DIAGNOSIS AND DISCUSSION
In situ hybridization for JCV demonstrated abundant intracellular and extracellular signal in bilateral cerebellar white matter (Fig. 16). Positive JCV ISH was not present in all other brain areas.
Correct and prompt diagnosis of a new onset lesion in Natalizumab treated MS patients is critical for clinical management. The differential diagnosis is mostly focused on acute exacerbation of MS versus PML. However, other rare forms of acute demyelinating disease might be considered (e.g. HIV encephalitis, mitochondria encephalopathies, acute disseminated encephalomyelitis). The distribution of new lesions can be helpful, as PML seldom involves optic nerves and the spinal cord.
MRI is a sensitive means to assess new onset lesions in MS. Acute MS lesions are characterized by marked peripheral contrast enhancement. PML lesions show asymmetric FLAIR/T2 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 (Fig. 2). Lesions can be localized or multifocal. Involvement of parieto-occipital lobes, arcuate fibers, corpus callosum, cerebellum, middle cerebellar peduncles and/or pons is common with sparing of periventricular white matter, optic nerves and spinal cord (6, 8). The majority of PML patients have cerebral hemisphere involvement (1). For unknown reasons PML in MS patients treated with Natalizumab is more likely to occur in the cerebellum and crescent-shaped cerebellar lesions are characteristic (2). Since the inflammation in PML is typically not intense, significant edema and contrast enhancement are atypical findings (4).
In this case, the periventricular and spinal cord demyelinating lesions showed relative preservation of axons (Fig. 8), minimal inflammation (Fig. 9) and no evidence of active demyelination (Fig. 10). These features, together with the clinical history of longstanding, treated MS, are diagnostic of quiescent MS plaques.
The patient's cerebellar demyelinating lesions were microscopically distinct by LFB/CV stain (Fig. 12). Macrophages with intracellular myelin debris, a hallmark of an active demyelinating process, were abundant (Figs. 13 and 14). 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 (Fig. 16). Positive JCV ISH was not present in all other brain areas. Although typical PML lesions show little or absent immune response, the pronounced CD8-positive T lymphocyte infiltrate (Fig. 15) in the regions of active demyelination, together with clinical deterioration in this case, are diagnostic of immune reconstitution inflammatory syndrome (IRIS) (4).
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 first isolated in 1971 (7). JCV has a high seroprevalence in adults (39 - 68%) (8). Primary JCV infection results in latency in the kidney, tonsil, leukocytes, and/or brain (10). Up to 30% of random urine samples are positive for JCV (5). The exact mode(s) of transmission, the relationship between different viral variants such as archetype and prototype (PML/neurotropic-type), and the development of PML remain to be fully investigated.
PML usually occurs in immunocompromised patients. 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 4), rituximab (anti-CD20), and efalizumab (anti-CD11a) (10). While Natalizumab has been shown to improve prognosis and quality of life of MS patient (7), it was withdrawn from the market briefly after the complication of PML was identified. Because of its marked beneficial effects in relapsing remitting MS patients Natalizumab was subsequently re-introduced (3). However, the association with PML has limited its application. The estimated risk of PML in MS treated with Natalizumab is around 0.14 - 0.24 %(7). Efalizumab was withdrawn from the market in 2009 after the occurrence of three PML cases.
Because early symptoms and signs of PML can mimic flare/relapse in MS patients or stroke, the diagnosis of PML should be considered with a high index of suspicion in treated patients with the appropriate clinical history and newly developed subacute, progressive neurologic symptoms. CSF PCR for JCV is often helpful for diagnosis of PML. It has a sensitivity of 72 - 92% and a specificity of 92 - 100% (6). Unfortunately viral loads in patients treated with Natalizumab or in HAART-treated AIDS patients are often low and may result in false negative tests (4). Hence, a negative CSF PCR result does not exclude the possibility of PML. Repeated CSF JCV PCR and brain biopsy should then 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, plasmapheresis to remove remaining immunosuppressants, and/or antiretroviral therapies in HIV-infected patients. Reversal of immunosuppression and antiretroviral therapies, however, expose the patients to developing IRIS. IRIS is defined clinically as paradoxical deterioration following immune reconstitution by plasmapheresis or antiretroviral therapies, and histologically by inflammation in the presence of CD8-positive T cells (4). The reactive lymphoid cells in IRIS can lead to encephalitis, acute demyelinating lesions, or exacerbate damage to PML lesions. IRIS occurs more frequently and are usually more severe in Natalizumab-associated PML (3). Early use of corticosteroids can decrease the severity of IRIS (9).
The prognosis of PML is poor (3) with a clinical course limited to a few weeks. Lesions involving the brainstem have the worst prognosis (6). Survivors of PML commonly have permanent neurological deficits. For more detailed information of PML, please refer to the following excellent review articles: Kleinschmidt-DeMasters et al. (4), Sahraian et al. (6), White et al. (10), Tavazzi et al. (7, 8), and Hellwig et al. (3).
The authors thank Jonette Werley for her technical support.
Contributed by Cheng-Hsuan Chiang, MD, PhD, Charleen T. Chu, MD, PhD, and Clayton A. Wiley, MD, PhD