this happen? The IDH mutation creates a state of chronic epigenetic instability (via 2-HG-mediated G-CIMP and impaired DNA repair), paradoxically providing a substrate for additional mutations to accumulate during cell division. The impaired DNA repair created by 2-HG (inhibition of α-KG-dependent repair enzymes) also increases mutational burden over time
• Detection: Regular MRI surveillance — new enhancement in a previously non-enhancing tumour, increasing T2/FLAIR volume, or increasing perfusion on pMRI should raise suspicion. Tissue confirmation at re-resection or re-biopsy is the gold standard
• Management: As per recurrence protocol — re-resection, RT (if not previously given), chemotherapy escalation, vorasidenib if not already on it, clinical trials

This complication has been discussed in detail in the clinical features section but is worth reiterating as a life-threatening complication at any stage of the disease:

• Mechanisms: tumour mass effect, vasogenic oedema (VEGF → BBB disruption), obstructive hydrocephalus (if tumour blocks CSF pathways, particularly at the foramen of Monro, aqueduct of Sylvius, or 4th ventricle outlets), and cerebral venous obstruction ^[1]
• Herniation syndromes:
  • Uncal (transtentorial): ipsilateral CN III palsy (fixed dilated pupil — "blown pupil"), contralateral hemiparesis, progressive ↓GCS → brainstem compression → death if untreated
  • Subfalcine (cingulate): cingulate gyrus herniates under the falx cerebri → ACA compression → contralateral leg weakness
  • Tonsillar: cerebellar tonsils through the foramen magnum → medullary compression → cardiorespiratory arrest (Cushing's triad is the late pre-terminal sign)
• Management: emergency neurosurgical decompression, dexamethasone, mannitol/hypertonic saline, EVD for hydrocephalus

• Seizures are the most common presenting symptom, but status epilepticus (continuous seizure activity > 5 minutes or ≥2 seizures without regaining consciousness) is a medical emergency
• Particularly common in cortical IDH-mutant tumours because of the epileptogenic nature of 2-HG (glutamate analogue → NMDA receptor activation → sustained excitotoxicity)
• Complications of status epilepticus itself: excitotoxic neuronal death, rhabdomyolysis, aspiration pneumonia, hyperthermia, metabolic acidosis, cardiorespiratory compromise
• Management: standard status epilepticus protocol — ABC, IV benzodiazepine (lorazepam/midazolam) → levetiracetam or phenytoin loading → if refractory, propofol/midazolam infusion in ICU

• Brain tumour patients have a markedly elevated risk of VTE (~20% cumulative incidence) — one of the highest rates among all cancer types
• Why? Multiple overlapping mechanisms:
  1. Tissue factor expression: glioma cells express tissue factor on their surface → activates the extrinsic coagulation cascade → hypercoagulable state
  2. Immobility: hemiparesis, post-operative bed rest, reduced mobility
  3. Perioperative factors: craniotomy, prolonged surgery, post-operative immobilisation
  4. Chemotherapy: temozolomide can cause thrombocytopaenia and paradoxically activate coagulation
  5. Dexamethasone: increases clotting factor synthesis, promotes a pro-thrombotic state
  6. Bevacizumab: anti-VEGF therapy increases arterial thromboembolic events
• Manifestations: deep vein thrombosis (DVT), pulmonary embolism (PE) — the latter can be fatal
• Management: prophylactic LMWH post-operatively and during hospitalisation; therapeutic anticoagulation for confirmed VTE. Important: LMWH is safe in brain tumour patients — the historical fear of intratumoural haemorrhage has not been borne out by evidence; the risk of VTE is greater than the risk of haemorrhage

• Progressive cognitive decline occurs even without visible tumour progression — caused by:
  1. Tumour infiltration of white matter tracts connecting cortical regions (disrupts neural networks)
  2. Peritumoral oedema impairing function in adjacent normal brain
  3. Epileptic activity (subclinical seizures can impair cognition)
  4. 2-HG neurotoxicity: 2-HG itself may impair neuronal function by disrupting neurotransmitter homeostasis (glutamate system)
• Manifests as: memory impairment, executive dysfunction, slowed processing speed, language difficulties, personality changes
• Significantly impacts quality of life and functional independence

• Uncommon in IDH-mutant astrocytomas but can occur, especially in Grade 4 disease and at recurrence
• Tumour cells spread via CSF pathways → coat the leptomeninges → produce cranial nerve palsies, radiculopathies, communicating hydrocephalus, and "sugar-coating" of the spinal cord/cauda equina
• Diagnosis: CSF cytology (malignant cells), gadolinium-enhanced MRI of the entire neuraxis (leptomeningeal enhancement)
• Prognosis is very poor once leptomeningeal dissemination develops

"Maximal safe resection without causing serious neurological sequelae is the key component of treatment" ^[6][7]

"Posterior fossa syndrome (Cerebellar mutism): post-operative complication caused by injury to cerebellar vermis or dentate nuclei during resection of tumours in midline cerebellum. Appears 1–2 days after surgery and resolves within weeks to months. Characterised by impaired language production with emotional lability" ^[6][7]

This specific complication is primarily relevant to paediatric posterior fossa tumours (medulloblastoma) rather than adult supratentorial astrocytomas, but illustrates the general principle that surgical complications are location-dependent.

Many patients require prolonged dexamethasone, leading to iatrogenic complications:

Often underappreciated but profoundly impactful for patients and families:

• Common in brain tumour patients (~15–20%)
• Two distinct mechanisms:
  1. SIADH (Syndrome of Inappropriate ADH Secretion): tumour or surgery-related disruption of hypothalamic-posterior pituitary axis → excessive ADH → water retention → dilutional hyponatraemia. Euvolaemic hyponatraemia. Management: fluid restriction, ± tolvaptan (vasopressin V2 receptor antagonist)
  2. Cerebral Salt Wasting (CSW): brain injury-related release of natriuretic peptides (BNP, ANP) → renal sodium wasting → hypovolaemic hyponatraemia with high urine sodium. Management: isotonic/hypertonic saline replacement and fludrocortisone
• Distinguishing SIADH from CSW is critical because the treatments are opposite (fluid restriction vs fluid administration)

• While seizures are a presenting symptom, they become a chronic complication requiring lifelong AED management in many patients
• ~30–50% of brain tumour epilepsy is drug-resistant (fails ≥2 appropriately chosen AEDs)
• Drug-resistant seizures significantly impair quality of life, driving eligibility, employment, and safety
• Management: AED optimisation (polytherapy if needed), tumour resection (the most effective "anti-epileptic" intervention), vagus nerve stimulation (rarely used in tumour epilepsy)