Progressive clumsiness in a patient with prior Hodgkins

This week’s episode of “Teaching through Clinical Cases” features a 69-year-old man with history of Hodgkins who developed dysarthria, left-sided dysmetria, and truncal ataxia. Dr. Joseph R. Berger helps us get through the case:

The patient was initially diagnosed with Hodgkins in October 1976 following biopsy of a mediastinal mass with staging laparotomy and splenectomy. He received mantle radiotherapy to his upper mediastinum and supraclavicular fossa, followed by six cycles of methchlorethamine, vincristine, procarbazine, and prednisone (MOPP). He later received para-aortic radiotherapy and was cured in 1977.

There were no complications from his disease or treatment until September 2016, when he presented with two months of progressive dysarthria, left-sided dysmetria, and gait ataxia. An MRI brain with and without contrast demonstrated a non-enhancing white matter lesion in the left cerebellar hemisphere and middle cerebellar peduncle.

Gadolinium-enhanced T1-weighted image of the cerebellum with associated FLAIR image.

While routine laboratory surveillance revealed normal white blood cell and absolute lymphocyte counts during the preceding decade, serum studies were notable for a negative HIV antibody, elevated JCV antibody, and CD4+ count of 260/uL. Diagnostic lumbar puncture was also notable for a normal cell count, protein, glucose, culture, flow cytometry, cytopathology; 8 oligoclonal bands; and negative JCV PCR. A stereotactic biopsy of his cerebellar lesion was later performed. Although preliminary pathology was concerning for a primary glial neoplasm, final histopathology confirmed PML. He was subsequently referred to the National Institutes of Health for a clinical trial involving pembrolizumab.

John Cunningham virus virion particles.

The JC virus, or John Cunningham virus, is a member of the polyomavirus family. When you’re exposed to it as a kid or young adult, you might not even notice it, or you might notice cold-like symptoms which are self-limiting. Not a huge deal at all. You get infected, you make antibodies, life goes on. As long as you’re immunocompetent. But that’s not the case in patients with impaired cellular immunity, as in cases of Hodgkins lymphoma (HL).

Although the gold standard for diagnosis is brain biopsy, you don’t need tissue to make the diagnosis of PML. In an immunocompromised patient with progressive neurologic changes, you’ll always need the MRI. This can exclude opportunistic processes like toxoplasmosis, cryptococcal meningitis, or CNS lymphoma, but will also be important to confirm the presence of white matter disease, which may or may not have enhancement 10-20% of the time, and may or may not have mass effect. Our patient had faint enhancement, as you can see from the images on the blog. Once the MRI confirms the predominant white matter involvement, you’ll need to identify JC virus in the CSF. However, in 5-25% of cases, the PCR for JC virus can be negative when a patient has true PML. Which was the case for our patient. So if the imaging is suggestive, but CSF is negative, you’ll need the brain biopsy to confirm the diagnosis. The full details of this diagnostic algorithm were published by Dr. Berger in the journal, Neurology, back in 2013, and they’ve remained the standard workup for PML ever since:

Diagnostic algorithm for PML (Berger, et al, 2013).

Treatment of PML involves addressing the underlying mechanism for impaired cellular immunity, including immune reconstitution with highly active anti-retroviral therapy for HIV patients or plasmapheresis for patients treated with monoclonal antibodies. For other patients, therapy is more limited. Check out the episode for more details.

In conclusion, for patients with a history of a hematologic malignancy like Hodgkins lymphoma, impaired cellular immunity can persist for decades following diagnosis and treatment, requiring annual laboratory surveillance. However, current NCCN guidelines fall short of recognizing that CD4+ lymphopenia may be masked by normal total lymphocyte counts in survivors of HL. Larger cohort studies are needed to quantify the patients who remain at risk for opportunistic CNS infections despite current standards of care.


[Jim Siegler]

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