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A case of pathologically confirmed progressive multifocal leucoencephalopathy presenting with unilateral parkinsonism and cognitive decline that significantly improved over a 12‐month period without any treatment is described. The patient had a background of chronic lymphocytic leukaemia, but had been in complete remission for 4 years at the time of diagnosis. This case is highly unusual not only in terms of the mode of clinical presentation in an apparently immunocompetent patient but also in that the patient spontaneously improved without any intervention. Progressive multifocal leucoencephalopathy should therefore be considered in the differential diagnosis of movement disorders developing in patients with a history of lymphoproliferative disease, even if they are in remission. Furthermore, such cases may not always require treatment, as the patient's immune system may overcome the viral disease process with spontaneous resolution of their neurological disorder.
A 39‐year‐old man presented with a 6‐month history of stiffness and clumsiness affecting the right hand as well as mild but progressive difficulties with memory, concentration and word finding. The patient had been diagnosed with B‐cell chronic lymphocytic leukaemia 11 years previously and had received treatment with chlorambucil, fludarabine, a course of CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone) and alemtuzumab (CamPath) before relapsing. He subsequently required two allogeneic bone marrow transplants (from the same donor) and a splenectomy, but had been in remission for 4 years at the time of presentation. During this 4‐year period, he had received no immunosuppressive treatment, but had been dependent on red cell and platelet transfusion. At the time of presentation, he was no longer requiring transfusions, but was still receiving regular desferrioxamine for transfusion‐related iron overload. He had not received cranial radiotherapy at any stage during his disease course.
Clinical examination showed hypomimia, micrographia and moderately severe bradykinesia and rigidity of the right upper limb. A diagnosis of idiopathic Parkinson's disease was suspected and he was started on cabergoline, 4 mg once daily, while imaging to exclude other pathology was awaited. Given the possibility of iron deposition in the basal ganglia as a possible contributory factor, venesection of 100 ml per week was also initiated. However, on review 3 weeks later, his right‐sided parkinsonism had worsened and he had developed dyspraxia in his right hand as well as an expressive dysphasia. He scored 85/100 on the Addenbrooke's Cognitive Examination (mean (SD) normative score 93.8 (3.5))1 at this stage. Formal neuropsychological testing showed moderate impairment in the domains of language (verbal fluency and semantic knowledge), verbal and non‐verbal anterograde memory, and executive function relative to his high predicted premorbid function. He was admitted for urgent investigation.
Blood tests showed a white cell count of 8.7×109/l with a neutrophil count of 3.0×109/l and lymphocyte count of 4.9×109/l, platelet count of 56×109/l, a haemoglobin level of 10.8 g/dl, a C‐reactive protein level of 4 mg/l and an increased ferritin level of 3486 μg/l (normal level 1–321 μg/l). Viral serology was negative for HIV and for human T lymphotropic virus types 1 and 2. The cerebrospinal fluid (CSF) was clear and acellular, with no organisms seen on gram and India ink stain and a negative cryptococcal antigen test; biochemical analysis showed a raised protein level of 0.81 g/l (normal 0.15–0.45 g/l), but normal CSF:serum glucose ratio (0.63). CSF polymerase chain reaction (PCR) was negative for Herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, enterovirus group and JC virus DNA. MRI of the brain (fig 1A1A)) showed diffuse superior hemispheric white matter changes bilaterally but more extensively on the left, without mass effect, suggestive of progressive multifocal leucoencephalopathy (PML). There was no basal ganglia or brainstem involvement. A subsequent right frontal lobe biopsy showed patchy demyelination with bizarre enlarged astrocytes and abnormally large cells with a round nuclear outline, consistent with JC viral infection (see supplementary fig A1 online at http://jnnp.bmjjournals.com/supplemental). A number of blood vessels exhibited a prominent perivascular lymphocytic cuff (see supplementary fig A2 online at http://jnnp.bmjjournals.com/supplemental) that immunocytochemically included CD20 B‐cells and CD3 T‐cells. Subtyping showed both CD4 and CD8 T‐cells, the latter comprising approximately 30% of the cells present (see supplementary fig A3 online at http://jnnp.bmjjournals.com/supplemental). Electron microscopy confirmed the presence of intranuclear viral inclusions, with appearances suggestive of polyoma virus infection (see supplementary fig B online at http://jnnp.bmjjournals.com/supplemental). DNA was extracted from the brain biopsy sample using standard techniques, and amplification of a target sequence within the viral protein 1 region of the JC virus genome using a nested PCR reaction proved positive. PCR products were separated on 2% agarose gel and visualised after ethidium bromide staining.
The patient had several seizures after the biopsy, which responded to carbamazepine. Treatment with the antiviral agent cidofovir was considered but not given, due in part to the lack of evidence to support its use in this context (see Discussion) and in part to the patient's clinical improvement, with spontaneous improvement in speech fluency and right upper limb dyspraxia being noted within 1 month from biopsy. At 1 year, his cognitive function had improved to normal: he scored 96/100 on the Addenbrooke's Cognitive Examination, and performance on computerised tests of frontal and temporal lobe function from the Cambridge Neuropsychological Automated Battery (CANTAB)2 was within the normal range. The right upper limb dyspraxia was considerably improved, but there was mild residual rigidity and bradykinesia, unresponsive to a 2 week trial of co‐beneldopa (250 mg daily). Neurological examination was otherwise normal. Further MRI of the brain at this stage showed a significant reduction in the extent of the cerebral white matter changes (fig 1B1B).
PML is a demyelinating disease of the central nervous sytem caused by JC virus, a member of the polyomavirus family of DNA viruses. The clinical spectrum of the disease varies with the distribution of demyelination, but typically includes visual impairment, sensory and motor deficits, gait abnormalities, speech and language disturbances, cognitive disorders and headaches.3 Although very rare, movement disorders including parkinsonism4 and isolated limb dystonia3 due to involvement of corticostriatal circuitry have been reported by previous authors. In our case, the principal clinical features of right‐sided parkinsonism, dyspraxia and dysphasia were in keeping with the predominantly left frontoparietal distribution of pathology. The imaging does not suggest involvement of the basal ganglia, hence the parkinsonism is presumed to reflect disruption of thalamocortical or corticostriatal projections.
The diagnosis of PML was established beyond doubt in this case after brain biopsy, as the CSF PCR for JC viral DNA was negative. Although PCR has a specificity of 99%, its sensitivity is only 60–80%,5 hence brain biopsy with subsequent detection of JC viral protein or DNA remains the gold standard for diagnosis.
This case is unusual not only in terms of its initial clinical presentation with parkinsonism but also with respect to the clinical context in which JC infection arose. The infection is opportunistic, affecting immunocompromised individuals, and nowadays occurs most frequently in the context of HIV infection (constituting an AIDS‐defining illness). However, the condition was first described in 1958 in individuals with lymphoproliferative disease,6 and before the emergence of HIV, chronic lymphocytic leukaemia was probably the most common disease association of PML. In such patients, however, PML is thought to almost always occur in the context of a low CD4 lymphocyte count and often in association with recent treatment with the purine analogue fludarabine,7,8 neither of which apply to our patient, who had been in remission for 4 years. The history of allogenic bone marrow transplantation in this patient may be relevant, although PML is very rare in bone marrow recipients,9 and the suppression of the immune response and resulting susceptibility to infection after bone marrow transplantation follow a predictable course and typically wanes after the first 12 months,10 so again, in our case, the development of PML is unusual as 8 years had elapsed after bone marrow transplantation. To our knowledge, only three similar cases of PML in apparently immunocompetent patients have been described in the literature.3,11,12 The mechanism of central nervous system infection in such individuals remains unclear, but it is possible that a qualitative rather than quantitative defect in CD4 lymphocytes allows reactivation of latent JC virus infection.
A further highly unusual feature of our case was the spontaneous recovery observed both clinically and radiologically. In the majority of cases, the natural history of PML is rapidly progressive neurological deterioration leading to death, usually within 6 months.5,6 In some organ transplant‐associated cases, intervention to reverse immunosuppression has resulted in an improved outcome,5 whereas in HIV‐associated cases, long‐term survival without significant neurological improvement has been reported with highly active antiretroviral therapy.13 In those with underlying haematological disease, successful outcomes have been reported in individual cases after treatment with the antiviral agent cidofovir12,14 although, given that this agent does not significantly reduce JCV replication in vitro15 and that open‐label trials in HIV‐associated PML have failed to show clinical efficacy,16,17 these reports may in fact reflect spontaneous regression of PML. Further cases of functional recovery18 or stabilisation19 of the disease in haematological patients without intervention with antiviral agents have been described in the literature, although this is very rare. Such a favourable outcome may relate to an individual's ability to mount an effective T lymphocyte response to the JC virus. In a study of 26 patients with possible or proved PML, early detection of a specific JCV CD8 T cell response was associated with improved prognosis,20 and in our case the presence of perivascular CD8 lymphocytic infiltrates in the brain biopsy suggests that such a response might have accounted for the rapid recovery observed.
In summary, we present a highly unusual case of PML causing an atypical parkinsonian syndrome in an apparently immunocompetent individual, but in the context of previous chronic lymphocytic leukaemia, in whom significant spontaneous improvement was observed both clinically and radiologically. We suggest that PML should be considered as part of the differential diagnosis of unusual neurological syndromes in patients with any lymphoproliferative disorder, even if in remission, and that such cases may not require active treatment as they can spontaneously resolve.
Supplementary figures A1–A3 and B are available online at http://jnnp.bmj.com/supplemental.
Copyright © 2007 BMJ Publishing Group Ltd
We thank the patient for permission to report his case. We also thank Professor R J Powles, consultant haematologist at the Royal Marsden Hospital (UK), for providing details of his previous haematological treatment, Dr R Bannon, Consultant Radiologist at the West Suffolk Hospital (UK), for providing the MRI images, Dr A Curry, Head of Electron Microscopy at the Manchester Royal Infirmary (UK), for providing external confirmation of the electron microscopy findings and Wendy Knowles at the Enteric, Respiratory and Neurological Virus Laboratory, Health Protection Agency (UK), for providing the JC virus PCR result on the brain biopsy sample.
CSF - cerebrospinal fluid
PCR - polymerase chain reaction
PML - progressive multifocal leucoencephalopathy
Competing interests: None declared.
Informed consent was obtained from the patient for publication of his case in this report.
Supplementary figures A1–A3 and B are available online at http://jnnp.bmj.com/supplemental.