Diagnosis: Neurofibromatosis Type 1 (NF1) - von Recklinghausen Disease

What the Slide Shows

• A large, lobulated hyperintense mass involving the optic chiasm, suprasellar region, and hypothalamus
• This is an optic pathway glioma (OPG) - the most characteristic CNS tumor in NF1
• The mass causes significant mass effect, explaining her headache and blurred vision in the left eye (increased intracranial pressure + direct optic pathway compression)

• Axillary freckling (Crowe sign): Clustered small hyperpigmented macules in both axillae (top-right images)
• Café-au-lait macules (CALMs): Multiple flat, light-brown oval patches on the trunk/back (bottom image)

Diagnostic Criteria for NF1 (Revised 2021)

Key Disease Facts

• Autosomal dominant; chromosome 17q11.2 (NF1 gene)
• Encodes neurofibromin, a 327 kDa tumor suppressor that negatively regulates RAS signaling
• Incidence: ~1 in 2,000-3,000 births; up to 50% are new (de novo) mutations
• Penetrance approaches 100% in adults but expressivity is highly variable

Optic Pathway Gliomas in NF1

• Occur in 15-20% of NF1 children (Bradley & Daroff's Neurology, p. 1578)
• NF1 accounts for ~50% of all treated OPG cases
• Histology: mostly pilocytic astrocytoma (WHO grade I)
• NF1-associated OPGs tend to have a more indolent course than sporadic OPGs
• ~20% of NF1 children imaged prospectively will show MRI abnormalities, but less than half develop progressive disease; occasional spontaneous regression occurs

• Unilateral/bilateral vision loss + blurring
• Proptosis (if optic nerve involved)
• Obstructive hydrocephalus -> headache (from hypothalamic/chiasmatic involvement)
• Diencephalic syndrome in infants (failure to thrive, nystagmus, irritability)

Management of OPG in NF1

1. Surveillance MRI - regular monitoring; many tumors are stable or regress spontaneously
2. Chemotherapy (first-line for progressive disease):
   • Carboplatin/vincristine (primary first-line)
   • Vinblastine monotherapy
   • Bevacizumab - shown to improve vision in patients with progressive visual loss
3. Targeted therapy (emerging):
   • MEK inhibitors (selumetinib) and BRAF inhibitors - impressive responses in early trials; selumetinib is now approved for NF1-related plexiform neurofibromas
   • Note: BRAF fusions are more common in non-NF1 OPGs
4. Radiation therapy - relatively contraindicated in NF1 due to very high risk of secondary high-grade gliomas and vasculopathies (moyamoya syndrome) (Bradley & Daroff's, p. 1578)
5. Surgery - limited role; biopsy for uncertain cases; partial resection only for symptomatic relief

Other NF1 Complications to Screen for

Summary

Diagnosis: Mesial Temporal Sclerosis (MTS) / Hippocampal Sclerosis

MRI Analysis - Four Sequences

From Harrison's Principles of Internal Medicine 22e - Figure 436-1: Left hippocampal sclerosis showing high signal intensity, blurring of internal architecture, and reduced size (arrow)

Classic MRI Triad of Hippocampal Sclerosis

1. Hippocampal volume loss (atrophy/small hippocampus) - most sensitive sign
2. Increased T2/FLAIR signal within the abnormally small hippocampus - due to gliosis replacing lost neurons
3. Loss of internal trilaminar architecture of the hippocampus

• Dilatation of the ipsilateral temporal horn (due to hippocampal atrophy)
• Atrophy of the ipsilateral mamillary body and fornix
• Small ipsilateral temporal lobe overall

Mesial Temporal Lobe Epilepsy Syndrome

Pathology

• Loss of neurons in the CA1 (Sommer sector) of the pyramidal cell layer - most vulnerable zone
• Often extends into CA3, CA4 and the dentate gyrus
• Granule cell layer dispersion in the dentate
• Ipsilateral fornix and mamillary body atrophy (secondary to lost hippocampal output)

Differential Diagnosis in a 23-Year-Old with Uncontrolled Seizures

Management

• Carbamazepine/oxcarbazepine are first-line for focal (temporal lobe) epilepsy
• This patient has uncontrolled seizures → likely drug-resistant (failure of ≥2 appropriate AEDs)

• High-resolution epilepsy-protocol MRI (3T, coronal FLAIR/T2)
• Video-EEG monitoring to confirm seizure lateralization
• Neuropsychological testing (memory, language)
• FDG-PET (interictal hypometabolism)
• Ictal SPECT (if needed)
• Wada test or fMRI for language/memory lateralization

• Anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy
• Outcomes: >80% experience significant seizure reduction; >60% become entirely seizure-free (Kaplan & Sadock's Comprehensive Psychiatry)
• Surgery is curative in up to 70% of patients with unilateral hippocampal sclerosis without dual pathology (Grainger & Allison's)
• Only delay to surgical referral predicts relapse post-surgery

• Laser interstitial thermal therapy (LITT/stereotactic laser amygdalohippocampectomy) - minimally invasive alternative
• Responsive neurostimulation (RNS) for bilateral or inoperable cases
• Vagus nerve stimulation (VNS)

Bottom Line

Diagnosis: Low-Grade Diffuse Glioma (WHO Grade 2) - Most Likely IDH-Mutant Astrocytoma

MRI Analysis - Three Sequences

1. T1 hypointense
2. T2 hyperintense (homogeneous)
3. Non-enhancing (intact blood-brain barrier - the most important distinguishing feature from high-grade glioma)

Fig. 55.8: T2-FLAIR mismatch sign in WHO grade II IDH-mutant 1p19q-intact astrocytoma - markedly T2 hyperintense solid mass with relatively suppressed FLAIR signal inside

WHO 2021 Classification of Adult Diffuse Gliomas

Molecular Pathogenesis

• IDH (isocitrate dehydrogenase) normally converts isocitrate → α-ketoglutarate
• Mutant IDH (most commonly IDH1 R132H, >90%) produces 2-hydroxyglutarate (2-HG) instead
• 2-HG is an oncometabolite that disrupts epigenetic regulation (DNA/histone hypermethylation) and impairs cellular differentiation
• 2-HG also mimics glutamate at NMDA receptors - this directly contributes to the high seizure burden seen in these patients
• Despite producing 2-HG, IDH-mutant gliomas have a significantly better prognosis than IDH-wildtype

• Markedly T2-hyperintense solid tumor with relatively suppressed FLAIR signal internally
• Present in ~50% of IDH-mutant astrocytomas; very high specificity when present

Why This Patient Has His Three Symptoms

Differential Diagnosis

Management

• Stereotactic biopsy if eloquent location
• Maximum safe resection if feasible - extends survival, reduces seizure burden, and provides adequate tissue for molecular profiling

• IDH1/2 mutation testing (immunohistochemistry ± sequencing)
• 1p/19q codeletion (FISH)
• ATRX expression
• MGMT promoter methylation
• TERT promoter mutation

• Radiotherapy + temozolomide chemotherapy (standard for high-risk grade 2: age >40, incomplete resection, or large tumor)
• For low-risk grade 2: active surveillance or chemotherapy alone to defer radiation

• Vorasidenib (dual IDH1/2 inhibitor) - FDA approved August 2024 for grade 2 IDH-mutant astrocytoma and oligodendroglioma after surgery
• The INDIGO Phase III trial showed vorasidenib prolonged progression-free survival from 11.1 → 27.7 months (HR 0.39)
• Brain-penetrant oral agent; delays need for chemoradiation and preserves cognitive function
• This represents a paradigm shift in management of grade 2 IDH-mutant gliomas

• Anti-seizure medications (levetiracetam preferred; avoid enzyme inducers)
• Tumor resection itself often reduces seizure frequency

Prognosis

• Left panel (Axial FLAIR or T1): The large left frontal mass is uniformly hypointense/dark, occupying a substantial portion of the left hemisphere with mild rightward midline shift and compression of the left ventricle
• Middle panel (Axial T2): Intensely, homogeneously hyperintense - nearly matching CSF signal - with a small focus of even brighter signal possibly representing a small cystic component. Minimal surrounding edema
• Right panel (Sagittal T1 post-contrast): The mass appears relatively hypointense to isointense with no significant enhancement, confirming intact blood-brain barrier

• Complete MRI characterization and the T2-FLAIR mismatch sign
• WHO 2021 molecular classification (IDH mutation, 1p/19q, ATRX)
• Pathogenesis (2-HG oncometabolite, NMDA receptor mechanism for seizures)
• Management including the 2024 FDA approval of vorasidenib
• Differential diagnosis and prognosis tableThis is the exact same image as the one you just sent moments ago - same case, same MRI, same patient (26-year-old man with seizure, headache, and slowness in thoughts).

1. Differentiating astrocytoma vs. oligodendroglioma - what additional imaging/tests help?
2. Surgical planning - eloquent cortex mapping, extent of resection strategy
3. The FLAIR-mismatch sign - how to apply it in this case
4. Vorasidenib and IDH inhibitors - mechanism and the INDIGO trial in detail
5. Seizure management in glioma patients
6. Malignant transformation - when and how to monitor for upgrade to grade 3/4

Diagnosis: Tuberous Sclerosis Complex (TSC) with Subependymal Giant Cell Astrocytoma (SEGA)

What the Slide Shows

• A well-circumscribed, intensely and homogeneously enhancing mass at the foramen of Monro (right side), projecting into the lateral ventricle
• Obstructive hydrocephalus with dilatation of the lateral ventricles bilaterally
• This is pathognomonic for a Subependymal Giant Cell Astrocytoma (SEGA) in the context of TSC

• Multiple reddish-brown papules and nodules distributed symmetrically over the nose, cheeks, and nasolabial folds - a butterfly/malar distribution
• Grossly resembles severe acne, but the symmetry, location, and texture are characteristic of facial angiofibromas (historically called "adenoma sebaceum")
• Present in 75-90% of TSC patients older than 4 years

Fig. 27.9 Angiofibromas (adenoma sebaceum) - Andrews' Diseases of the Skin

Tuberous Sclerosis Complex (TSC) - Overview

• Autosomal dominant; up to 50-86% are spontaneous (de novo) mutations
• Two genes: TSC1 (chromosome 9q34.3, encodes hamartin) and TSC2 (chromosome 16p13.3, encodes tuberin)
• TSC1 and TSC2 proteins form a complex that inhibits mTOR signaling (via suppression of RHEB GTPase)
• Loss of function → constitutive mTOR activation → uncontrolled hamartoma growth throughout the body
• TSC2 mutations = more severe disease (more SEGA, angiomyolipomas, intellectual disability)

Diagnostic Criteria (2012 International Consensus)

Major Features

Minor Features

Neurological Features

Systemic Manifestations

Management

• Surgical resection - standard treatment when symptomatic; can be curative for the obstructive hydrocephalus
• Everolimus (mTOR inhibitor) - FDA approved; shrinks SEGA in >50% of patients; useful to avoid/delay surgery or for recurrent/unresectable SEGA; also reduces angiomyolipoma size
• Regular MRI surveillance (every 1-3 years) for growing SENs to catch SEGA early

• Anti-seizure medications (vigabatrin preferred for infantile spasms in TSC - more effective than ACTH)
• Everolimus also has anti-seizure effects (mTOR pathway involved in epileptogenesis)
• Resective epilepsy surgery if seizures localize to 1-2 tubers
• Corpus callosotomy for severe cases

• Embolization or nephron-sparing surgery for lesions >4 cm (risk of hemorrhage)
• Everolimus shrinks angiomyolipomas

• Topical rapamycin (sirolimus) gel - effective in reducing angiofibromas
• Laser ablation for cosmesis

Why This Was Misdiagnosed as "Severe Acne"

Diagnosis: Cystic Tumor with Enhancing Mural Nodule - Most Likely Pilocytic Astrocytoma (WHO Grade I) or Pleomorphic Xanthoastrocytoma (PXA)

MRI Analysis - Four Sequences

Grainger & Allison's Fig. 55.10 - Cyst with mural nodule morphology in pilocytic astrocytoma (cerebellar). The same pattern appears in this supratentorial case.

Key Diagnostic Feature: The "Cyst with Enhancing Mural Nodule" Pattern

• Primary diagnosis: Pilocytic Astrocytoma (PA) or PXA - both WHO low-grade, both present in young adults with seizures and headache, both show cyst+mural nodule
• PXA is favored if the lesion truly abuts the meninges (dural tail sign) - it has a predilection for the temporal lobe but can occur in the parietal lobe
• PA is favored if the mural nodule is the only enhancing component with complete non-enhancement of the cyst wall

Pilocytic Astrocytoma - Key Facts

• Bipolar cells with long "pilocytic" processes
• Rosenthal fibers (corkscrew eosinophilic inclusions) - pathognomonic
• Eosinophilic granular bodies
• Microcysts

• BRAF-KIAA1549 fusion (most common, ~70%) → constitutive MAPK/ERK activation
• BRAF V600E mutation (~10%) - more common in cerebral/non-cerebellar location; worse prognosis
• IDH mutation: absent (unlike adult diffuse gliomas)

• Large cyst + small enhancing mural nodule (especially cerebellar)
• Solid homogeneously enhancing mass (supratentorial)
• Minimal surrounding edema despite large size
• Non-infiltrating, well-circumscribed margins

Pleomorphic Xanthoastrocytoma (PXA) - Why it Fits

• Young adult with seizures (blackouts) - PXA is strongly associated with cortical epilepsy
• Superficial cortical location abutting the meninges - PXA "hugs" the brain surface
• Cystic + solid enhancing component - in >50% of PXA
• Parietal lobe - less common than temporal but well-documented
• T1 hypointense, T2 hyperintense solid component
• May show a "dural tail sign" mimicking meningioma

Management

• Gross total resection (GTR) is the treatment of choice for both PA and PXA
• For PA: GTR is essentially curative - 5-year recurrence-free survival >90% after complete resection
• For PXA: GTR + resection of adjacent cortex (seizure focus); recurrence rate ~20% WHO II, higher for anaplastic (WHO III)
• Functional mapping needed given right parietal location (sensorimotor, visuospatial functions)

• For PA: observation only after GTR; chemotherapy (carboplatin/vincristine) for incompletely resected/progressive tumors
• For PXA: adjuvant radiotherapy if anaplastic features; BRAF V600E+ tumors respond to dabrafenib ± trametinib (BRAF/MEK inhibition)

• Pre-operatively: anti-seizure medications (levetiracetam)
• Surgical resection of the tumor + epileptogenic cortex often achieves seizure freedom

Differential to Exclude

Diagnosis: Ganglioglioma (WHO Grade I) - Most Likely; DNET as Close Differential

What the Imaging Shows

• Axial non-contrast CT shows a right temporal lobe lesion with dense, clumped calcification - this is the single most diagnostic CT feature
• Calcification is "gritty" and coarse - classic for ganglioglioma ("solid portions are firm, gray, and gritty due to calcium deposits")
• The surrounding low-density region represents the cystic component

Bradley & Daroff's Fig. 75.6 - Ganglioglioma: T2 prolongation (A) and cystic-solid enhancing mass (B)

Why Ganglioglioma Fits Perfectly

Ganglioglioma - Key Facts

• 4-8% of all pediatric brain tumors; 80% occur in patients < age 30
• Most common site: temporal lobe >> other lobes >> cerebellum >> spinal cord

• Dysmorphic ganglion cells (clustered, binucleate/multinucleate, lack polarity) - pathognomonic
• Eosinophilic granular bodies (EGBs)
• Perivascular lymphocytic cuffing
• Rosenthal fibers at tumor edges
• Microcystic spaces + collagen deposition
• Calcification in the solid component

• BRAF V600E mutation in 18-50% of cases - targetable
• Other MAPK pathway mutations: KRAS, NF1, FGFR1/2
• These mutations distinguish gangliogliomas from reactive/entrapped neurons in diffuse gliomas

• Grade I (vast majority) - typical ganglioglioma
• Grade III (rare) - anaplastic ganglioglioma; almost always in the glial component

Why Status Epilepticus?

• Temporal lobe gangliogliomas are intimately associated with refractory focal epilepsy
• SE may be the first presentation in a patient with a long-standing but previously undiagnosed slow-growing tumor
• The combination of cortical irritation from tumor + direct involvement of the hippocampal circuit drives the hyperexcitable focus
• BRAF V600E mutation → constitutive MAPK activation → abnormal neuronal excitability

Differential Diagnosis

Management

• Gross total resection (GTR) is curative in most cases
• Should include the tumor + epileptogenic cortex (if temporal: amygdalohippocampectomy may be needed)
• After GTR: 5-year survival ~89%; seizure freedom achieved in majority
• Incomplete resection → local recurrence risk (significant given propensity for recurrence despite low grade)

• Video-EEG to confirm seizure focus localization
• fMRI/Wada test for language and memory lateralization (right temporal - dominant only if left-handed)
• Neuropsychological testing
• Molecular testing (BRAF V600E) on surgical specimen

• Dabrafenib ± trametinib (BRAF + MEK inhibition) - active in BRAF V600E+ CNS tumors
• Carboplatin/vincristine if BRAF wildtype

• Phase 1 (0-5 min): Lorazepam IV (0.1 mg/kg) or diazepam
• Phase 2 (5-20 min): Levetiracetam IV, valproate IV, or fosphenytoin IV
• Phase 3 (>20 min - refractory SE): Anesthesia - propofol, midazolam infusion, or pentobarbital
• Definitive treatment: Surgical removal of the epileptogenic tumor

• Levetiracetam (preferred; no enzyme induction)
• Surgical resection often achieves complete seizure freedom

Summary

Diagnosis: Intraventricular Cavernous Malformation (Cavernoma) with Obstructive Hydrocephalus

Imaging Analysis - Five Panels

The "Popcorn Sign" - Why It Is Pathognomonic

• Distended, back-to-back vascular channels (no intervening brain parenchyma) with collagenized walls
• Recurrent micro- and macrohemorrhages at different time points → blood products in all stages simultaneously:

Cavernous Malformation - Key Facts

• Sporadic (single lesion) in most cases
• Familial (autosomal dominant, multiple lesions) - mutations in:
  • CCM1 (KRIT1, chromosome 7q)
  • CCM2 (chromosome 7p)
  • CCM3 (PDCD10, chromosome 3q)
• Rapidly growing lesions also require gain-of-function PIK3CA mutations (cancer-like second hit)

• Prevalence ~0.4-0.6% on MRI
• Accounts for 10-25% of all cerebral vascular malformations
• 80% supratentorial, 15% infratentorial, 5% intraspinal
• Intraventricular cavernomas: ~2.5-10% of all cavernomas; arise from choroid plexus or ventricular wall

• "Low-flow" lesions - do NOT participate in arteriovenous shunting
• Grow by recurrent microhemorrhages - each bleed expands the lesion and deposits hemosiderin
• Annual hemorrhage risk: ~0.25-0.7% per year (parenchymal); rebleed risk ~4.5%

Why This Patient Has Her Symptoms

Differential Diagnosis for Intraventricular Mass with Hemorrhage

Management

• Urgent neurosurgical consultation
• External ventricular drain (EVD) if acutely decompensating (rapidly rising ICP → herniation risk)
• Osmotherapy (mannitol) as bridge

• Complete surgical resection is the gold standard for intraventricular cavernomas
• Approach options: transcallosal, transcortical (transventricular)
• Complete removal resolves hydrocephalus and removes the hemorrhage source
• Reported cure rates high after GTR
• The associated developmental venous anomaly (DVA) (found in 20-60% of cases alongside cavernomas) must be preserved - do NOT resect it (causes venous infarction)

• Small, asymptomatic, non-eloquent location, no recurrent hemorrhages → watchful waiting
• This patient's obstructive hydrocephalus makes surgery mandatory

• Continue/optimize (levetiracetam preferred)
• Post-resection seizure freedom expected in most cases once the hemosiderin-laden epileptogenic focus is removed

• Controversial; considered for deep eloquent/inaccessible lesions
• Does NOT acutely resolve hydrocephalus

Zabramski MRI Classification (for completeness)