• © 2007 by American Society of Clinical Oncology

Presentation of Hodgkin's Lymphoma With Ophelia Syndrome

A 69-year-old white woman, with past medical history of high blood pressure, presented with symptoms of depression, short-term memory loss, confusion, and asthenia of 6 months' duration. She was initially treated with fluoxetine and nimodipine without any improvement. During this period the patient developed new symptoms including myoclonus, weight loss, and profuse night sweat. She had a seizure and was referred to our hospital for neurological examination. Physical examination revealed a 2-cm lymph node in the left supraclavicular area. An excisonal lymph node biopsy was taken and various studies were performed to rule out other causes of subacute dementia (viral encephalitis, metabolic encephalitis, vascular dementia, Creutzfeldt-Jakob disease, primary or secondary brain tumor, paraneoplastic dementia, and autoimmune nonparaneoplastic dementia). Routine blood and chemistry tests revealed an erythrocyte sedimentation rate more than 30 mm and elevation of both lactate dehydrogenase and β-2-microglobulin levels. Thyroid function and vitamins B1 and B12 were within the normal ranges. Syphilis and serum virus screening (including HIV) was only positive for Epstein-Barr virus immunoglobulin G antibody. CSF examination showed a normal cell count and an elevated protein level without any oligoclonal band. CSF screening for antineuronal antibodies including anti-Hu, anti-Yo, anti-Ri, anti-Ta, and anti-Ma were negative. The protein 14 to 3-3 test and the prion protein gene analysis for mutations were negative. An electroencephalography revealed a mild diffuse nonspecific background slowing. Finally, single-photon emission computed tomography showed decreased activity in the front pole of temporal lobe (Fig 1A; arrow shows a decreased activity in the front pole of left temporal lobe); and a brain magnetic resonance imaging scan revealed a (arrow) soft expansion of temporal horn and left hippocampus atrophy in T1-weighted images (Fig 1B). The results of the lymph node histopathology confirmed the diagnosis of Hodgkin's lymphoma (HL) mixed cellularity subtype (Fig 1D; arrow shows a Hodgkin's-Reed-Stemberg cell with positive staining for CD30, magnification ×600). After this histology-based diagnosis, the patient underwent further work-up. The computed tomography (CT) scan of her body showed mediastinal node enlargement (Fig 1C); the bone marrow biopsy was negative for HL. She was considered to have clinical stage IIB and was assigned to a high-risk early stage HL defined by the European Organisation for Research and Treatment of Cancer criteria (erythrocyte sedimentation rate > 30 mm plus B symptoms and older than 50 years). The patient received standard chemotherapy treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and the neurological symptoms ceased after only one cycle of chemotherapy. The patient had an unconfirmed complete response after three cycles of ABVD, but unfortunately she died 5 weeks later from severe bleomycin-related pneumonitis and subsequent pneumonia.

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Fig 1.

Paraneoplastic limbic encephalitis (PLE) in the HL setting is also known as the Ophelia syndrome and was first described by Carr¹ in his teenage daughter. Since then, few similar cases have been reported and several have recently been summarized.² The diagnosis of PLE requires a neuropathological examination or all four criteria.³ This case fulfilled all four criteria: a compatible clinical presentation with neuropsychiatric symptoms due to involvement of the limbic system (up to 30% to 40% of patients with PLE may develop extralimbic symptoms,³ such as myoclonies); an interval of less than 4 years between the onset of neurological symptoms and the cancer diagnosis; the exclusion of other cancer-related complications that may cause a limbic dysfunction; a brain magnetic resonance imaging showing unilateral atrophy of the hippocampus on T1-weighted images. The improvement of the PLE symptoms after chemotherapy has been previously described in some cases.^2-3 There is little experience in the use of emission tomography techniques in PLE, but left-sided temporal hypoperfusion has been described before by Bak et al⁴ in a PLE context. Other case reports have described the utility of positron emission tomography in this setting.⁵ The application of emission tomography techniques, like single-photon emission computed tomography, could be useful in the diagnosis of the Ophelia syndrome, a very rare first manifestation of HL.