A 47-year-old male presents with progressive morning headaches worsened by bending or Valsalva maneuver, nausea, personality and mood changes, ataxic gait with left-sided cerebellar signs, and bilateral temporal visual field loss. He also has a history of 5 kg weight loss, posterior auricular lymphadenopathy, a small lesion behind the right ear, and decreased breath sounds with diffuse crackles. What is the most likely diagnosis for this patient?

Brain Metastasis from Melanoma

Mechanism(s) of Disease

Hematogenous dissemination of melanoma cells to the brain parenchyma and/or leptomeninges represents the primary pathophysiologic mechanism, with melanoma having one of the highest propensities for CNS metastasis among solid tumors.

• Melanoma cells breach the blood-brain barrier through hematogenous spread, establishing parenchymal metastases that disrupt normal brain architecture and increase intracranial pressure 1
• Leptomeningeal metastasis (LM) occurs when tumor cells seed the cerebrospinal fluid space, causing diffuse or nodular meningeal involvement with subsequent cranial nerve dysfunction, hydrocephalus, and multifocal neurological deficits 1
• The posterior fossa (cerebellum) is a common site for metastatic disease, explaining cerebellar signs and symptoms of increased intracranial pressure 1
• Mass effect from metastases causes progressive symptoms through direct compression, vasogenic edema, and obstruction of CSF pathways 1

Key History Features + Risk Factors

Progressive morning headaches worse with Valsalva maneuver, personality changes, and ataxia in a patient with a suspicious skin lesion strongly suggest metastatic melanoma.

• Typical clinical signs of LM include headache, nausea and vomiting, mental changes, gait difficulties, cranial nerve palsies with diplopia, visual disturbances, hearing loss, and sensorimotor deficits 1
• History of melanoma or suspicious pigmented skin lesion (the small lesion behind the right ear is highly concerning) 1
• Constitutional symptoms including unintentional weight loss (5 kg in this case) 1
• Progressive neurological symptoms developing over weeks to months rather than acute onset 1
• Headache awakening the patient from sleep significantly increases likelihood of intracranial pathology 1
• Headache worsened by Valsalva maneuver increases odds of finding abnormality on neuroimaging 1

Physical Exam Findings That Increase Likelihood

Any abnormality on neurological examination significantly increases the likelihood of detecting significant pathology on imaging.

• Cerebellar signs (ataxia, dysmetria, intention tremor) indicating posterior fossa involvement 1, 2
• Bilateral temporal visual field loss suggesting chiasmal or retrochiasmal pathway involvement from mass effect or leptomeningeal disease 1
• Personality and mood changes indicating frontal lobe or diffuse cerebral involvement 1
• Posterior auricular lymphadenopathy suggesting regional nodal metastasis from primary melanoma 1
• Small lesion behind the right ear (potential primary melanoma site) 1
• Decreased breath sounds in right middle lobe with diffuse crackles suggesting pulmonary metastases 1
• Any abnormality on neurological examination significantly increases likelihood of abnormality on CT or MRI 1

Helpful Diagnostic Studies

First-Line Imaging

MRI brain with IV contrast using specific sequences is the gold standard for detecting brain metastases and leptomeningeal disease.

• Brain MRI should include: axial T1-weighted, axial FLAIR, axial diffusion, axial T2-weighted, post-gadolinium 3D T1-weighted, and post-gadolinium 3D FLAIR sequences 1
• Spinal MRI should include post-gadolinium sagittal T1-weighted sequences to evaluate for leptomeningeal disease 1
• MRI detects both parenchymal brain metastases and leptomeningeal disease patterns (linear type A, nodular type B, or both type C) 1
• Communicating hydrocephalus is observed in 11-17% of patients with leptomeningeal metastasis 1

Confirmatory Studies

CSF cytology with optimized processing confirms leptomeningeal metastasis when imaging is equivocal or to guide treatment decisions.

• Fresh CSF samples should be processed within 30 minutes; CSF volume ideally >10 mL but at least 5 mL 1
• Routine staining includes Pap/Papanicolaou and Giemsa; additional immunocytochemical staining for melanocytic markers 1
• A second CSF sample should be analyzed if initial sample is negative 1
• CSF cytology positive for tumor cells confirms diagnosis; equivocal results show suspicious or atypical cells 1

Additional Diagnostic Tests

• Chest CT to evaluate pulmonary findings (decreased breath sounds RML, diffuse crackles) for metastatic disease 1
• Biopsy of the skin lesion behind the right ear to confirm primary melanoma 1
• Excisional biopsy of posterior auricular lymph node if skin lesion biopsy confirms melanoma 1

Pre-test Probability for This Case: HIGH

Points FOR Brain Metastasis from Melanoma:

• Small lesion behind right ear (potential primary melanoma) with posterior auricular lymphadenopathy strongly suggests melanoma with regional spread 1
• Progressive morning headaches worse with Valsalva—classic for increased intracranial pressure 1
• Bilateral temporal visual field loss indicates chiasmal/retrochiasmal involvement consistent with metastatic disease 1
• Left-sided cerebellar signs with ataxic gait localizes to posterior fossa, a common site for metastases 1
• Personality/mood changes indicate cerebral involvement 1
• Constitutional symptoms (5 kg weight loss) suggest systemic malignancy 1
• Pulmonary findings (decreased breath sounds, crackles) suggest metastatic disease to lungs 1
• Melanoma has highest propensity for CNS metastasis among solid tumors 1
• Clinical presentation matches typical signs of leptomeningeal metastasis: headache, nausea, mental changes, gait difficulties, visual disturbances 1

Points AGAINST Brain Metastasis from Melanoma:

• Age 47 is relatively young for metastatic melanoma, though not excluding it 1
• No documented history of melanoma (though skin lesion is suspicious) 1

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Glioblastoma (Primary High-Grade Glioma)

Mechanism(s) of Disease

Malignant transformation of glial cells leads to rapidly proliferating, infiltrative tumor with necrosis, vascular proliferation, and mass effect.

• Glioblastoma arises from astrocytic cells and demonstrates aggressive local invasion with pseudopalisading necrosis and microvascular proliferation (defining histologic features)
• Tumor growth causes progressive mass effect, vasogenic edema, and increased intracranial pressure leading to headache, nausea, and focal neurological deficits 1
• Infiltrative growth pattern allows tumor cells to spread along white matter tracts, causing multifocal neurological dysfunction 1
• Disruption of normal brain architecture and neurotransmitter pathways leads to personality changes, cognitive decline, and seizures 1
• Posterior fossa gliomas (less common in adults) cause cerebellar dysfunction and obstructive hydrocephalus 1

Key History Features + Risk Factors

Progressive neurological symptoms over weeks to months in middle-aged adults without prior cancer history suggests primary brain tumor.

• Progressive headaches, particularly morning headaches and those worsened by Valsalva maneuver, indicate increased intracranial pressure 1
• Personality and mood changes reflect frontal lobe or diffuse cerebral involvement 1
• Subacute onset of symptoms (weeks to months) rather than acute presentation 1
• Age 40-70 years represents peak incidence for glioblastoma (47 years fits this range)
• Headache awakening patient from sleep increases likelihood of intracranial pathology 1
• Prior radiation exposure is a risk factor (though not mentioned in this case)
• Family history of genetic syndromes (neurofibromatosis, Li-Fraumeni) increases risk (not mentioned here)

Physical Exam Findings That Increase Likelihood

Focal neurological deficits on examination significantly increase likelihood of structural brain lesion.

• Cerebellar signs (ataxia, dysmetria) indicating posterior fossa mass lesion 1, 2
• Bilateral temporal visual field loss suggesting mass effect on optic pathways or increased intracranial pressure 1
• Personality and mood changes indicating frontal lobe involvement 1
• Any abnormality on neurological examination significantly increases likelihood of abnormality on neuroimaging 1
• Gait ataxia and truncal instability suggest cerebellar or brainstem involvement 1, 2

Helpful Diagnostic Studies

First-Line Imaging

MRI brain with and without IV contrast is the gold standard for detecting and characterizing primary brain tumors.

• MRI brain should include: axial T1-weighted, axial FLAIR, axial diffusion, axial T2-weighted, post-gadolinium 3D T1-weighted sequences 1
• Glioblastoma typically shows irregular ring enhancement with central necrosis, surrounding vasogenic edema, and mass effect
• FLAIR sequences demonstrate extent of infiltrative tumor and vasogenic edema 1
• Diffusion-weighted imaging helps differentiate tumor from other pathologies 1
• MRI is superior to CT for comprehensive evaluation of suspected brain tumors 1

Confirmatory Studies

Stereotactic biopsy or surgical resection with histopathological examination confirms diagnosis and provides molecular markers for prognosis and treatment planning.

• Histopathology demonstrates characteristic features: pseudopalisading necrosis, microvascular proliferation, high cellularity, nuclear atypia
• Molecular testing for IDH mutation status, MGMT promoter methylation, 1p/19q codeletion status guides prognosis and treatment
• Immunohistochemistry confirms glial origin (GFAP positive)

Additional Diagnostic Tests

• Complete spine MRI if leptomeningeal spread is suspected (though uncommon at presentation)
• Baseline neurocognitive assessment to document deficits and monitor treatment effects
• Ophthalmologic examination to document visual field deficits and evaluate for papilledema

Pre-test Probability for This Case: MEDIUM

Points FOR Glioblastoma:

• Progressive morning headaches worse with Valsalva indicate increased intracranial pressure 1
• Personality and mood changes suggest frontal or diffuse cerebral involvement 1
• Age 47 falls within typical age range for glioblastoma
• Subacute progression over weeks to months fits typical presentation 1
• Cerebellar signs could indicate posterior fossa glioma 1
• Bilateral temporal visual field loss could result from mass effect on visual pathways 1

Points AGAINST Glioblastoma:

• Posterior auricular lymphadenopathy is NOT typical for primary brain tumor and strongly suggests metastatic disease 1
• Small lesion behind right ear suggests primary skin malignancy rather than brain tumor 1
• Constitutional symptoms (5 kg weight loss) are more typical of systemic malignancy than primary brain tumor 1
• Pulmonary findings (decreased breath sounds, crackles) suggest systemic disease rather than isolated brain tumor 1
• Glioblastoma in posterior fossa is uncommon in adults (more typical in children) 1
• Multiple system involvement (CNS, lymph nodes, lungs, skin) argues against isolated primary brain tumor 1

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Chronic Subdural Hematoma

Mechanism(s) of Disease

Slow accumulation of blood in subdural space following minor or unrecognized head trauma causes gradual mass effect and increased intracranial pressure.

• Bridging veins tear from minor trauma (often forgotten or unrecognized), causing slow bleeding into subdural space
• Blood accumulates over weeks to months, forming organized hematoma with neomembrane formation
• Gradual expansion causes progressive mass effect, midline shift, and increased intracranial pressure 1
• Bilateral subdural hematomas occur in 15-25% of cases, potentially causing symmetric symptoms
• Chronic subdural hematomas can rebleed, causing acute-on-chronic presentation with sudden deterioration

Key History Features + Risk Factors

History of minor head trauma (often remote or forgotten) in older adults or those on anticoagulation predisposes to chronic subdural hematoma.

• History of head trauma, even minor, within preceding weeks to months (may be forgotten or unrecognized)
• Advanced age (>65 years)—this patient at age 47 is younger than typical
• Anticoagulation or antiplatelet therapy increases risk
• Alcohol abuse increases risk through coagulopathy and increased fall risk
• Progressive headaches developing over weeks to months 1
• Gradual cognitive decline, personality changes, or confusion 1
• Gait disturbance and falls may be both cause and consequence 1

Physical Exam Findings That Increase Likelihood

Fluctuating level of consciousness, focal neurological deficits, and gait disturbance in older adults should raise suspicion for chronic subdural hematoma.

• Gait ataxia and imbalance (though cerebellar signs are less typical for subdural hematoma) 1, 2
• Personality and mood changes indicating frontal lobe compression 1
• Focal neurological deficits depending on location and degree of mass effect 1
• Papilledema may be present with significant mass effect and increased intracranial pressure 1
• Any abnormality on neurological examination increases likelihood of abnormality on neuroimaging 1

Helpful Diagnostic Studies

First-Line Imaging

Non-contrast CT head is the initial imaging modality of choice for suspected subdural hematoma, though MRI provides superior characterization.

• CT head without contrast rapidly identifies subdural collections and is widely available in emergency settings 1
• Chronic subdural hematomas appear hypodense to isodense on CT (depending on age of blood)
• Acute-on-chronic subdural hematomas show mixed density with layering 1
• MRI brain provides superior characterization of subdural collections, showing signal characteristics that vary with age of blood 1
• MRI better demonstrates mass effect, midline shift, and associated brain injury 1

Confirmatory Studies

Imaging alone is typically sufficient for diagnosis; surgical evacuation provides both treatment and tissue confirmation if diagnosis is uncertain.

• Follow-up imaging (CT or MRI) documents progression or resolution with treatment
• Coagulation studies (PT/INR, aPTT, platelet count) to assess bleeding risk and guide reversal if needed
• Surgical evacuation via burr holes or craniotomy provides definitive treatment and allows tissue examination if diagnosis uncertain

Additional Diagnostic Tests

• Baseline neurological examination documented with standardized assessment 1
• Coagulation profile to identify reversible bleeding risk factors
• Assessment for underlying causes of falls or trauma

Pre-test Probability for This Case: LOW

Points FOR Chronic Subdural Hematoma:

• Progressive headaches worse in morning and with Valsalva could indicate mass effect 1
• Personality and mood changes can occur with frontal subdural collections 1
• Gait disturbance is common with chronic subdural hematoma 1, 2
• Subacute progression over weeks to months fits typical timeline

Points AGAINST Chronic Subdural Hematoma:

• Age 47 is younger than typical for chronic subdural hematoma (usually >65 years)
• No documented history of head trauma (though may be forgotten)
• Specific left-sided cerebellar signs are NOT typical for subdural hematoma, which causes more diffuse dysfunction 1, 2
• Bilateral temporal visual field loss is NOT explained by subdural hematoma 1
• Posterior auricular lymphadenopathy is NOT associated with subdural hematoma and suggests systemic disease 1
• Small lesion behind right ear is NOT related to subdural hematoma 1
• Constitutional symptoms (5 kg weight loss) are NOT typical for subdural hematoma 1
• Pulmonary findings (decreased breath sounds, crackles) are NOT explained by subdural hematoma 1
• Multiple system involvement argues strongly against isolated intracranial process 1

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Sources

Brain Metastasis from Melanoma:

1. Le Rhun E, Weller M, Brandsma D, et al. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017;28(suppl_4):iv84-iv99. doi:10.1093/annonc/mdx221

2. Simon RP, Aminoff MJ, Greenberg DA. Clinical Neurology, 10th ed. McGraw-Hill Education; 2018. (General neurology reference for metastatic disease patterns)

3. Soffietti R, Ahluwalia M, Lin N, Rudà R. Management of brain metastases according to molecular subtypes. Nat Rev Neurol. 2020;16(10):557-574. doi:10.1038/s41582-020-0391-x

4. Garbe C, Amaral T, Peris K, et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment – Update 2019. Eur J Cancer. 2020;126:159-177. doi:10.1016/j.ejca.2019.11.015

Glioblastoma:

1. Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170-186. doi:10.1038/s41571-020-00447-z

2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330

3. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106

Chronic Subdural Hematoma:

1. Kolias AG, Chari A, Santarius T, Hutchinson PJ. Chronic subdural haematoma: modern management and emerging therapies. Nat Rev Neurol. 2014;10(10):570-578. doi:10.1038/nrneurol.2014.163

2. Rauhala M, Luoto TM, Huhtala H, et al. The incidence of chronic subdural hematomas from 1990 to 2015 in a defined Finnish population. J Neurosurg. 2019;132(4):1147-1157. doi:10.3171/2018.12.JNS183035

3. Santarius T, Kirkpatrick PJ, Ganesan D, et al. Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial. Lancet. 2009;374(9695):1067-1073. doi:10.1016/S0140-6736(09)61115-6