Unusual association of diseases/symptoms
CASE REPORT
Lymphomatosis cerebri mimicking iatrogenic Creutzfeldt-Jakob disease Elena Rivero Sanz,1 Miguel Ángel Torralba Cabeza,2 Francisco Sanjuán Portugal,3 Federico García-Bragado4 1
Department of Neurology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain 2 Department of Internal Medicine, Hospital Clinico Universitario Lozano Blesa, Zaragoa, Spain 3 Fundación Hospital de Calahorra, Calahorra, Spain 4 Department of Internal Medicine, Complejo Hospitalario de NavarraHospital Virgen del Camino, Pamplona, Spain Correspondence to Dr Elena Rivero Sanz, [email protected] Accepted 18 August 2014
SUMMARY Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL) whereby individual lymphoma cells infiltrate the cerebral white matter without causing a mass effect. The disease characteristically presents as a rapidly progressive dementia, which opens an ample differential diagnosis of toxic, metabolic, neurodegenerative and infective causes. Other presentations also include changes in personality, myoclonus and psychotic symptoms. Here we report a patient who presented with a rapidly progressive dementia with a unique surgical history of a dural mater graft in the 1970s. The diagnosis of iatrogenic Creutzfeldt-Jakob disease (iCJD) was initially considered. However, the patient’s clinical status deteriorated rapidly with no response to symptomatic treatment and she died 2 months after symptom onset. A diagnosis of T-type LC was reached at autopsy.
BACKGROUND
To cite: Rivero Sanz E, Torralba Cabeza MiguelÁ, Portugal FS, et al. BMJ Case Rep Published online: [please include Day Month Year] doi:10.1136/bcr-2013201246
Rapidly progressive dementias involve a set of disorders that are characterised by an accelerated decline in cognitive, behavioural and motor function in less than 2 years. The differential diagnosis is vast, including infectious, neurodegenerative, toxic-metabolic, neoplastic and autoimmune processes; this presents a challenge to physicians and requires meticulous work up to reach the correct diagnosis.1 2 The most fatal diagnosis is Creutzfeldt-Jakob disease (CJD), a neurodegenerative disorder resulting from the accumulation of a pathological isoform of the prion protein, of which there are sporadic (sCJD), familial (fCJD), variant (vCJD) and iatrogenic (iCJD) types. sCJD is characterised by a plaeomorphic rapidly progressive dementia accompanied by hallucinations, delusions, changes in personality and myoclonic jerks.3 4 Primary central nervous system lymphomas (PCNSL) account for 3–5% of all primary brain tumours5 but are an increasing prevalent group of tumours that can share clinical features of sporadic CJD and should therefore be included in the differential diagnosis of a rapidly progressive dementia. Lymphomatosis cerebri is a rare variant of PCNSL, differing from the latter in that it is a diffuse infiltration of the cerebral white matter by individual lymphoma cells without formation of a discernible cohesive tumour mass.6 This case illustrates the presentation of T-type lymphomatosis cerebri (LC), which shared clinical features of CJD of rapidly progressive dementia, changes in personality and
myoclonus. A literature review of other cases of T-cell lymphoma and LC is also included.
CASE PRESENTATION A woman in her early 60s was admitted to hospital with a 2-week history of cognitive decline, changes in personality, disorientation and mutism. Her family also mentioned a deterioration in her shortterm memory, increased somnolence and acute confusional episodes, which worsened at night. There was no loss of power in any of the four limbs, and no history of headache. There were no symptoms suggestive of infection such as fever, cough, vomiting or diarrhoea and systems review was unremarkable. The patient had a medical history of craneofaringioma at the age of 35 and required a dura mater allogenic graft, which was performed in the 1970s. As a consequence of the intervention, she developed secondary panhipopituitarism. She also had type two diabetes mellitus and a 5 cm left renal angiolipoma. Neurological examination showed the patient was partially disorientated in time, person and place. She had difficulty in initiating verbal and motor responses despite having an intact sensory, motor and higher brain functions, compatible with akinetic mutism. Cranial nerves were normal, although peripheral fields could not be elicited due to difficulty in communication. She had an intention tremor as well as spontaneous, involuntary muscle contractions in the upper limbs, consistent with myoclonic jerks, with no deficit in power or sensitivity in the four limbs. Extrapyramidal signs could not be elicited. There was no nuchal rigidity or lymphadenopathy.
INVESTIGATIONS Biochemical and haematological tests were unremarkable apart from an erythrocyte sedimentation rate (ESR) of 40 mm/h. Rheumatological tests (complement 3, complement 4, CH50, rheumatoid factor, antinuclear antibodies) were negative, as was the C reactive protein (CRP). Her folic acid and vitamin B12 levels were within normal range. HIV test and rapid plasma reagin/venereal disease research laboratory (RPR/VDRL) tests were also negative. Serological tests for Borrelia burgdorferi showed an elevated IgG >9 U/mL (normal values 1–1.2) with a low IgM level of 0.23 U/mL (1–1.20). A CT showed neurosurgical access sequelae through right temporal lobe with non-specific white mater infiltration, which was confirmed
Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
1
Unusual association of diseases/symptoms subsequently with a MRI (figure 1). Diffusion-weighted images (DWI) to detect cortical ribboning were not available. A lumbar puncture was performed and cerebrospinal fluid (CSF) examination revealed a raised protein of 40 mg/dL. Glucose, red blood cell and white cell counts were normal. There were no malignant cells detected and Gram staining and cultures showed no growth. AntiBorrelia IgG as well as western blot from CSF samples were negative. CSF analysis for 14-3-3 protein was also negative and a genetic test showed methionine homozygosity at codon 129 in the prion protein gene. Neuron-specific enolase and τ were not checked. An EEG showed triphasic waves approximately every second, of 400 ms and 120 μV in amplitude (up to 400 μV in the frontal regions) without myoclonic activity (figure 2A).
DIFFERENTIAL DIAGNOSIS The presentation of a rapidly progressive dementia with myoclonus raises the possibility of a limited number of possible aetiologies. One of the most common causes are toxic–metabolic and particularly lithium, but the differential diagnosis must exclude other heavy metal intoxications, tricyclic antidepressants and barbiturate toxicity.2 In our patient, these causes were excluded as she had no drug history of taking these medications nor had she a psychiatric history and laboratory parameters were normal. Other differentials considered were herpes simplex encephalitis, Lyme disease or subacute sclerosing panencephalitis. These again were ruled out as there were no CSF or radiological findings to support these diagnoses. Although DWI were not obtained, MRI supported the main differential diagnoses of inflammatory and vascular causes and CJD, however, definite diagnosis can only be reached with brain biopsy.7 The characteristic triphasic wave pattern and periodic EEG activity is not specific for CJD. Periodic spike wave complexes seen in middle and late stages of CJD can also be present in toxic encephalopathy, such as lithium, subacute sclerosing panencephalitis and Hashimoto’s encephalitis. sCJD can be classified as possible, probable or definite cases according to clinical, electrophysiological and neuropathological findings.3 8 Possible sCJD cases are usually characterised as having a rapidly progressive dementia with at least two of the following: myoclonus, pyramidal or extrapyramidal signs, cerebellar or visual symptoms, or akinetic mutism, and a disease course of less than 2 years. Probable cases
are when they additionally have characteristic EEG changes or increased CSF levels of 14-3-3. Definite cases are defined by the presence of spongiform changes or PrP(Sc) reactivity in the brain. Our patient met the criteria of probable CJD that could be of the sporadic, variant or iatrogenic type. Given the surgical history of a cadaveric dura mater allogenic graft in the 1970s and subsequently presenting with a rapidly progressive dementia with myoclonus and personality changes, iCJD was considered the most likely diagnosis using the CDC’s diagnostic criteria for CJD 2010.9 10
TREATMENT Owing to the patient’s symptoms, EEG findings and a probable diagnosis of iCJD, she received off license chlorpromazine for symptom control. Derivatives of acridine and phenothiazine, similar to chlorpromazine, have been shown to be effective in crossing the blood–brain barrier and to have antiprion properties, and have been seen to inhibit the formation of disease causing isoform PrP (Sc) in animal studies.3 11 A repeat EEG was performed 2 months after the patient’s initial EEG, which showed similar findings, and chlorpromazine was changed to phenytoin to control repetitive seizures (figure 2B).
OUTCOME AND FOLLOW-UP Two months after presenting to the hospital the patient continued to deteriorate despite the mentioned treatment and died. At autopsy, the fixed brain weighed 1300 g. There were signs of oedema as flattening convolutions and ventricular lumen collapse. The histological examination revealed a diffuse lymphocytic infiltration, predominantly in the white matter, composed of atypical cells with a lobular nucleus, which were arranged around the vessels (figure 3A). These lesions were associated with reactive gliosis, large numbers of macrophages and large areas of demyelisation. There was no spongiosis in the cortex nor evidence of prionic protein deposit (PrP; figure 3B). Immunohistochemically, the tumour cells were CD20−, CD3+, Granzyme and TIA-1+, CD5−, CD7−, CD4−, CD8−, CD56−, CD57− (figure 3C). Epstein-Barr virus in situ hibridisation (EBER) was negative as was the John Cunningham virus. Molecular studies (T-cell receptor γ gene rearrangement) showed a clonal appearance and a T-type primary cerebral lymphoma was confirmed.
Figure 1 A brain MRI showing bilateral hyperintense signal in the white matter of the frontal lobes and the caudate nuclei, putamen and thalamus in fluid-attenuated inversion recovery and T2-weighted images.
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Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
Unusual association of diseases/symptoms
Figure 2 (A) An EEG study on admission showing paroxysmal sharp-wave periodic complexes suggesting the diagnosis of Creutzfeldt-Jacob disease. (B) A repeat EEG showing 2 months after admission with similar findings to the first EEG.
DISCUSSION PCNSL accounts for 3–5% of primary brain tumours and has an incidence of five per 1 million person-years. It is an uncommon subgroup of extranodal non-Hodgkin lymphomas and by definition is confined to the CNS including eyes, meninges and cranial nerves.5 12 About 90% of PCNSL are diffuse large B-cell lymphomas and only 5% constitute low grade B-cell type lymphoma, including mucosa-associated lymphoid tissue type and T-cell type lymphoma.12 13 Its incidence is increasing
steadily in immunocompetent patients due to an ageing population and better diagnosis while decreasing in patients with AIDS since the development of highly active antiretroviral therapies.5 PCNSL has a male preponderance of 1.5–1 with a median age at onset in immunocompetent patients in the sixth decade13 and between 30–40 years in immunocompromised patients.12 Initial symptoms are mostly focal neurological deficits depending on tumour location, or signs of increased intracranial pressure with 10% of patients suffering from visual disturbances.13 However,
Figure 3 (A) Atypical lymphoid cells in close relation with blood vessels. (B) Absence of spongiform changes in the cerebral cortex. (C) Positive CD3 staining of the tumour cells. Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
3
Unusual association of diseases/symptoms non-specific organic brain syndromes and personality changes are now the most common presenting feature of PCNSL, especially if the location is deep seated.5 12 On CT imaging PCNSL appears as a hyperdense mass that commonly exhibits homogeneous uptake. Contrast-enhanced MRI is the method of choice when PCNSL is suspected with lesions appearing as isointense or hypointense on T1-weighted and hyperintense on T2-weighted images, although up to 90% in immunocompetent patients show homogeneous contrast enhancement with slightly cloudy margins. The tumour is mostly located in the brain hemispheres and periventricular zone, but can also be in deeper brain structures such as basal ganglia, corpus callosum and brain stem.6 12 CSF findings show a moderate increase of protein in 70–90% of patients with only 10–30% having detectable malignant cells. Diagnosis of PCNSL should always be made in histological grounds via stereotactic biopsy. Steroid therapy should be stopped 7–10 days prior to biopsy where possible due to the proapoptotic effect of steroids on lymphocytes causing short-term partial or complete remission.12 13 Once the diagnosis has been established, steroids may be administered to reduce cerebral oedema causing mass effect.14 Staging should be followed including slit-lamp examination to detect ocular involvement, and whole body CT and bone marrow biopsy to detect any systemic involvement.13 The prognosis of PCNSL is greatly influenced by age and performance status (11). Median survival ranges from 313 to 25 months.14 Radiotherapy and chemotherapy increase survival rates to 60 months and up to 8.5 years in treated patients 50 years or younger.12 However, multiple lesions, leptomeningeal involvement or T-cell lymphoma are not prognostically relevant.13 Currently, first-line therapy for PCNSL is based on high-dose methotrexate-based (HD-MTX) chemotherapy with 18–65% achieving complete remission, although long-term survival after HD-MTX alone is rare. For example, in the Bonn-Bochum protocol, HD-MTX is combined with high-dose cytarabine, ifosfamide, cyclophosphamide, vinca-alkaloids, steroids, and intrathecal/intraventricular MTX and Ara-C.12 Common side effects of polychemotherapy include acute hepatotoxicity, nephrotoxicity, anaemia, thrombocytopaenia and maintenance of remission in elderly patients.15 High-dose whole-brain radiation therapy (WBRT) is no longer part of first-line treatment due to the propensity of inducing late neurotoxicity with most patients relapsing.13 16 Radiation therapy has a role if there is a recurrence or lack of response to primary therapy.14 There is no role for gross surgical resection in PCNSL other than debulk tumour mass to impede neurological deterioration secondary to brain herniation.12 15 Owing to the rarity of PCNSL and the small number included in trials, more randomised controlled trials with larger numbers of patients and longer follow-up periods are needed to assess the efficacy of different combination chemo and radiotherapy strategies in different age groups to determine ideal dosages, duration of treatment and prognosis.14 T type lymphomas account for a small percentage of PCNSL, with few reported cases in the literature. Three cases over the course of 6 years presented with a different combination of clinical symptoms: the first with seizure, the second with headache and diplopia and the third with instability, occipital headache, diplopia and paralysis. All showed mass lesions on CT in different locations of the brain with incongruent signals on T1 and T2 MRI, which demonstrates the heterogeneity of clinical presentation and radiological findings. All had tumour excision followed by courses of chemotherapy and holocraneal 4
radiotherapy with differences in survival outcomes (from a few months up to 6 years).17 In another case, a 56-year-old immunocompetent man had a 6 week history of confusion, lethargy, memory disturbance and focal neurological signs of diplopia, and weakness. CT showed low attenuation in the brainstem and MRI revealed widespread non-enhancing areas with increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging with widespread extension with no mass effect or midline shift. Lumbar puncture examination revealed non-specific raised white cell count and an elevated protein. Definite diagnosis was achieved via biopsy with positive staining (for CD3, CD45, CD10, CD99) confirming primary CNS T-cell lymphoma.16 Despite treatment with intrathecal and intravenous methotrexate-based chemotherapy with initial clinical and radiological improvement, the patient subsequently died of the disease 15 months after discharge. Certain neoplasms such as meningiomas, schwannomas and pituitary adenomas have a predilection in women, with primary CNS lymphoma having an incidence of 0.02 per 100 000 women years. One case of particular rarity is of a 33-year-old woman who was diagnosed at 32 weeks of gestation of a T-cell lymphoma after presenting with headache, vomiting and drowsiness. MRI showed a midline mass at the anterior cranial fossa with compression of the third ventricle. After allowing fetal lung maturation with corticosteroids, the patient had a caesarean section and tumour evacuation under the same anaesthetic. She subsequently received high-dose methotrexate with radiation but died on the 10th day postpartum.18 This case highlights the rarity of T-type lymphoma in young women, particularly during pregnancy. Long-term immunosuppressive therapy (eg, cyclosporin A, tacrolimus), or any underlying disease with associated immunosuppression, such as after organ transplantation, raises the risk for PCNSL. Risk factors in immunocompetent patients are not known, although viruses have been proposed.13 HTLV-1 affects around 15 million people and is commonly associated with adult T-cell leukaemia/lymphoma and tropical spastic paraparesis/ HTVL-1 associated myelopathy (TSP/HAM). An immunocompetent 29-year-old man was diagnosed with high-grade T-cell PCNSL with only a positive HTLV-1 serology as the relevant medical history. He had a 4-month history of confusion, drowsiness, visual hallucinations and psychotic thinking. CT and EEG showed no abnormalities 1 month after symptom onset. MRI demonstrated multifocal lesions that were hyperintense on T2 FLAIR and hypointense on T1 involving various structures such as the corpus callosum. Diagnosis was reached after an open biopsy. Despite treatment with methotrexate and whole brain irradiation the patient died 14 months after initial diagnosis.19 Another virus that has been associated with T-cell lymphoma is the EBV, which was reported in an elderly woman who presented with rapidly progressive mental deterioration. MRI revealed typical T1 and T2 images of multiple lesions in bilateral frontal and temporal lobes and left occipital lobe. In situ hybridisation revealed EBV-encoded RNAs in the tumour cell nuclei. This is an unusual case as almost all cases of EBV are associated with B-type PCNSL.20 LC is a rare variant of PCNSL. Unlike the latter, which often presents as one or more discrete mass lesions, LC is the diffuse infiltration of the cerebral white matter by lymphoma cells without causing a mass effect and without taking up contrast, which is similar to that seen in gliomatosis cerebri.6 21 Between 1999 and 2011, 17 cases of LC have been reported in immunocompetent patients, 15 were B-cell type and the Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
Unusual association of diseases/symptoms remaining were T-type or unspecified. Common clinical presentations included insidious cognitive decline, forgetfulness and changes in personality. All cases showed white matter involvement on MRIs. However, due to its rarity and difficulty interpreting the MRI findings, which overlap with other causes of leucoencephalopathy, diagnosis still poses a challenge to physicians and delays prompt treatment. The prognosis of LC is shorter than that of PCNSL.6 The last two reported cases of B-cell LC were of two immunocompetent women aged 56 years6 and 58 years.22 The first presented with insidious changes in personality, apathy and forgetfulness over a 4-month period (similar to our patient) while the second had a progressive paraparesis, postural hypotension and weight loss over a 3-month period. CSF findings in both cases showed raised protein with no atypical cells detected on cytology, as in our patient. Brain MRIs showed multiple non-enhancing foci with typical hyperintensity on FLAIR images, while our patient had non-specific white matter infiltration. The first patient’s diagnosis was reached via stereotactic biopsy and she received steroids and WBRT; whereas the second patient and our patient deteriorated and required an autopsy to reach a diagnosis. Both cases described had positive markers for B-cell LC, namely CD20+ whereas our patient had negative CD20 markers and positive markers for T-cell LC, namely CD3+, a much rarer subtype of LC.22 Our case is of interest for various reasons. The presentation of a rapidly progressive dementia in a middle-aged woman opens a wide range of differential diagnoses, such as from neurodegenerative, infective and metabolic causes, which were ruled out with routine tests. Iatrogenic CJD was considered due to the course of the patient’s illness and her exceptional surgical history of a dura mater allogenic graft in the 1970s, with numerous cases emerging at that time due to the unknown routes of transmission and decontamination methods for surgical instruments. This caused diagnostic confusion, as have other reported cases in the literature, of rapidly progressive dementias that are ultimately shown to be PCNSL. Owing to her rapid clinical deterioration diagnosis could not be reached until autopsy, the results of which demonstrated it to be T-cell LC—an exception-
ally rare form of disease progression, which involves an infiltrative process of the white matter of the CNS without causing a mass effect as seen in PCNSL, with an even rarer histological cell type. Our case mimics other reported cases of T-cell PCNSL and LC in that presentation is of a rapidly progressive dementia with personality changes. The only positive findings in the tests performed were an elevated protein in the CSF and non-specific inflammation of the white matter on MRIs. This case illustrates the rarity of T-cell LC and demonstrates the increased awareness that physicians require in any rapidly progressive dementia to diagnose it and to start treatment promptly. Contributors ERS was involved in collecting data, including journals, drafting and writing the article. MATC was involved in supervising and revising the article. FJSP undertook the patient’s autopsy, and FGB contributed in providing the histological images and approving the final draft. Competing interests None. Patient consent Not obtained. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2 3 4 5 6
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10 11 12
Learning points
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▸ Lymphomatosis cerebri (LC) is a subtype of primary central nervous system lymphoma (PCNSL) in which lymphoma cells infiltrate the white matter without causing mass effect. ▸ Presentation is usually of a rapidly progressive dementia with personality changes and can have similar characteristics as Creutzfeldt-Jakob disease (CJD), but the triphasic wave pattern detected on EEG is not specific for CJD. ▸ MRI are deemed to be the most useful diagnostic tool, with hyperintense images showing on T2 and fluid-attenuated inversion recovery images. ▸ If PCNSL or LC is suspected, a stereotactic biopsy should be carried out. ▸ Prompt treatment, based on high-dose methotrexate polychemotherapy, is showing encouraging survival rates, especially in patients under the age of 65 years.
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Rosenbloom MH, Atri A. The evaluation of rapidly progressive dementia. Neurologist 2001;17:67–74. Geschwind MD, Shu H, Haman A, et al. Rapidly progressive dementia. Ann Neurol 2008;64:97–108. Appleby BS, Lyketsos CG. Rapidly progressive dementias and the treatment of human prion diseases. Expert Opin Pharmacother 2011;12:1–12. Colby DW, Prusiner SB. Prions. Cold Spring Harb Perspect Biol 2011;3:a006833. Ricard D, Idabaih A, Ducray F, et al. Primary brain tumours in adults. Lancet 2012;379:1984–96. Kitai R, Hashimoto N, Yamate K, et al. Lymphomatosiscerebri: clinical characteristics, neuroimaging, and pathological findings. Brain Tumour Pathol 2012;29:47–53. Schott JM, Reiniger L, Thom M, et al. Brain biopsy in dementia: clinical indications and diagnostic approach. Acta Neuropathol 2010;120:327–41. Imran M, Mahmood S. An overview of human prion diseases. Virol J 2011;8:559–67. Hamaguchi T, Noguchi-Shinohara M, Nozaki I, et al. The risk of iatrogenic Creutzfeldt-Jakob disease through medical and surgical procedures. Neuropathology 2009;29:625–31. Brown P, Brandel J, Sato T, et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis 2012;18:901–7. Korth C, May BCH, Cohen FE, et al. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 2001;98:9836–41. Roth P, Korfel A, Martus P, et al. Pathogenesis and management of primary CNS lymphoma. Expert Rev Anticancer Ther 2012;12:623–33. Schäfer N, Glas M, Herrlinger U. Primary CNS lymphoma: a clinician’s guide. Expert Rev Neurother 2012;12:1197–206. Briastanos PK, Batchelor TT. Primary central nervous system lymphoma. Hematol Oncol Clin North Am 2012;26:897–916. Bergner N, Monsef I, Illerhaus G, et al. Role of chemotherapy additional to high dose methotrexate for primary central nervous system lymphoma (PCNSL) (Review). Cochrane Database Syst Rev 2012;(11):1–29. Clark AJ, Lee K, Broaddus WC, et al. Primary brain T-cell lymphoma of the lymphoblastic type presenting as altered mental status. Acta Neurochir (Wien) 2010;152:163–8. Barrena-Carballo MR, Blanch-Labrador MA, Giménez-Mas JA, et al. T-type primary lymphoma of the central nervous system in immunocompetent patients. Rev Neurol 2003;36:125–30. Ilker A, Aykut B, Muge H, et al. Primary brain T-cell lymphoma during pregnancy. J Pak Med Assoc 2012;62:394–6. Lotan I, Khlebtovsky A, Inbar E, et al. Primary brain T-cell lymphoma in an HTLV-1 serologically positive male. J Neurol Sci 2012;314:163–5. Ogura R, Aoki H, Natsumeda M, et al. Epstein-Barr virus-associated primary central nervous system cytotoxic T-cell lymphoma. Neuropathology 2013;33:436–41. deToledo M, López-Valdés E, Ferreiro M, et al. Lymphomatosiscerebri as the cause of leukoencephalopathy. Rev Neurol 2008;46:667–70. Keswani A, Bigio E, Grimm S. Lymphomatosiscerebri presenting with orthostatic hypotension, anorexia, and paraparesis. J Neurooncol 2012;109:581–6.
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Unusual association of diseases/symptoms
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Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
CASE REPORT
Lymphomatosis cerebri mimicking iatrogenic Creutzfeldt-Jakob disease Elena Rivero Sanz,1 Miguel Ángel Torralba Cabeza,2 Francisco Sanjuán Portugal,3 Federico García-Bragado4 1
Department of Neurology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain 2 Department of Internal Medicine, Hospital Clinico Universitario Lozano Blesa, Zaragoa, Spain 3 Fundación Hospital de Calahorra, Calahorra, Spain 4 Department of Internal Medicine, Complejo Hospitalario de NavarraHospital Virgen del Camino, Pamplona, Spain Correspondence to Dr Elena Rivero Sanz, [email protected] Accepted 18 August 2014
SUMMARY Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL) whereby individual lymphoma cells infiltrate the cerebral white matter without causing a mass effect. The disease characteristically presents as a rapidly progressive dementia, which opens an ample differential diagnosis of toxic, metabolic, neurodegenerative and infective causes. Other presentations also include changes in personality, myoclonus and psychotic symptoms. Here we report a patient who presented with a rapidly progressive dementia with a unique surgical history of a dural mater graft in the 1970s. The diagnosis of iatrogenic Creutzfeldt-Jakob disease (iCJD) was initially considered. However, the patient’s clinical status deteriorated rapidly with no response to symptomatic treatment and she died 2 months after symptom onset. A diagnosis of T-type LC was reached at autopsy.
BACKGROUND
To cite: Rivero Sanz E, Torralba Cabeza MiguelÁ, Portugal FS, et al. BMJ Case Rep Published online: [please include Day Month Year] doi:10.1136/bcr-2013201246
Rapidly progressive dementias involve a set of disorders that are characterised by an accelerated decline in cognitive, behavioural and motor function in less than 2 years. The differential diagnosis is vast, including infectious, neurodegenerative, toxic-metabolic, neoplastic and autoimmune processes; this presents a challenge to physicians and requires meticulous work up to reach the correct diagnosis.1 2 The most fatal diagnosis is Creutzfeldt-Jakob disease (CJD), a neurodegenerative disorder resulting from the accumulation of a pathological isoform of the prion protein, of which there are sporadic (sCJD), familial (fCJD), variant (vCJD) and iatrogenic (iCJD) types. sCJD is characterised by a plaeomorphic rapidly progressive dementia accompanied by hallucinations, delusions, changes in personality and myoclonic jerks.3 4 Primary central nervous system lymphomas (PCNSL) account for 3–5% of all primary brain tumours5 but are an increasing prevalent group of tumours that can share clinical features of sporadic CJD and should therefore be included in the differential diagnosis of a rapidly progressive dementia. Lymphomatosis cerebri is a rare variant of PCNSL, differing from the latter in that it is a diffuse infiltration of the cerebral white matter by individual lymphoma cells without formation of a discernible cohesive tumour mass.6 This case illustrates the presentation of T-type lymphomatosis cerebri (LC), which shared clinical features of CJD of rapidly progressive dementia, changes in personality and
myoclonus. A literature review of other cases of T-cell lymphoma and LC is also included.
CASE PRESENTATION A woman in her early 60s was admitted to hospital with a 2-week history of cognitive decline, changes in personality, disorientation and mutism. Her family also mentioned a deterioration in her shortterm memory, increased somnolence and acute confusional episodes, which worsened at night. There was no loss of power in any of the four limbs, and no history of headache. There were no symptoms suggestive of infection such as fever, cough, vomiting or diarrhoea and systems review was unremarkable. The patient had a medical history of craneofaringioma at the age of 35 and required a dura mater allogenic graft, which was performed in the 1970s. As a consequence of the intervention, she developed secondary panhipopituitarism. She also had type two diabetes mellitus and a 5 cm left renal angiolipoma. Neurological examination showed the patient was partially disorientated in time, person and place. She had difficulty in initiating verbal and motor responses despite having an intact sensory, motor and higher brain functions, compatible with akinetic mutism. Cranial nerves were normal, although peripheral fields could not be elicited due to difficulty in communication. She had an intention tremor as well as spontaneous, involuntary muscle contractions in the upper limbs, consistent with myoclonic jerks, with no deficit in power or sensitivity in the four limbs. Extrapyramidal signs could not be elicited. There was no nuchal rigidity or lymphadenopathy.
INVESTIGATIONS Biochemical and haematological tests were unremarkable apart from an erythrocyte sedimentation rate (ESR) of 40 mm/h. Rheumatological tests (complement 3, complement 4, CH50, rheumatoid factor, antinuclear antibodies) were negative, as was the C reactive protein (CRP). Her folic acid and vitamin B12 levels were within normal range. HIV test and rapid plasma reagin/venereal disease research laboratory (RPR/VDRL) tests were also negative. Serological tests for Borrelia burgdorferi showed an elevated IgG >9 U/mL (normal values 1–1.2) with a low IgM level of 0.23 U/mL (1–1.20). A CT showed neurosurgical access sequelae through right temporal lobe with non-specific white mater infiltration, which was confirmed
Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
1
Unusual association of diseases/symptoms subsequently with a MRI (figure 1). Diffusion-weighted images (DWI) to detect cortical ribboning were not available. A lumbar puncture was performed and cerebrospinal fluid (CSF) examination revealed a raised protein of 40 mg/dL. Glucose, red blood cell and white cell counts were normal. There were no malignant cells detected and Gram staining and cultures showed no growth. AntiBorrelia IgG as well as western blot from CSF samples were negative. CSF analysis for 14-3-3 protein was also negative and a genetic test showed methionine homozygosity at codon 129 in the prion protein gene. Neuron-specific enolase and τ were not checked. An EEG showed triphasic waves approximately every second, of 400 ms and 120 μV in amplitude (up to 400 μV in the frontal regions) without myoclonic activity (figure 2A).
DIFFERENTIAL DIAGNOSIS The presentation of a rapidly progressive dementia with myoclonus raises the possibility of a limited number of possible aetiologies. One of the most common causes are toxic–metabolic and particularly lithium, but the differential diagnosis must exclude other heavy metal intoxications, tricyclic antidepressants and barbiturate toxicity.2 In our patient, these causes were excluded as she had no drug history of taking these medications nor had she a psychiatric history and laboratory parameters were normal. Other differentials considered were herpes simplex encephalitis, Lyme disease or subacute sclerosing panencephalitis. These again were ruled out as there were no CSF or radiological findings to support these diagnoses. Although DWI were not obtained, MRI supported the main differential diagnoses of inflammatory and vascular causes and CJD, however, definite diagnosis can only be reached with brain biopsy.7 The characteristic triphasic wave pattern and periodic EEG activity is not specific for CJD. Periodic spike wave complexes seen in middle and late stages of CJD can also be present in toxic encephalopathy, such as lithium, subacute sclerosing panencephalitis and Hashimoto’s encephalitis. sCJD can be classified as possible, probable or definite cases according to clinical, electrophysiological and neuropathological findings.3 8 Possible sCJD cases are usually characterised as having a rapidly progressive dementia with at least two of the following: myoclonus, pyramidal or extrapyramidal signs, cerebellar or visual symptoms, or akinetic mutism, and a disease course of less than 2 years. Probable cases
are when they additionally have characteristic EEG changes or increased CSF levels of 14-3-3. Definite cases are defined by the presence of spongiform changes or PrP(Sc) reactivity in the brain. Our patient met the criteria of probable CJD that could be of the sporadic, variant or iatrogenic type. Given the surgical history of a cadaveric dura mater allogenic graft in the 1970s and subsequently presenting with a rapidly progressive dementia with myoclonus and personality changes, iCJD was considered the most likely diagnosis using the CDC’s diagnostic criteria for CJD 2010.9 10
TREATMENT Owing to the patient’s symptoms, EEG findings and a probable diagnosis of iCJD, she received off license chlorpromazine for symptom control. Derivatives of acridine and phenothiazine, similar to chlorpromazine, have been shown to be effective in crossing the blood–brain barrier and to have antiprion properties, and have been seen to inhibit the formation of disease causing isoform PrP (Sc) in animal studies.3 11 A repeat EEG was performed 2 months after the patient’s initial EEG, which showed similar findings, and chlorpromazine was changed to phenytoin to control repetitive seizures (figure 2B).
OUTCOME AND FOLLOW-UP Two months after presenting to the hospital the patient continued to deteriorate despite the mentioned treatment and died. At autopsy, the fixed brain weighed 1300 g. There were signs of oedema as flattening convolutions and ventricular lumen collapse. The histological examination revealed a diffuse lymphocytic infiltration, predominantly in the white matter, composed of atypical cells with a lobular nucleus, which were arranged around the vessels (figure 3A). These lesions were associated with reactive gliosis, large numbers of macrophages and large areas of demyelisation. There was no spongiosis in the cortex nor evidence of prionic protein deposit (PrP; figure 3B). Immunohistochemically, the tumour cells were CD20−, CD3+, Granzyme and TIA-1+, CD5−, CD7−, CD4−, CD8−, CD56−, CD57− (figure 3C). Epstein-Barr virus in situ hibridisation (EBER) was negative as was the John Cunningham virus. Molecular studies (T-cell receptor γ gene rearrangement) showed a clonal appearance and a T-type primary cerebral lymphoma was confirmed.
Figure 1 A brain MRI showing bilateral hyperintense signal in the white matter of the frontal lobes and the caudate nuclei, putamen and thalamus in fluid-attenuated inversion recovery and T2-weighted images.
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Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
Unusual association of diseases/symptoms
Figure 2 (A) An EEG study on admission showing paroxysmal sharp-wave periodic complexes suggesting the diagnosis of Creutzfeldt-Jacob disease. (B) A repeat EEG showing 2 months after admission with similar findings to the first EEG.
DISCUSSION PCNSL accounts for 3–5% of primary brain tumours and has an incidence of five per 1 million person-years. It is an uncommon subgroup of extranodal non-Hodgkin lymphomas and by definition is confined to the CNS including eyes, meninges and cranial nerves.5 12 About 90% of PCNSL are diffuse large B-cell lymphomas and only 5% constitute low grade B-cell type lymphoma, including mucosa-associated lymphoid tissue type and T-cell type lymphoma.12 13 Its incidence is increasing
steadily in immunocompetent patients due to an ageing population and better diagnosis while decreasing in patients with AIDS since the development of highly active antiretroviral therapies.5 PCNSL has a male preponderance of 1.5–1 with a median age at onset in immunocompetent patients in the sixth decade13 and between 30–40 years in immunocompromised patients.12 Initial symptoms are mostly focal neurological deficits depending on tumour location, or signs of increased intracranial pressure with 10% of patients suffering from visual disturbances.13 However,
Figure 3 (A) Atypical lymphoid cells in close relation with blood vessels. (B) Absence of spongiform changes in the cerebral cortex. (C) Positive CD3 staining of the tumour cells. Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
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Unusual association of diseases/symptoms non-specific organic brain syndromes and personality changes are now the most common presenting feature of PCNSL, especially if the location is deep seated.5 12 On CT imaging PCNSL appears as a hyperdense mass that commonly exhibits homogeneous uptake. Contrast-enhanced MRI is the method of choice when PCNSL is suspected with lesions appearing as isointense or hypointense on T1-weighted and hyperintense on T2-weighted images, although up to 90% in immunocompetent patients show homogeneous contrast enhancement with slightly cloudy margins. The tumour is mostly located in the brain hemispheres and periventricular zone, but can also be in deeper brain structures such as basal ganglia, corpus callosum and brain stem.6 12 CSF findings show a moderate increase of protein in 70–90% of patients with only 10–30% having detectable malignant cells. Diagnosis of PCNSL should always be made in histological grounds via stereotactic biopsy. Steroid therapy should be stopped 7–10 days prior to biopsy where possible due to the proapoptotic effect of steroids on lymphocytes causing short-term partial or complete remission.12 13 Once the diagnosis has been established, steroids may be administered to reduce cerebral oedema causing mass effect.14 Staging should be followed including slit-lamp examination to detect ocular involvement, and whole body CT and bone marrow biopsy to detect any systemic involvement.13 The prognosis of PCNSL is greatly influenced by age and performance status (11). Median survival ranges from 313 to 25 months.14 Radiotherapy and chemotherapy increase survival rates to 60 months and up to 8.5 years in treated patients 50 years or younger.12 However, multiple lesions, leptomeningeal involvement or T-cell lymphoma are not prognostically relevant.13 Currently, first-line therapy for PCNSL is based on high-dose methotrexate-based (HD-MTX) chemotherapy with 18–65% achieving complete remission, although long-term survival after HD-MTX alone is rare. For example, in the Bonn-Bochum protocol, HD-MTX is combined with high-dose cytarabine, ifosfamide, cyclophosphamide, vinca-alkaloids, steroids, and intrathecal/intraventricular MTX and Ara-C.12 Common side effects of polychemotherapy include acute hepatotoxicity, nephrotoxicity, anaemia, thrombocytopaenia and maintenance of remission in elderly patients.15 High-dose whole-brain radiation therapy (WBRT) is no longer part of first-line treatment due to the propensity of inducing late neurotoxicity with most patients relapsing.13 16 Radiation therapy has a role if there is a recurrence or lack of response to primary therapy.14 There is no role for gross surgical resection in PCNSL other than debulk tumour mass to impede neurological deterioration secondary to brain herniation.12 15 Owing to the rarity of PCNSL and the small number included in trials, more randomised controlled trials with larger numbers of patients and longer follow-up periods are needed to assess the efficacy of different combination chemo and radiotherapy strategies in different age groups to determine ideal dosages, duration of treatment and prognosis.14 T type lymphomas account for a small percentage of PCNSL, with few reported cases in the literature. Three cases over the course of 6 years presented with a different combination of clinical symptoms: the first with seizure, the second with headache and diplopia and the third with instability, occipital headache, diplopia and paralysis. All showed mass lesions on CT in different locations of the brain with incongruent signals on T1 and T2 MRI, which demonstrates the heterogeneity of clinical presentation and radiological findings. All had tumour excision followed by courses of chemotherapy and holocraneal 4
radiotherapy with differences in survival outcomes (from a few months up to 6 years).17 In another case, a 56-year-old immunocompetent man had a 6 week history of confusion, lethargy, memory disturbance and focal neurological signs of diplopia, and weakness. CT showed low attenuation in the brainstem and MRI revealed widespread non-enhancing areas with increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging with widespread extension with no mass effect or midline shift. Lumbar puncture examination revealed non-specific raised white cell count and an elevated protein. Definite diagnosis was achieved via biopsy with positive staining (for CD3, CD45, CD10, CD99) confirming primary CNS T-cell lymphoma.16 Despite treatment with intrathecal and intravenous methotrexate-based chemotherapy with initial clinical and radiological improvement, the patient subsequently died of the disease 15 months after discharge. Certain neoplasms such as meningiomas, schwannomas and pituitary adenomas have a predilection in women, with primary CNS lymphoma having an incidence of 0.02 per 100 000 women years. One case of particular rarity is of a 33-year-old woman who was diagnosed at 32 weeks of gestation of a T-cell lymphoma after presenting with headache, vomiting and drowsiness. MRI showed a midline mass at the anterior cranial fossa with compression of the third ventricle. After allowing fetal lung maturation with corticosteroids, the patient had a caesarean section and tumour evacuation under the same anaesthetic. She subsequently received high-dose methotrexate with radiation but died on the 10th day postpartum.18 This case highlights the rarity of T-type lymphoma in young women, particularly during pregnancy. Long-term immunosuppressive therapy (eg, cyclosporin A, tacrolimus), or any underlying disease with associated immunosuppression, such as after organ transplantation, raises the risk for PCNSL. Risk factors in immunocompetent patients are not known, although viruses have been proposed.13 HTLV-1 affects around 15 million people and is commonly associated with adult T-cell leukaemia/lymphoma and tropical spastic paraparesis/ HTVL-1 associated myelopathy (TSP/HAM). An immunocompetent 29-year-old man was diagnosed with high-grade T-cell PCNSL with only a positive HTLV-1 serology as the relevant medical history. He had a 4-month history of confusion, drowsiness, visual hallucinations and psychotic thinking. CT and EEG showed no abnormalities 1 month after symptom onset. MRI demonstrated multifocal lesions that were hyperintense on T2 FLAIR and hypointense on T1 involving various structures such as the corpus callosum. Diagnosis was reached after an open biopsy. Despite treatment with methotrexate and whole brain irradiation the patient died 14 months after initial diagnosis.19 Another virus that has been associated with T-cell lymphoma is the EBV, which was reported in an elderly woman who presented with rapidly progressive mental deterioration. MRI revealed typical T1 and T2 images of multiple lesions in bilateral frontal and temporal lobes and left occipital lobe. In situ hybridisation revealed EBV-encoded RNAs in the tumour cell nuclei. This is an unusual case as almost all cases of EBV are associated with B-type PCNSL.20 LC is a rare variant of PCNSL. Unlike the latter, which often presents as one or more discrete mass lesions, LC is the diffuse infiltration of the cerebral white matter by lymphoma cells without causing a mass effect and without taking up contrast, which is similar to that seen in gliomatosis cerebri.6 21 Between 1999 and 2011, 17 cases of LC have been reported in immunocompetent patients, 15 were B-cell type and the Rivero Sanz E, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201246
Unusual association of diseases/symptoms remaining were T-type or unspecified. Common clinical presentations included insidious cognitive decline, forgetfulness and changes in personality. All cases showed white matter involvement on MRIs. However, due to its rarity and difficulty interpreting the MRI findings, which overlap with other causes of leucoencephalopathy, diagnosis still poses a challenge to physicians and delays prompt treatment. The prognosis of LC is shorter than that of PCNSL.6 The last two reported cases of B-cell LC were of two immunocompetent women aged 56 years6 and 58 years.22 The first presented with insidious changes in personality, apathy and forgetfulness over a 4-month period (similar to our patient) while the second had a progressive paraparesis, postural hypotension and weight loss over a 3-month period. CSF findings in both cases showed raised protein with no atypical cells detected on cytology, as in our patient. Brain MRIs showed multiple non-enhancing foci with typical hyperintensity on FLAIR images, while our patient had non-specific white matter infiltration. The first patient’s diagnosis was reached via stereotactic biopsy and she received steroids and WBRT; whereas the second patient and our patient deteriorated and required an autopsy to reach a diagnosis. Both cases described had positive markers for B-cell LC, namely CD20+ whereas our patient had negative CD20 markers and positive markers for T-cell LC, namely CD3+, a much rarer subtype of LC.22 Our case is of interest for various reasons. The presentation of a rapidly progressive dementia in a middle-aged woman opens a wide range of differential diagnoses, such as from neurodegenerative, infective and metabolic causes, which were ruled out with routine tests. Iatrogenic CJD was considered due to the course of the patient’s illness and her exceptional surgical history of a dura mater allogenic graft in the 1970s, with numerous cases emerging at that time due to the unknown routes of transmission and decontamination methods for surgical instruments. This caused diagnostic confusion, as have other reported cases in the literature, of rapidly progressive dementias that are ultimately shown to be PCNSL. Owing to her rapid clinical deterioration diagnosis could not be reached until autopsy, the results of which demonstrated it to be T-cell LC—an exception-
ally rare form of disease progression, which involves an infiltrative process of the white matter of the CNS without causing a mass effect as seen in PCNSL, with an even rarer histological cell type. Our case mimics other reported cases of T-cell PCNSL and LC in that presentation is of a rapidly progressive dementia with personality changes. The only positive findings in the tests performed were an elevated protein in the CSF and non-specific inflammation of the white matter on MRIs. This case illustrates the rarity of T-cell LC and demonstrates the increased awareness that physicians require in any rapidly progressive dementia to diagnose it and to start treatment promptly. Contributors ERS was involved in collecting data, including journals, drafting and writing the article. MATC was involved in supervising and revising the article. FJSP undertook the patient’s autopsy, and FGB contributed in providing the histological images and approving the final draft. Competing interests None. Patient consent Not obtained. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2 3 4 5 6
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Learning points
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▸ Lymphomatosis cerebri (LC) is a subtype of primary central nervous system lymphoma (PCNSL) in which lymphoma cells infiltrate the white matter without causing mass effect. ▸ Presentation is usually of a rapidly progressive dementia with personality changes and can have similar characteristics as Creutzfeldt-Jakob disease (CJD), but the triphasic wave pattern detected on EEG is not specific for CJD. ▸ MRI are deemed to be the most useful diagnostic tool, with hyperintense images showing on T2 and fluid-attenuated inversion recovery images. ▸ If PCNSL or LC is suspected, a stereotactic biopsy should be carried out. ▸ Prompt treatment, based on high-dose methotrexate polychemotherapy, is showing encouraging survival rates, especially in patients under the age of 65 years.
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