# Clinical Cases: Neuro-oncology

## Case 1: Glioblastoma Multiforme

### Patient Demographics
- **Age:** 62 years
- **Sex:** Male
- **Occupation:** Retired accountant

### Chief Complaint
"Progressive headaches and weakness in my left arm for 3 weeks."

### History of Present Illness
The patient presents with a 3-week history of progressively worsening headaches, initially intermittent but now constant. The headaches are worse in the morning and improve somewhat as the day progresses. He has noted nausea, particularly in the morning, and vomited twice last week. Over the past 2 weeks, his wife has noticed weakness in his left arm - he has difficulty buttoning his shirt and dropped a coffee mug. She also reports subtle personality changes: he has become apathetic, less engaged in conversation, and has made poor financial decisions recently. Three days ago, he had a witnessed generalized tonic-clonic seizure lasting approximately 2 minutes, which prompted this emergency department visit. No prior history of seizures, no significant medical history, non-smoker.

### Neurological Examination Findings

**Vital Signs:**
- BP: 142/88, HR: 78, RR: 14, Temp: 36.8C

**Mental Status Examination:**
- Alert and oriented to person, place; disoriented to date
- Flat affect, reduced spontaneity of speech
- MMSE: 24/30 (impaired recall, attention)
- Impaired executive function on frontal testing

**Cranial Nerves:**
- Pupils: 3mm, equal, reactive
- **Papilledema present bilaterally** - blurred disc margins
- Visual fields: Left homonymous hemianopia (incomplete)
- Facial sensation intact
- Mild left central facial droop

**Motor Examination:**
- Right side: 5/5 throughout
- **Left upper extremity: 3/5** (deltoid through hand intrinsics)
- Left lower extremity: 4+/5
- Left-sided pronator drift present
- Mildly increased tone on left

**Sensory Examination:**
- Decreased sensation to light touch, left arm and face
- Extinction to double simultaneous stimulation on left

**Reflexes:**
- Right: 2+
- Left: 3+ (hyperreflexia)
- **Left Babinski: Extensor**

**Coordination:**
- Right: Normal
- Left: Limited by weakness

**Gait:**
- Left hemiparetic gait with circumduction

### Localization
- Right frontal-parietal lesion (contralateral motor and sensory deficits, personality changes, left homonymous hemianopia from involvement of optic radiation)

### Neuro Workup

**CT Head without Contrast (Emergency):**
- Large heterogeneous mass in right frontal-parietal region
- Surrounding hypodense edema
- Mass effect with 8mm midline shift to left
- Effacement of right lateral ventricle

**MRI Brain with and without Contrast:**
- **5.2 cm heterogeneous mass** in right frontal-parietal lobe
- **Ring enhancement** with irregular, thick walls
- Central necrosis (T1 hypointense, T2 hyperintense)
- **Extensive surrounding vasogenic edema** (T2/FLAIR hyperintensity)
- Mass effect with subfalcine herniation
- No restricted diffusion in center (unlike abscess)
- Involvement of corpus callosum ("butterfly pattern" early)

**MR Spectroscopy:**
- Elevated choline (cell membrane turnover)
- Decreased N-acetylaspartate (neuronal loss)
- Elevated choline/NAA ratio
- Lipid/lactate peak (necrosis)

**Laboratory Studies:**
- CBC, CMP, coagulation: Normal
- No evidence of systemic malignancy on initial screening

### Diagnosis
**Suspected High-Grade Glioma (Glioblastoma)**
- Final diagnosis requires tissue confirmation and molecular profiling

### Surgical Management

**Preoperative Management:**
1. **Dexamethasone 10mg IV load, then 4mg q6h** - reduce peritumoral edema
2. **Levetiracetam 500mg BID** - seizure prophylaxis
3. Neurosurgery consultation

**Surgical Resection:**
- **Maximal safe resection** performed with:
  - Intraoperative neuronavigation
  - Motor mapping/cortical stimulation (preserve motor cortex)
  - Awake craniotomy considered given proximity to eloquent cortex
- Gross total resection achieved based on post-operative MRI

**Pathology Results:**
- **Glioblastoma, IDH-wildtype, WHO Grade 4**
- Histology: High cellularity, nuclear atypia, mitotic figures, microvascular proliferation, necrosis with pseudopalisading
- **IDH1/2 mutation: Negative** (wildtype - worse prognosis)
- **MGMT promoter methylation: Present** (favorable - better response to temozolomide)
- EGFR amplification: Present
- TERT promoter mutation: Present

### Adjuvant Treatment (Stupp Protocol)

**Concurrent Chemoradiation:**
1. **Radiation therapy:** 60 Gy in 30 fractions (2 Gy/day x 6 weeks)
2. **Temozolomide:** 75 mg/m2 daily during radiation

**Adjuvant Chemotherapy:**
3. **Temozolomide:** 150-200 mg/m2 x 5 days every 28 days x 6 cycles
4. **Tumor-treating fields (TTFields):** Considered for maintenance

**Supportive Care:**
- Continue dexamethasone, taper as tolerated
- PCP prophylaxis (TMP-SMX) while on temozolomide + steroids
- Antiemetics for temozolomide
- VTE prophylaxis (high risk in GBM)
- Physical/occupational therapy for left-sided weakness
- Driving restriction given seizure history

### Prognosis Discussion

**With Standard Treatment:**
- Median overall survival: ~15-18 months
- 2-year survival: ~25-30%
- 5-year survival: <10%

**Favorable Prognostic Factors in This Patient:**
- MGMT methylation present (better temozolomide response)
- Achieved gross total resection
- Good performance status at diagnosis

**Unfavorable Factors:**
- IDH-wildtype (compared to IDH-mutant gliomas)
- Age >60 years

### Clinical Image
![Glioblastoma MRI](case_01_image.jpg)

**Image Description:** Sagittal T1-weighted MRI with contrast showing a glioblastoma multiforme with characteristic ring enhancement, central necrosis, and surrounding vasogenic edema.

**Attribution:** Image from Wikimedia Commons. Public domain. Source: https://commons.wikimedia.org/wiki/File:Glioblastoma_-_MR_sagittal_with_contrast.jpg

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## Case 2: Brain Metastases with Unknown Primary

### Patient Demographics
- **Age:** 58 years
- **Sex:** Female
- **Occupation:** Administrative assistant

### Chief Complaint
"Terrible headaches and I feel off-balance for 2 weeks."

### History of Present Illness
The patient presents with 2 weeks of progressively worsening headaches, initially mild and intermittent but now constant and severe. The headaches are worse when lying down and first thing in the morning. She has had persistent nausea and has vomited three times this week. She has noticed difficulty with balance and coordination, walking into door frames, and feeling "drunk." Her husband reports she has been confused at times and had word-finding difficulties. She had a 30 pack-year smoking history, quit 5 years ago. She has had an unintentional 15-pound weight loss over the past 3 months, which she attributed to stress. No prior cancer diagnosis.

### Neurological Examination Findings

**Vital Signs:**
- BP: 138/82, HR: 88, RR: 16, Temp: 37.0C

**Mental Status Examination:**
- Alert, oriented to person and place, vague on date
- Mild word-finding difficulty
- MMSE: 26/30

**Cranial Nerves:**
- Pupils: Equal, reactive
- **Papilledema present** (bilateral disc swelling)
- Visual fields: Right superior quadrantanopia
- Eye movements: Full, no nystagmus at rest
- **Gaze-evoked nystagmus** on lateral gaze
- Facial sensation and movement intact

**Motor Examination:**
- 5/5 strength throughout
- Normal tone

**Sensory Examination:**
- Intact

**Reflexes:**
- 2+ symmetric
- Plantar responses flexor

**Coordination:**
- **Dysmetria on finger-to-nose bilaterally** (left > right)
- **Dysdiadochokinesia**
- Impaired heel-to-shin bilaterally

**Gait:**
- **Wide-based, ataxic gait**
- Unable to tandem walk
- Positive Romberg (falls backward)

### Localization
- Bilateral cerebellar involvement (ataxia, dysmetria, gait instability)
- Possible left temporal/parietal involvement (quadrantanopia, word-finding)
- Elevated ICP (headache, papilledema, vomiting)

### Neuro Workup

**MRI Brain with Contrast:**
- **Multiple (>10) ring-enhancing lesions** throughout the brain
- Largest lesion: 3.2 cm in left cerebellar hemisphere
- Additional lesions in: Right temporal, left parietal, bilateral frontal lobes
- **Gray-white matter junction predominance**
- Surrounding vasogenic edema
- Hydrocephalus from cerebellar mass effect on fourth ventricle

**CT Chest/Abdomen/Pelvis:**
- **3.5 cm spiculated mass in right upper lobe of lung**
- Hilar and mediastinal lymphadenopathy
- No liver or adrenal metastases

**PET-CT:**
- Hypermetabolic right upper lobe lung mass
- Hypermetabolic mediastinal lymph nodes
- Brain lesions show increased uptake

**Laboratory Studies:**
- CBC: Normal
- CMP: Normal
- CEA: Elevated (12.5 ng/mL)

**CT-guided Lung Biopsy:**
- **Non-small cell lung cancer - adenocarcinoma**
- Molecular testing:
  - EGFR mutation: Negative
  - ALK rearrangement: Negative
  - ROS1: Negative
  - PD-L1: 60% (high)
  - KRAS G12C: Positive

### Diagnosis
**Metastatic Non-Small Cell Lung Cancer (Adenocarcinoma) to Brain**
- Stage IV (cT2N2M1b)
- Multiple brain metastases (>10 lesions)

### Management

**Immediate Treatment:**
1. **Dexamethasone 10mg IV load, then 4mg q6h** - reduce edema, improve symptoms
2. **Levetiracetam** - seizure prophylaxis (supratentorial lesions)
3. PPI for GI prophylaxis while on steroids

**Neurosurgical Consultation:**
- Posterior fossa decompression NOT indicated given multiple lesions
- No role for surgical resection with diffuse metastatic disease

**Radiation Oncology:**
- **Whole-brain radiation therapy (WBRT)** recommended
  - 30 Gy in 10 fractions OR 37.5 Gy in 15 fractions
  - Hippocampal-sparing technique considered to reduce cognitive effects
  - Memantine added to reduce cognitive decline
- Stereotactic radiosurgery (SRS) not appropriate given >10 lesions

**Medical Oncology:**
- **Systemic therapy** initiated after WBRT:
  - First-line: Pembrolizumab (anti-PD-1) + chemotherapy given high PD-L1
  - KRAS G12C inhibitor (sotorasib) as potential later option
- Tyrosine kinase inhibitors not indicated (no actionable mutations)

**Supportive Care:**
- Physical therapy for ataxia and fall prevention
- Occupational therapy
- Speech therapy if needed
- Palliative care consultation for goals of care discussion
- Advanced care planning

### Prognosis Discussion

**Prognostic Assessment:**
- **Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for NSCLC:**
  - Multiple brain metastases, no targetable mutation
  - Estimated median survival: 4-7 months with WBRT

**Factors in This Case:**
- Unfavorable: Multiple metastases, no EGFR/ALK mutation, symptomatic
- Favorable: Good performance status, high PD-L1 (may respond to immunotherapy)

**Goals of Care Discussion:**
- Discussed palliative nature of treatment
- Focus on quality of life and symptom control
- Established healthcare proxy
- Discussed hospice as future option

### Clinical Image
![Brain Metastases MRI](case_02_image.jpg)

**Image Description:** T1-weighted MRI with contrast showing multiple ring-enhancing brain metastases at the gray-white matter junction with surrounding vasogenic edema, characteristic of metastatic disease.

**Attribution:** Image from Wikimedia Commons. Licensed under CC BY-SA 3.0. Source: https://commons.wikimedia.org/wiki/File:Hirnmetastase_MRT-T1_KM.jpg

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## Key Teaching Points

### Glioblastoma
1. Most common and most aggressive primary brain tumor
2. Characteristic imaging: Ring enhancement, central necrosis, edema
3. **IDH-wildtype** defines glioblastoma (poor prognosis vs IDH-mutant)
4. **MGMT methylation** predicts temozolomide response
5. Standard treatment: Maximal safe resection + Stupp protocol (RT + temozolomide)
6. Median survival ~15 months despite treatment

### Brain Metastases
1. **More common than primary brain tumors** (10:1 ratio)
2. Most common primaries: Lung, breast, melanoma, renal, colorectal
3. Imaging: Multiple lesions at gray-white junction, ring-enhancing
4. Always search for primary if unknown
5. Treatment based on number, size, primary tumor, molecular markers
6. Options: Surgery (single, accessible), SRS (limited number), WBRT (multiple)
7. Systemic therapy increasingly important (targeted therapy, immunotherapy)