Review Question - QID 217002

This patient on long-term therapy with natalizumab, who presents with subacute neurological deficits (difficulty concentrating, weakness, and loss of coordination) and a confluent white matter lesion on MRI likely has progressive multifocal leukoencephalopathy (PML). PML is caused by the reactivation of the John Cunningham (JC) virus, a DNA polyomavirus.

Natalizumab is a humanized monoclonal antibody against alpha-4-integrin that inhibits cell adhesion molecules that guide T-lymphocyte movement into organs. This immunosuppressive medication is used for the treatment of multiple sclerosis and Crohn disease. However, long-term use of this medication is associated with the reactivation of the JC virus, which destroys oligodendrocytes and causes the widespread central nervous system (CNS) demyelination seen in PML. PML presents with subacute neurological deficits that include hemiparesis or monoparesis, ataxia, and altered mental status. The risk of natalizumab-associated PML increases with the length of time on the therapy and increases with pre-treatment seropositivity for anti-JC virus antibodies. Treatment is to stop the agent and initiate plasmapheresis.

Bloomgren et al. quantify the risk of developing natalizumab-associated progressive multifocal leukoencephalopathy and identify key risk-factors to be anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment.

Figure/Illustration A shows a T2-weighted-Fluid-Attentuated-Inversion-Recovery (T2-FLAIR) magnetic resonance imaging (MRI) sequence. In this sequence, cerebrospinal fluid (CSF) is dark, normal white matter is dark gray, cortex is light gray, fat is bright, and inflammation is bright. There is an extensive area of hyperintensity (red arrow) in the subcortical regions of the right frontoparietal lobe that is characteristic of inflammation due to destruction of oligodendrocytes by JC virus in PML.

Incorrect Answers:
Answer 1: Acute disseminated encephalomyelitis (ADEM) is an autoimmune inflammatory demyelination of the central nervous system that is usually secondary to infection or vaccination. ADEM generally presents with acute, progressive, multifocal neurological deficits including changes in cognition, ataxia, sensory deficits, motor deficits, and cranial neuropathy. In this patient with a more subacute presentation of neurological deficits, long-term natalizumab use, and no recent history of infection, PML is more likely than ADEM.

Answer 2: Arylsulfatase deficiency leads to an inability to degrade sulfatides and myelin breakdown, and is the enzyme deficiency underlying the autosomal recessive lysosomal storage disease, metachromatic leukodystrophy (MLD). The adult form of MLD can present as a progressive dementia or psychiatric disorder. However, this disease usually has a more insidious course than the subacute presentation seen in this patient.

Answer 3: An autoantibody against aquaporin-4 (AQP-4) is associated with neuromyelitis optica (NMO). Classically, NMO is a monophasic illness that presents with the triad of optic neuritis, longitudinally extensive myelitis, and anti-AQP4 autoantibody. This patient’s subacute presentation, lack of symptoms of optic neuritis, and confluent white matter lesion on MRI are more suggestive of PML. Of note, while natalizumab is an effective medication for MS, it is not effective for NMO.

Answer 5: A multiple sclerosis (MS) relapse may present with multifocal neurological deficits similar to in this patient, including changes in cognition, coordination, and weakness. However, in this patient on the immunosuppressant medication natalizumab and with confluent lesions on her T2-FLAIR MRI sequence, PML is more likely.

Bullet Summary:
Long term use of natalizumab can lead to reactivation of latent JC virus and progressive multifocal leukoencephalopathy.