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PA34.1-3,PA35.1 | Nervous System & Eye — PBL Case

CLINICAL SETTING

The Pathology department of a government medical college in Varanasi receives two referrals in the same afternoon. The first is from the Emergency Department: Priya Tiwari, an 18-year-old first-year nursing student, was brought in by her classmates with a 4-day history of gradually worsening headache, fever (38.9°C), nausea, and a stiff neck. She had an upper respiratory infection three weeks ago. She has no prior illnesses, is fully immunised, and does not use immunosuppressant drugs. On examination she is drowsy but rousable, photophobic, and has moderate neck stiffness. Kernig and Brudzinski signs are elicited. No rash is noted. A lumbar puncture is performed. The second referral is from the Paediatric Ophthalmology outpatient clinic: 3-year-old Aryan Sharma is accompanied by his anxious mother, who noticed three weeks ago that his right eye appeared to have a 'white glow' in photographs taken with a flash. The ophthalmologist confirms leukocoria in the right eye under examination. There is no family history of eye disease. Aryan is otherwise healthy with normal developmental milestones.

Trigger 1: The CSF Report

Priya's CSF results are returned: Opening pressure: 220 mmH₂O (raised). Appearance: clear. WBC: 210 cells/µL (88% lymphocytes, 12% monocytes). Protein: 145 mg/dL (elevated). Glucose: 32 mg/dL with simultaneous serum glucose 88 mg/dL (CSF:serum ratio = 0.36, markedly reduced). Gram stain: negative. India ink stain: negative. ZN smear for AFB: pending. The tube of CSF is set aside to stand overnight and the next morning the lab notes a fine 'cobweb' coagulum floating in the fluid. Concurrent chest X-ray shows subtle apical haziness with calcified hilar lymph nodes bilaterally. Mantoux test: 18 mm induration.

DISCUSSION POINTS

  • Interpret the CSF profile systematically. The lymphocytic pleocytosis, high protein, and markedly low CSF glucose together with the cobweb coagulum, positive Mantoux, and apical chest X-ray changes point to a specific form of meningitis. Name it, explain which organism causes it, and describe how it reaches the meninges from the primary focus.
  • Explain the pathogenesis of the low CSF glucose in this form of meningitis. What three mechanisms reduce glucose in meningeal inflammation, and which is most important in the bacterial versus this form?
  • The 'cobweb coagulum' is mentioned as a characteristic finding. What constitutes this coagulum — what does it contain on histology — and why does it form specifically in this type of meningitis rather than in viral or acute bacterial meningitis?
  • Construct the CSF comparison table comparing acute bacterial, viral (aseptic), and this form of meningitis across the following parameters: appearance, WBC count and cell type, protein level, glucose level, and special stain or test needed for diagnosis. Identify the one parameter where all three forms overlap (making it least discriminating as a standalone test).
Click to reveal Trigger 2: Priya's Clinical Course and Aryan's Biopsy (discuss previous trigger first!)

Trigger 2: Priya's Clinical Course and Aryan's Biopsy

Priya is started on antitubercular therapy. Over the next 10 days she improves but then develops acute onset double vision and a dilated right pupil. MRI brain reveals basal exudate obliterating the basal cisterns, with enhancement around the cranial nerves at the base, and early hydrocephalus. Meanwhile, Aryan undergoes examination under anaesthesia; a white intraocular mass is seen arising from the posterior pole. A CT of the orbit shows a densely calcified intraocular mass with no extraocular extension. Enucleation is performed. Histology: sheets of small, round, hyperchromatic cells with scant cytoplasm and frequent mitoses, areas of calcification, and two types of rosette-like structures — some with a central lumen lined by columnar cells, and others with cells arranged around a central bundle of cytoplasmic fibrillary processes without a lumen.

DISCUSSION POINTS

  • Priya's new cranial nerve palsy (CN III — dilated pupil and diplopia) arises 10 days into treatment. Explain mechanistically how basal meningeal inflammation causes cranial nerve palsies, and name at least three other neurological complications of this form of meningitis, linking each to its underlying pathological mechanism (e.g., arteritis, hydrocephalus, vasculitis).
  • Aryan's tumour histology describes two types of rosettes. Name both rosette types, state what each represents in terms of degree of tumour differentiation, and identify which of the two is pathognomonic for this tumour versus which is seen in other small round blue cell tumours of childhood.
  • The enucleation specimen shows dense calcification within the tumour. Explain why calcification occurs so characteristically in this tumour (relate to rapid growth, tumour necrosis, and calcium deposition dynamics), and state the clinical significance of the calcification sign on CT imaging — why is CT superior to MRI for this specific finding?
  • Aryan's mother asks whether the other eye is at risk and whether her unborn second child could inherit the disease. Explain the two-hit hypothesis as it applies to this tumour: what are the two hits in the hereditary versus sporadic form, and how does knowing the germline status change screening and surveillance for this family?
Click to reveal Trigger 3: A Third Patient — Brain Biopsy (discuss previous trigger first!)

Trigger 3: A Third Patient — Brain Biopsy

The same afternoon, the Pathology department receives brain biopsy slides from a 58-year-old software company executive, Mr. Venkataraman, who presented to the neurosurgery department with progressive right-sided weakness and frontal headache over three months. MRI shows a large, ring-enhancing mass in the left frontal lobe crossing the corpus callosum, with surrounding oedema, central necrosis, and satellite lesions. He has no fever and is immunocompetent. Histology: highly cellular tumour with pleomorphic cells, prominent microvascular proliferation (glomeruloid tufts), and a striking area of geographic necrosis bordered by densely packed tumour cells arranged radially in a 'picket-fence' pattern. An additional slide from a 45-year-old woman shows a well-delineated extra-axial tumour with meningothelial cells arranged in concentric whorls and laminated, calcified concentric spheres.

DISCUSSION POINTS

  • The histology of Mr. Venkataraman's tumour shows pseudopalisading necrosis and microvascular proliferation — two features that are together diagnostic of a specific tumour. Name it, assign it a WHO grade, and explain why each of these two histological features arises: what metabolic and hypoxic events drive pseudopalisading, and what growth factor drives the microvascular proliferation?
  • Mr. Venkataraman is 58 years old and his tumour crosses the corpus callosum. Name two molecular markers whose status has the greatest impact on prognosis in this tumour type. Distinguish between a primary (de novo) and secondary (progressive) form of this tumour — which is more likely here and why?
  • The second slide from the 45-year-old woman shows the calcified concentric spheres (psammoma bodies) in a whorled pattern. Name this tumour and its cell of origin, explain why it produces psammoma bodies, and contrast its clinical behaviour (natural history, recurrence risk, metastatic potential) with Mr. Venkataraman's tumour.
  • Mr. Venkataraman's tumour is causing raised intracranial pressure and herniation risk. Describe the Monro-Kellie doctrine, name the three types of cerebral herniation (uncal, central, tonsillar), and for each state the characteristic neurological sign that the examining doctor would use to detect it at the bedside.

Group Task Assignments

Group 1: CSF interpretation framework

  • Construct the full CSF comparison table for acute bacterial, viral (aseptic), tubercular, and cryptococcal meningitis covering all parameters: appearance, opening pressure, WBC count and differential, protein, glucose (absolute and CSF:serum ratio), Gram stain, special stain/test, and characteristic clinical clue.
  • Design a one-page decision algorithm (flowchart) for a junior resident in a district hospital to determine — based on CSF results alone — whether to start antibiotics, antifungals, or ATT empirically while awaiting culture confirmation.

Competencies: PA34.1, PA34.3

Group 2: CNS tumour classification and recognition

  • Produce a master classification table of primary CNS tumours divided by cell of origin: astrocytic (GBM, low-grade glioma), oligodendroglial, ependymal, meningeal (meningioma), nerve sheath (schwannoma), embryonal (medulloblastoma). For each: WHO grade, peak age, location, defining histological feature, and key molecular marker.
  • For each tumour in the table, identify whether it occurs more commonly in children or adults and write one sentence that captures the single most useful histological feature for identification at the practical exam.

Competencies: PA34.2

Group 3: Retinoblastoma genetics and counselling

  • Prepare a diagram illustrating the two-hit hypothesis as it applies to hereditary versus sporadic retinoblastoma, showing at what stage each allele is lost, how this determines laterality and age of onset, and what downstream cell-cycle consequence follows loss of both RB1 alleles (E2F release → uncontrolled S-phase entry).
  • Write a structured counselling note for Aryan's mother covering: risk to the left eye (bilateral screening protocol), risk to the unborn sibling (germline testing rationale), surveillance plan for Aryan after treatment (second malignancy risk — osteosarcoma, the most common second tumour in survivors of hereditary retinoblastoma), and what leukocoria in any future pregnancies/newborns should trigger.

Competencies: PA35.1

Group 4: Complications and herniation

  • Map the complications of each of the three CNS conditions in this case (tubercular meningitis, GBM, retinoblastoma) onto a single diagram, organising them into acute (≤72 hours) and subacute/chronic (weeks–months) categories, and linking each complication to its specific pathological mechanism.
  • For raised ICP from CNS tumours: describe the Monro-Kellie doctrine, the three types of herniation (uncal, central, tonsillar), and the bedside clinical signs (pupillary change, vital sign changes, motor posturing, Cushing response) that signal each type in order of severity.

Competencies: PA34.1, PA34.2

Group 5: Small round blue cell tumour differential

  • Prepare a differential diagnosis table for the 'small round blue cell tumour' of childhood: medulloblastoma, Ewing sarcoma, rhabdomyosarcoma, retinoblastoma, and neuroblastoma. For each: site, age, defining translocation or molecular marker, histological feature that distinguishes it, and IHC panel used to confirm.
  • Explain why calcification is a helpful differentiating feature in the context of intraocular small round blue cell tumours, and contrast the rosette types found in retinoblastoma (Flexner-Wintersteiner vs Homer-Wright) with Homer-Wright rosettes in medulloblastoma.

Competencies: PA34.2, PA35.1

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PA34.1] How is meningitis classified by CSF cell type? What are the causative organisms by age group for bacterial meningitis? Describe the pathogenesis of tubercular meningitis from haematogenous dissemination to basal exudate formation, and the histology of the resulting granuloma. What are the CSF findings that distinguish bacterial, viral, and tubercular meningitis — and what is the 'cobweb coagulum'?
  2. [PA34.2] How are CNS tumours classified? Describe the pathology, molecular markers, WHO grade, location, and key histological features of: glioblastoma (pseudopalisading necrosis, microvascular proliferation, IDH/EGFR/MGMT status), oligodendroglioma (fried-egg cells, 1p/19q codeletion), meningioma (psammoma bodies, whorls, arachnoid cap cell origin), medulloblastoma (SRBCS, cerebellar location, WNT/SHH subgroups), schwannoma (Antoni A/B zones, Verocay bodies, NF2), and metastatic disease (grey-white junction, ring enhancement, commonest primaries).
  3. [PA34.3] Given a set of CSF parameters (appearance, pressure, WBC differential, protein, glucose, special stains), identify whether the meningitis pattern is consistent with acute bacterial, viral, tubercular, or cryptococcal aetiology. What is the CSF:serum glucose ratio threshold for normal and for each meningitis type?
  4. [PA35.1] What is the RB1 gene, where is it located, and what is the function of its protein pRb in the cell cycle? Explain the two-hit hypothesis as it applies to hereditary versus sporadic retinoblastoma. Describe the clinical presentation (leukocoria, age, laterality), histological features (SRBC, Flexner-Wintersteiner rosettes, Homer-Wright rosettes, calcification), routes of spread, and complications including the risk of second malignancies (especially osteosarcoma) in hereditary survivors.