Progressive Multifocal Leukoencephalopathy (Grand Rounds)

From EyeWiki
Original article contributed by: Mona A. Kaleem, MD
All contributors: Nagham Al-Zubidi, MD
Assigned editor: Andrew Go Lee, MD
Review: Assigned status Up to Date by Nagham Al-Zubidi, MD on January 10, 2016.


Progressive Multifocal Leukoencephalopathy (PML)

Chief Complaint

The Mysterious "Stroke"?

Mona A. Kaleem, M.D.

History

Chief complaint

Referred for abnormal visual fields with speech disturbance and right arm weakness

HPI

70 y/o right-handed white male attorney with progressively worsening right upper extremity weakness x 2 months associated with dysarthna and dysphagia. MRI of the brain performed at onset of initial symptoms revealed small vessel ischemic disease with white matter lesions in the left parietal and occipital lobes on DWI.

ROS

  • Word finding difficulties
  • Lethargy
  • Loss of balance

POH

Pseudophakia OU

PMH

  • Hyperlipidemia (HLP)
  • Prostate cancer s/p prostatectomy
  • Obstructive sleep apnea (OSA)
  • Pneumonia with persistent cough

Social history

  • Married
  • Attorney
  • C/A/D: + cigars/ 1-2 alcoholic beverages per week/no illicits

Family history

  • Pancreatic cancer (father)
  • Subarachnoid hemorrhage (mother)

Medications

  • Valsartan/HCTZ
  • Amlodipine
  • Metoprolol
  • Simvastatin
  • Aspirin

Allergies

  • Ciprofloxacin
  • Metronidazole

Examination

  • BCVa (cc)
    • OD: 20/25
    • OS: 20/20
  • CVF:
    • OU: right inferior homonymous quadrantanopsia
  • EOM:
    • OU: full
  • Pupils:
    • No APD
  • IOP:
    • OD: 10 mm Hg
    • OS: 15 mm Hg

Anterior Segment

  • Lids and Adnexa (L/L/L):
    • OU: normal
  • Conjunctiva/Sclera (CIS):
    • OU: normal
  • Cornea:
    • OU: normal
  • Tear film:
    • OU: normal
  • Anterior Chamber (A/C):
    • OU: deep and quiet
  • Iris:
    • OU: normal
  • Lens:
    • OU: PCIOL

Posterior Segment

  • Vitreous:
    • OU: normal
  • Optic nerve:
    • OU: cup to disk ratio of 0.3 with full rim
    • OU: optic disk drusen
  • Macula:
    • OU: full foveal reflex
  • Vessels:
    • OU: normal
  • Periphery:
    • OU: normal

Neurological Examination

  • Mental status:
    • Oriented to time (off by one day)
    • Recall of 3/3 objects at 5 minutes in tact
    • Difficulty spelling WORLD backwards
    • Unable to sequence presidents
    • Follows commands
  • Cranial nerves:
    • Right nasolabial fold flattening
    • Speech dysarthria and word finding difficulties
  • Sensation:
    • Graphesthesia diminished in right hand
  • Strength:
    • Right upper extremity: 4/5
  • No signs of neglect

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Interim History

  • Patients symptoms worsen requiring inpatient admission

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MRI

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Inpatient Work-Up

  • Vitals:
    • BP: 142/75
    • HR: 91 bpm
    • RR: 18 breaths/min
    • Pulse Ox: 96%
  • Pertinent labs:
    • WBC: 2.6 cells/ul
    • HSV 1 & 2 PCR negative
  • CSF analysis:
    • Protein: 56 mg/dl
    • Glucose: 50 mg/dl
    • RBC: 4/hpf
    • WBC: 4/hpf
    • Negative studies for:
      • HSV 1 & 2
      • Measles
      • Mumps
      • Culture & gram stain

Differential Diagnosis

  • Uncommon infections:
    • Progressive Multifocal Leukoencephalopathy (PML)
    • Atypical Creutzfeldt Jakob Disease (CJD)
  • Multiple small emboli:
    • Marantic Endocarditis
    • Septic Endocarditis
  • Autoimmune diseases:
    • Sarcoidosis
    • Atypical Multiple Sclerosis (MS) (late onset primary progressive)
  • Vasculitis:
    • Wegener's Granulomatosis
    • Systemic Lupus Erythematosus
    • Sjogren's (SLE)
    • Primary CNS Angiitis
    • Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
  • Malignancy:
    • Paraneoplastic
    • Lymphoma

Putting the Puzzle Together

  • HIV screening test:
    • Positive
    • CD4 count: 42 cells/ul
  • A review of the patient's pre-marital history revealed...
    • Chlamydia
    • Syphilis

Final Diagnosis

Progressive Multifocal Leukoencephalopathy (PML)

  • A human viral demyelinating disorder caused by polyomavirus JC (JCV)
  • First patient in 1958, John Cunningham
  • Infection of oligodendrocytes
  • Affects 3-5% of AIDS patients
  • May also occur in other immunocompromised states
  • Rare cases reported in MS patients taking natalizumab (Tysabri)

PML: Epidemiology

  • Immunocompromised states:
    • Medical therapy:
      • Corticosteroids: 40%
      • Chemotherapy: 16%
      • Natalizumab: 0.3%
    • Lympho and myelo proliferative states: 4.5%
    • Solid tumors: 4.5%
    • Congenital immunodeficiency disorders: 4.5%
    • HIV: 85%
      • PML is the initial AIDS defining illness in 25% of cases


Weber T. Progressive Multifocal Leukoencephalopathy. Neurologic Clinics 2008;26:833-854


PML: Clinical Manifestations

  • Signs and symptoms are largely nonspecific
  • Typically, a hemiparesis followed by aphasia, difficulty in gait and balance
  • Presenting symptoms:
    • Limb weakness: 52%
    • Cognitive deficits: 45%
    • Speech/visual deficits: 30%
    • Limb dyscoordination: 20%
    • Seizures/headaches/sensory symptoms


Weber T. Progressive Multifocal Leukoencephalopathy. Neurologic Clinics 2008;26: 833-854

PML: Pathophysiology

  • Double stranded circular DNA virus
    • Papoviridae family
  • Viral uptake by respiratory route --> remains latent in extra-neural sites --> disseminates to the CNS through the blood stream
  • JCV binds to receptors on oligodendrocytes and astrocytes, but not cortical neurons
  • Induces a humoral IgG and IgM response
  • Productive infection by JVC leads to multiple, small foci of myelination in the white matter > gray matter which coalesce

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PML vs. MS Relapse in Patients Treated with Natalizumab

Characteristic PML MS

Disease Course

Progressive worsening

Relapse and remission

Localization

Brain (diffuse and subcortical)

Brain, spinal cord & optic nerves (focal)

Imaging

Large & non-enhancing

Small & enhancing (Gad)


  • Diagnostic suspicion:
    • Send for serum, urine, and CSF samples for JCV detection
    • Treat with plasmapheresis


To establish criterion for the diagnosis PML algorithm have been recommended.

Two approaches to establish the diagnosis of PML

1. The presence of characteristic histopathological features of PML (triad of demyelination, enlarged oligodendroglial nuclei and bizarre astrocytes) with evidence of JC virus on electron microscopy, immunohistochemistry, or PCR

Or

2. The presence of clinical features or classic radiographic criteria with a positive CSF JC virus PCR.


PML: Diagnosis

  • Clinical presentation
  • MRI:
    • Focal or multifocal lesions of subcortical white matter without mass effect or contrast enhancement
      • T1: hypointense (dark) lesions
      • T2: hyperintense (bright) lesions
      • FLAIR: helpful for demonstrating periventricular disease
  • Cerebrospinal fluid analysis for JCV (PCR):
    • Sensitivity: 80%
    • Specificity: 95%
  • Detection of JCV in plasma:
    • 50% chance of diagnosis by serial plasma JCV load measurement
  • Brain biopsy**

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Management

PML: Treatment

  • HIV:
    • Highly active anti-retroviral therapy (HAART)
    • Cidofovir
  • Non-HIV:
    • Cytarabine
    • Mirtazapine
    • Mefloquine
    • Very poor prognosis
    • No cure

Discussion

Please use the discussion tab for this page to discuss this case.

References

  • Mwanza JC, et al. Neuro-ophthalmological disorders in HIV infected subjects with neurological manifestations 2004;88: 1455-1459.
  • Tan CS, Koralnik IJ. JC, BC, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy. In: Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier; 2010;2051-2058.
  • Vaklavas C, et al. Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression. Virology Journal 2010, 7;256: 1-5.
  • Weber T. Progressive Multifocal Leukoencephalopathy. Neurologic Clinics 2008;26: 833-854.
  • Wein F, et al. Neuro-ophthalmic findings in progressive multifocal leukoencephalopathy. Canadian Journal of Ophthalmology 1998, 33;5: 270-175.
  • Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013 Apr 9;80(15):1430-8.

Bibliography

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Acknowledgements

  • Dr. David Katz
    • Clinical Assistant Professor
    • Director of Neuro-ophthalmology
    • Howard University Hospital 1997 - present
  • Dr. John Millwater
    • Ophthalmologist in private practice, Washington D.C.
  • Dr. Dennis Cullen
    • Internist in private practice, Bethesda, Maryland