A 67 Year‐Old Man with Multiple Sclerosis and New Cerebellar Lesions

Clinical History

The patient was a 67‐year‐old male with a 39‐year history of relapsing multiple sclerosis (MS). He had been treated with 54 doses of Natalizumab (Tysabri) during the past 5 years. Due to new onset of neurological symptoms including bilateral upper extremity dysmetria, slurred speech and choking, MRI of the brain was performed. FLAIR/T2 showed longstanding lesions in the cerebral periventricular regions bilaterally (Fig. 1a) and new hyperintense foci in bilateral cerebellar white matter extending into the middle cerebellar peduncles (Fig. 1b). The larger left‐sided cerebellar lesion measured 2.7 x 2.4 cm. The cerebral and cerebellar lesions had well‐defined borders with no significant mass effect and minimal peripheral contrast enhancement. CSF analysis showed an opening pressure of 12 mm H₂O, a normal differential count and glucose level with an elevated protein level, elevated IgG index and oligoclonal bands. HHV6, HSV1, HSV2, and cytology studies were negative. The patient was admitted. Natalizumab was discontinued, and plasmapheresis and IV Dexamethasone initiated. Despite the treatment, his neurological condition continued to deteriorate. He was discharged to hospice and expired 8 days afterward.

Figure 1.

 

Autopsy Neuropathology Findings

Autopsy revealed multiple grossly well‐defined lesions in the bilateral cerebral periventricular areas (Fig. 1c), cerebellar white matter (Fig. 1d) and gray and white matter of the spinal cord. Cerebellar lesions appeared softened and depressed after sectioning.

Microscopic Neuropathology Findings

LFB/CV stains demonstrated multiple well‐defined periventricular chronic demyelinating lesions (Fig. 1e), and multiple areas of demyelination in both gray and white matter of the spinal cord with mild loss of motor neurons in demyelinated gray matter areas. LFB/H&E stain showed chronic demyelination of the right optic nerve (Fig. 1f). Periventricular and spinal cord demyelinating lesions showed preserved axons with minimal inflammation and few macrophages. Lightly myelinated axons were present in the periphery of the lesions. The cerebellar lesions showed significant areas of demyelination with indistinct borders (Fig. 1g). Abundant myelin debris was seen in the extracellular space and within macrophages. CD68 immunostain demonstrated abundant macrophages (Fig. 1h). A marked CD3‐positive, CD8‐positive T lymphocyte infiltrate was also present (Fig. 1i). What additional stain is required for the diagnosis of the cerebellar lesions? (Fig  1 j) What are your final diagnoses?

Diagnosis and Discussion

Additional stain:

In situ hybridization for JCV demonstrated abundant intracellular and extracellular signal in bilateral cerebellar white matter (Fig. 1j). Positive JCV ISH was not present in all other brain areas.

Diagnosis

1. Progressive multifocal leukoencephalopathy (PML) involving bilateral cerebellar white matter, dentate nuclei and middle cerebellar peduncles, with superimposed immune reconstitution inflammatory syndrome (IRIS).

2. Quiescent multiple sclerosis plaques in multiple areas of the cerebral periventricular white matter, gray and white matter of the spinal cord, and the right optic nerve.

Discussion

Prompt diagnosis of a new onset lesion in Natalizumab treated MS patients is critical for management. The differential diagnosis is mostly focused on acute exacerbation of MS versus PML. The distribution of new lesions can be helpful, as PML seldom involves optic nerves and the spinal cord.

MRI is a sensitive to assess new onset lesions in MS patients. Acute MS lesions are characterized by marked peripheral contrast enhancement. PML lesions show asymmetric FLAIR hyperintensity and T1 hypointensity in white matter with sharp borders and a central hypointensive area, usually without significant mass effect and minimal peripheral contrast enhancement. Involvement of parieto‐occipital lobes, corpus callosum, middle cerebellar peduncles and/or pons is common with sparing of periventricular white matter, optic nerves and spinal cord 2.

In this case, the periventricular and spinal cord demyelinating lesions showed relative preservation of axons, minimal inflammation and no evidence of active demyelination. These features, together with the clinical history, are diagnostic of quiescent MS plaques.

The patient's cerebellar lesions were distinct by LFB/CV stain. Macrophages with intracellular myelin debris, a hallmark of an active demyelinating process, were abundant. Oligodendrocytes with enlarged nuclei and reactive astrocytes could also be identified. In situ hybridization (ISH) for JCV demonstrated abundant intracellular and extracellular signal in bilateral cerebellar white matter. The pronounced CD8+ T lymphocyte infiltrate in the regions of active demyelination, together with clinical deterioration in this case, are diagnostic of immune reconstitution inflammatory syndrome (IRIS).

PML is a central nervous system demyelinating disease caused by infection and lysis of oligodendrocytes by polyomavirus JC, a double‐stranded, circular DNA virus of the Polyomaviridae family. Before the introduction of new immunomodulatory monoclonal antibodies for treatment of MS, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, PML primarily occurred in organ transplant recipients, human immunodeficiency virus (HIV)‐infected patients, or patients with immunosuppression due to lymphoproliferative or autoimmune diseases. PML has more recently been associated with monoclonal antibodies including Natalizumab (anti‐integrin α4), rituximab (anti‐CD20), and efalizumab (anti‐CD11a) 4. The estimated risk of PML in MS treated with Natalizumab is around 0.14–0.24% 3.

Because early symptoms and signs of PML can mimic flare/relapse or stroke, the diagnosis should be considered with a high index of suspicion in patients with the appropriate clinical history and newly developed subacute, progressive neurologic symptoms. CSF PCR for JCV is often helpful for diagnosis. It has a sensitivity of 72–92% and a specificity of 92–100% 2. Unfortunately viral loads in patients treated with Natalizumab or HAART are often low and may result in false negative tests 1. Hence, a negative CSF PCR result does not exclude the possibility of PML. Repeated CSF JCV PCR and brain biopsy should be considered in appropriate clinical settings. Post‐mortem JCV ISH permits definitive diagnosis.

The only effective treatment for PML is immune reconstitution including discontinuing or decreasing immunosuppressive drugs and plasmapheresis to remove remaining immunosuppressants. Reversal of immunosuppression, however, exposes the patients to developing IRIS. IRIS is defined clinically as paradoxical deterioration following immune reconstitution, and histologically by inflammation in the presence of CD8+ T cells 1.

The prognosis of PML is poor with a clinical course limited to a few weeks. Lesions involving the brainstem have the worst prognosis 2. Survivors of PML commonly have permanent neurological deficits.