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Case 22.6 – Creutzfeldt-Jacob Disease [SDL]

Category: Medicine | Discipline: Neurology | Setting: Emergency Department / Neurology Ward

Case

Annette Hay is a 29 year old woman who presents with a first seizure. She has been having intermittent headaches over the last few weeks. On examination she has a mild pyrexia and a reduced level of consciousness. Neurological examination reveals a left homonymous hemianopia and left arm weakness. The patient has recently returned from overseas travel.

Questions

1. What is the most likely diagnosis and what are the differential diagnoses?

Most Likely Diagnosis: Cerebral Abscess

Rationale:

  • Subacute presentation (weeks of symptoms)
  • Triad of features suggesting space-occupying lesion with infection:
    • Headache (raised ICP from mass effect)
    • Fever (infection)
    • Focal neurological signs (left hemianopia, left arm weakness - suggests right hemisphere lesion)
  • Seizure (common with cerebral abscess)
  • Reduced consciousness (raised ICP)
  • Recent overseas travel (potential exposure to infections)
  • Young age (cerebral abscess can occur at any age)

DIFFERENTIAL DIAGNOSES:

1. Brain Tumor (Primary or Metastatic):

  • Space-occupying lesion causing headache, seizures, focal signs
  • BUT: Less likely to cause fever (unless tumor necrosis)
  • Primary brain tumors: Glioma (glioblastoma, astrocytoma), meningioma, lymphoma
  • Metastases: Lung, breast, melanoma, renal, colon

2. Stroke (Hemorrhagic or Large Ischemic):

  • Can cause focal signs and seizures
  • BUT: Usually sudden onset (not weeks of symptoms)
  • Fever uncommon unless aspiration pneumonia develops

3. Encephalitis (Viral or Autoimmune):

  • Viral encephalitis (HSV, VZV): Fever, reduced consciousness, seizures
  • BUT: Usually more diffuse symptoms, less commonly focal signs
  • Autoimmune encephalitis: Behavioral changes, psychiatric symptoms, seizures, movement disorders

4. Tuberculoma:

  • Space-occupying CNS TB lesion (granuloma)
  • Similar presentation to abscess
  • Consider especially if from TB-endemic area or immunocompromised

5. Toxoplasmosis (if immunocompromised):

  • Multiple ring-enhancing lesions
  • Most common in HIV/AIDS patients with CD4 <100

6. Neurocysticercosis:

  • Parasitic infection (Taenia solium - pork tapeworm)
  • Cysts in brain causing seizures, headaches, focal signs
  • Consider if travel to endemic areas (Latin America, Asia, Africa)

7. Other Infections:

  • Subdural empyema
  • Cerebral malaria (if travel to malaria-endemic area)
  • Fungal abscess (if immunocompromised)
2. What investigations would you perform and what management would you initiate?

INVESTIGATIONS FOR SUSPECTED CEREBRAL ABSCESS:

1. URGENT IMAGING:

CT Brain with Contrast:

  • First-line investigation - quick, widely available
  • Classic findings of cerebral abscess:
    • Ring-enhancing lesion (abscess capsule enhances with contrast)
    • Central hypodensity (pus)
    • Surrounding edema (low density)
    • Mass effect (midline shift, ventricular compression)
  • Can be single or multiple lesions

MRI Brain with Contrast (if available):

  • More sensitive than CT
  • Better for posterior fossa lesions
  • DWI (diffusion-weighted imaging): Abscess shows restricted diffusion (bright on DWI, dark on ADC) - helps distinguish abscess from tumor/other lesions
  • Better characterization of lesion and surrounding structures

2. BLOOD TESTS:

  • FBC: Leukocytosis (elevated WCC)
  • CRP, ESR: Elevated (markers of infection/inflammation)
  • Blood cultures: May identify causative organism (positive in ~10% of cerebral abscess)
  • U&Es, LFTs: Baseline, assess for organ dysfunction
  • HIV test: If risk factors or multiple lesions (toxoplasmosis)
  • Malaria film: If travel to endemic area

3. LUMBAR PUNCTURE:

  • CONTRAINDICATED if space-occupying lesion suspected
  • Risk of cerebral herniation (coning) due to raised ICP
  • DO NOT perform LP until imaging done and no mass effect/raised ICP
  • If safe to do (no mass effect), CSF may show:
    • Elevated protein
    • Pleocytosis (if abscess ruptures or meningitis coexists)
    • BUT CSF often normal or non-specific with cerebral abscess

4. MICROBIOLOGY:

Aspiration/Biopsy of Abscess (Neurosurgical procedure):

  • Gold standard for identifying organism
  • Send pus for:
    • Gram stain
    • Bacterial culture (aerobic and anaerobic)
    • Fungal culture
    • TB culture and PCR
    • Toxoplasma PCR
  • Also sends tissue for histology

5. INVESTIGATIONS TO FIND SOURCE:

  • Chest X-ray: Pneumonia, lung abscess
  • Echocardiography (TTE/TOE): Endocarditis (source of septic emboli)
  • Dental examination: Dental infections common source
  • Sinus CT: Sinusitis (especially frontal)
  • Ear examination + temporal bone CT: Otitis media, mastoiditis

IMMEDIATE MANAGEMENT OF CEREBRAL ABSCESS:

1. RESUSCITATION AND SUPPORTIVE CARE:

  • ABC assessment
  • Airway protection if GCS <8
  • IV access
  • Oxygen if hypoxic
  • IV fluids (but avoid fluid overload - can worsen cerebral edema)

2. SEIZURE MANAGEMENT:

  • If actively seizing: IV benzodiazepines (lorazepam or diazepam)
  • Anticonvulsant prophylaxis: Start in ALL patients with cerebral abscess (high seizure risk)
    • Levetiracetam or phenytoin
    • Continue for at least duration of treatment, often longer

3. RAISED ICP MANAGEMENT:

  • Nurse head-up 30°
  • Avoid hypotension (maintain adequate cerebral perfusion)
  • Dexamethasone:
    • Controversial - may reduce edema but can impair antibiotic penetration and host immune response
    • Consider if severe mass effect/impending herniation
    • Dose: Dexamethasone 4-10mg IV 6-hourly
    • Taper once mass effect improves
  • Osmotherapy (if severe raised ICP): Mannitol or hypertonic saline
  • Neurosurgical referral if deteriorating

4. EMPIRICAL ANTIBIOTICS (start immediately after imaging/cultures):

Choice depends on likely source:

Unknown source / Multiple sources:

  • Ceftriaxone 2g IV 12-hourly (or cefotaxime)
  • PLUS Metronidazole 500mg IV 8-hourly (for anaerobic coverage)
  • PLUS Vancomycin 15-20mg/kg IV 8-12 hourly (if risk of Staph aureus, e.g., post-trauma, post-surgery, endocarditis)

Post-neurosurgery / Penetrating head trauma:

  • Vancomycin PLUS Ceftazidime (or meropenem)
  • Covers MRSA, Pseudomonas, Gram-negatives

If immunocompromised (HIV, transplant, steroids):

  • Consider toxoplasmosis: Empirical treatment with pyrimethamine + sulfadiazine + folinic acid
  • Also consider fungal causes: Add amphotericin B or voriconazole

Duration:

  • Prolonged antibiotics required: Minimum 4-6 weeks IV (often 6-8 weeks)
  • Guided by clinical response and repeat imaging

5. NEUROSURGICAL INTERVENTION:

Indications for surgery:

  • Diagnostic: Aspiration/biopsy to identify organism (if not responding to empirical antibiotics)
  • Therapeutic: Drainage or excision if:
    • Large abscess (\>2.5 cm)
    • Significant mass effect
    • Deteriorating despite antibiotics
    • Posterior fossa location (risk of herniation)
    • Multiloculated or thick-walled abscess (poor antibiotic penetration)

Surgical options:

  • Aspiration (stereotactic or open): Less invasive, can be repeated
  • Excision: Complete removal of abscess (for accessible, encapsulated abscesses)

6. MONITORING AND FOLLOW-UP:

  • Serial imaging (CT/MRI) to monitor response (typically weekly initially)
  • Monitor inflammatory markers (CRP, WCC)
  • Neurology/neurosurgery follow-up
  • Continue anticonvulsants long-term (high seizure risk even after treatment)

7. TREAT UNDERLYING SOURCE:

  • Dental treatment if dental abscess
  • ENT referral if sinusitis/otitis media
  • Antibiotics for endocarditis if present
3. What is Creutzfeldt-Jakob Disease (CJD)? Describe the clinical features, investigations, and prognosis.

CREUTZFELDT-JAKOB DISEASE (CJD)

CJD is a rare, rapidly progressive, fatal neurodegenerative disease caused by prions (infectious proteins).

PATHOPHYSIOLOGY:

  • Prion disease: Caused by misfolded prion proteins (PrPSc) that induce normal prion proteins (PrPC) to misfold
  • Results in accumulation of abnormal prion proteins in brain
  • Causes neuronal death, spongiform (sponge-like) changes in brain tissue
  • Progressive, irreversible, always fatal

TYPES OF CJD:

1. Sporadic CJD (sCJD) - ~85% of cases:

  • Most common form
  • Cause unknown (spontaneous misfolding of prion protein)
  • Peak age: 60-70 years
  • Rapid progression (median survival ~4-6 months from symptom onset)

2. Familial/Genetic CJD (~10-15%):

  • Inherited mutations in PRNP gene (prion protein gene)
  • Autosomal dominant
  • Earlier age of onset (can be <50 years)

3. Acquired CJD (~1%):

a) Variant CJD (vCJD) - "Mad Cow Disease":

  • Linked to consumption of BSE-infected beef (bovine spongiform encephalopathy)
  • Younger age of onset (median ~28 years)
  • Longer duration (~14 months)
  • Different clinical features: Psychiatric symptoms prominent early, painful sensory symptoms
  • Very rare now (peak in UK in 1990s-2000s)

b) Iatrogenic CJD:

  • Transmission via contaminated medical procedures
  • Sources: Contaminated neurosurgical instruments, dura mater grafts, corneal transplants, human growth hormone (from cadaver pituitary glands - no longer used)
  • Very rare now due to infection control measures

CLINICAL FEATURES OF SPORADIC CJD:

Early symptoms (first weeks-months):

  • Rapidly progressive dementia: Memory loss, confusion, cognitive decline
  • Behavioral/psychiatric changes: Depression, anxiety, apathy, personality change
  • Ataxia: Unsteady gait, incoordination
  • Visual disturbances: Blurred vision, visual field defects, cortical blindness

Progressive symptoms (weeks-months):

  • Myoclonus: Sudden, brief, involuntary muscle jerks (very characteristic of CJD - present in ~90%)
  • Often stimulus-sensitive (startle to noise/touch)
  • Pyramidal and extrapyramidal signs: Rigidity, spasticity, tremor
  • Further cognitive decline: Severe dementia
  • Akinetic mutism: Late stage - patient awake but unresponsive, mute, immobile

Terminal stage:

  • Akinetic mutism
  • Bedbound
  • Death usually from aspiration pneumonia or other complications

INVESTIGATIONS:

1. MRI Brain:

  • DWI (diffusion-weighted imaging) and FLAIR sequences: Most sensitive
  • Classic findings:
    • "Cortical ribboning": Hyperintensity of cerebral cortex
    • "Hockey stick sign" or "pulvinar sign": Hyperintensity in basal ganglia (caudate, putamen) and thalamus
  • High sensitivity and specificity for CJD

2. EEG (Electroencephalogram):

  • Classic finding: Periodic sharp wave complexes (PSWCs)
  • Generalized, bilaterally synchronous, 1-2 Hz
  • Present in ~65% of sporadic CJD (less sensitive than MRI)
  • Can be triggered by stimuli

3. CSF Analysis:

  • 14-3-3 protein: Elevated in ~90% of sporadic CJD
    • Released from dying neurons
    • Sensitive but not specific (also elevated in other rapid neurodegenerative conditions, stroke, encephalitis)
  • RT-QuIC (Real-Time Quaking-Induced Conversion):
    • Newer test - detects prion protein in CSF
    • Very high sensitivity (\>95%) and specificity (\>99%)
    • Becoming gold standard CSF test for CJD
  • Total tau protein: Markedly elevated (\>1200 pg/mL suggests CJD)
  • Routine CSF (cell count, protein, glucose): Usually normal or non-specific

4. Brain Biopsy:

  • Rarely done (diagnosis usually made on clinical + MRI + CSF)
  • Shows spongiform changes, neuronal loss, gliosis
  • Immunohistochemistry for prion protein

5. Genetic Testing:

  • PRNP gene sequencing if familial CJD suspected (family history, young age)

DIAGNOSTIC CRITERIA FOR SPORADIC CJD:

Definite CJD:

  • Neuropathological or immunohistochemical confirmation

Probable CJD:

  • Rapidly progressive dementia PLUS
  • At least 2 of: Myoclonus, visual/cerebellar signs, pyramidal/extrapyramidal signs, akinetic mutism
  • PLUS at least one of:
    • Typical EEG (periodic sharp waves)
    • Positive 14-3-3 CSF with clinical duration <2 years
    • MRI showing high signal in caudate/putamen or ≥2 cortical regions

Possible CJD:

  • Progressive dementia
  • Plus 2 of the 4 clinical features listed above
  • But no EEG/MRI/CSF support
  • Duration <2 years

DIFFERENTIAL DIAGNOSIS:

  • Other rapidly progressive dementias:
    • Alzheimer's disease (but usually slower progression)
    • Dementia with Lewy bodies
    • Frontotemporal dementia
  • Autoimmune encephalitis: Anti-NMDA receptor, anti-LGI1, etc. (TREATABLE - important to exclude!)
  • Paraneoplastic syndromes
  • Metabolic encephalopathy: Hepatic, uremic, Hashimoto's encephalopathy
  • Viral encephalitis
  • Cerebral vasculitis
  • Toxic: Lithium, bismuth

MANAGEMENT:

  • NO CURE OR DISEASE-MODIFYING TREATMENT
  • Supportive care only:
    • Symptomatic management (myoclonus - clonazepam, valproate)
    • Psychological support for patient and family
    • Advance care planning
    • Palliative care
    • Manage complications (dysphagia, aspiration, infections)

INFECTION CONTROL:

  • Prions extremely resistant to standard sterilization
  • Special decontamination protocols for surgical instruments
  • Autopsy/biopsy: Special precautions
  • NOT transmissible by casual contact
  • Standard precautions for healthcare workers

PROGNOSIS:

  • Sporadic CJD: Median survival 4-6 months from symptom onset
  • 90% die within 1 year
  • Invariably fatal
  • Death usually from pneumonia, sepsis, or other complications of immobility

NOTIFICATION:

  • CJD is a notifiable disease in many countries
  • Surveillance important for tracking variant CJD and other forms