Parenchymal Central Nervous System Involvement Research Articles

Relapsed mantle cell lymphoma with parenchymal central nervous system involvement successfully treated with chimeric antigen receptor T-cell therapy—a case report

Relapsed mantle cell lymphoma with parenchymal central nervous system involvement successfully treated with chimeric antigen receptor T-cell therapy—a case report

Characteristics of Patients With Behçet Disease From the Van Province, Eastern Turkey: Definition of Disease Clusters in a Tertiary Referral Center.

Behçet disease (BD) is a chronic inflammatory systemic disease that affects skin mucosa, joints, eyes, and blood vessels. Behçet disease shows some clinical differences in terms of disease manifestations and prognosis among the Silk Road countries, as well as various ethnicities even in the same country. In this study, we aimed to evaluate the clinical features and disease course of BD using cluster analysis in Van province, Eastern Turkey. This study was carried out in a tertiary referral center in Van province, by reviewing medical records. Seven disease manifestations were included to the cluster analysis as follows: mucocutaneous findings (oral ulcer, genital ulcer, erythema nodosum-like lesions, pseudofolliculitis), uveitis, superficial thrombophlebitis, musculoskeletal involvement, gastrointestinal system involvement, vascular involvement, and parenchymal central nervous system involvement. We identified 467 patients. After the exclusion of 6 patients who had missing data and 17 patients who did not live in Van, 444 patients (59.2% male) included into the study. Meeting the International Study Group and the International Criteria for Behçet Disease criteria were 91.6% and 96%, respectively, and 91.3% (n = 379/415) of these patients met both criteria. Four clusters were identified in the analyses: 132 patients (31.2%) in vascular (C1), 66 patients (15.6%) in ocular (C2), 60 patients (14.2%) in musculoskeletal (C3), and 165 patients (39%) in mucocutaneous (C4) clusters. Male gender ( p = 0.002; odds ratio [OR], 6.5; 95% confidence interval [CI], 2-21.4), superficial thrombophlebitis ( p = 0.001; OR, 4.7; 95% CI, 1.9-11.4), and uveitis ( p = 0.01; OR, 3.6; 95% CI, 1.3-9.9) were associated with vascular involvement in multivariate analysis. In our study, 4 clusters were detected in patients with BD from Van province. The prevalence of severe manifestations of BD may be related to genetic or environmental factors, such as differences in ethnicity and/or geographical differences. Despite the higher proportion of patients with a more severe disease, a favorable outcome was observed in our cohort.

Paraneoplastic neurological syndromes of the central nervous system: a single institution 7-year case series.

Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity. We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included. A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients. Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment.

Lesion probability map in cerebral vein thrombosis due to Behçet's disease.

Behçet's disease (BD) is a multisystemic inflammatory disease. Cerebral venous sinus thrombosis (CVST) is the second most common form of neuro-BD after parenchymal central nervous system involvement. The purpose of this study was to construct flow-void probability maps of patients with CVST with and without BD to visually illustrate the impacted cerebral venous sinuses, to compare the subgroups of patients, and investigate the effect of thrombus localization on clinical findings. Seventeen patients with a diagnosis of BD-related CVST (CVST-BD) and 23 patients with a diagnosis of CVST related to other etiologies (CVST-O) were included. We collected data including gender, age at onset of BD and CVST, presenting symptoms, neurological findings, and the etiology. High-resolution magnetic resonance venographies obtained during CVST were used to mark and digitalize thrombosed areas. Thrombus probability and subtraction maps were created to reveal the differences between the subgroups. Remarkably, all patients with CVST-BD had thrombosis in the transverse sinus (TS). However, TS was affected in 73.9% of the CVST-O patients (17/17 in CVST-BD vs 17/23 in CVST-O, P=.03). Thrombosis developed mostly in the superior sagittal sinus (SSS) and TS in the CVST-O group (11/23, 47.8% and 17/23, 73.9%, respectively). The frequency of SSS thrombosis tended to be higher in the CVST-O (47.8% vs 23.5%, P=.19). Venous infarction and hemorrhage were less common in patients with CVST-BD. The only clinical symptom in most of the CSVT patients with BD was headache due to elevated intracranial pressure. TS thrombosis was more common in patients with BD.

Parenchymal central nervous system involvement in aggressive B-cell lymphoma: retrospective analysis of clinical and MRI features in a Chinese population

BackgroundSecondary central nervous system lymphoma (SCNSL) is defined as secondary central nervous system (CNS) involvement in patients with systemic lymphoma. It is considered a profoundly adverse complication with inferior clinical outcome. Parenchymal involvement in the CNS in aggressive B-cell lymphoma is not frequently seen and remains a diagnostic dilemma.MethodsIn our study, we retrospectively analyzed the clinical and magnetic resonance imaging (MRI) features of 26 parenchymal SCNSL patients. In addition, we compared MRI features of SCNSL and primary CNS lymphoma (PCNSL) patients after 1:1 propensity score matching. Also we presented two SCNSL cases with atypical MRI appearance.ResultsAmong SCNSL patients, the median CNS relapse time was 3 months, and multiple lesions were found in 76.9% of the cases. In PCNSL, this percentage was 42.3% (p = 0.011). None of the SCNSL patients and 23.1% of the PCNSL patients had solitary infratentorial lesions (p = 0.003).ConclusionsThe majority of parenchymal involvement occurred within the first year of systemic lymphoma, in which mostly cases presenting with multiple and supratentorial locations, unlike what was found in PCNSL.

Neuro-behçet disease cases with parenchymal and non-parenchymal involvement

Neuro-Behçet’s Disease (NBD) is classified as parenchymal and non-parenchymal involvement. The diagnosis is made by the diagnosis of aphthous lesions, as well as by eye, skin findings, positive pathergy test and vascular lesions. In this article, we aimed to present three cases who presented to our clinic with different neurological complaints and were diagnosed with NBH as a result of clinical evaluations. Our first patient was diagnosed with NBH because of recurrent oral aphthae, genital scar, pathergy test and HLA B51 positivity, magnetic resonance (MR) involvement, and previous Behçet’s disease (BD). In our second case, non-parenchymal involvement was present and widespread cerebral venous thrombosis was detected. The development of gastrointestinal system bleeding with anticoagulant stimulation was associated with GIS involvement and was stimulatory in terms of possible complications of GI. In our last case, there were more than 3 oral aphthae per year, intermittent arthralgia complaints and parenchymal central nervous system involvement and HLA B51 was positive. We wanted to emphasize the need for detailed history and examination of BD in patients with headache, consciousness changes or acute neurological deficits and emphasize the importance of this disease which is common in our country.

Risk of Death, Relapse or Progression, and Loss of Life Expectancy at Different Progression-Free Survival Milestones in Primary Central Nervous System Lymphoma

▪Primary Central Nervous System Lymphoma (PCNSL) is a rare aggressive non-Hodgkin lymphoma involving exclusively the central nervous system (CNS). The majority of PCNSLs are diffuse large B-cell lymphomas (DLBCL), but treatment and prognosis differ from systemic DLBCL due to differences in biology and the difficulty of delivering effective therapies with high penetration across the blood-brain barrier (BBB). While PCNSL often responds to initial therapy, relapses are common even after achieving a complete remission. The aims of this study were to estimate the risk of death or relapse and the loss of life expectancy in PCNSL after primary treatment with high-dose methotrexate (HD-MTX) containing regimens. Outcomes were assessed at baseline and for patients reaching pre-defined milestones of progression-free survival (PFS).Data on PCNSL patients were extracted from the nationwide Danish lymphoma register. The inclusion criteria were I) histologically-proven DLBCL morphology, II) involvement restricted to parenchymal or leptomeningeal CNS involvement without ocular involvement, III) treatment protocols containing HD-MTX, and IV) diagnosis between 2000-2017. PFS was defined as the time from diagnosis until death, relapse/progression, or end-of-treatment response assessment for patients with stable or progressive disease at the response assessment. The five-year PFS event probability risk was estimated for all patients and conditional on patients reaching different PFS milestones. The five-year restricted loss of lifetime (5y-RLEL) was defined as the numeric difference in the number of days patients and individuals from a background population are expected to live in the following five year period. This was estimated for all patients and for subsets of patients free of PFS events after one (PFS1), two (PFS2), or three (PFS3) years. Additionally, the results were stratified according to gender, ECOG performance status 0-1/> 1, elevated LDH status, treatment with/without rituximab, and age at diagnosis ≤60/>60 years. The survival of an age- and gender-matched general population was calculated by using life tables from the Human Mortality Database.In total 253 patients were included in the analyses; 60% were male, median age at diagnosis was 66 (range 27 - 85), 46% had an ECOG performance status > 1, and 33% had elevated LDH levels. Consolidation therapy (radiotherapy and/or high-dose therapy with autologous stem cell transplantation) was used in 23% of patients and 36% received rituximab in first line. The median follow-up was 6.9 years (range 0.7 - 17.7), the 5-year overall survival was 35% (95% CI 29-42), and the five-year PFS was 28% (95% CI 22-34). Patients reaching PFS1 had a 51% (95% CI 41-61) probability of a PFS event in the following five years (Figure 1A). After the PFS1 milestone, the five-year probability of a PFS event did not change substantially (Figure 1A) and the event probability remained high even after three years of PFS. On average, the PCNSL patients lost 2.2 living years (95% CI 1.9 - 2.4) in the five years after first pathologic diagnosis of PCNSL (Figure 1B). At PFS1, the 5y-RLEL decreased to 1.0 years (95% CI 0.7 - 1.3) (Figure 1B). The achievement of later PFS milestones only led to minor additional decreases in 5y-RLEL (PFS3: 0.7 years [95% CI 0.3 - 1.1]) (Figure 1B). The 5y-RLEL estimates were substantially larger for patients with an ECOG performance status > 1 vs patients with an ECOG performance status ≤ 1 (Figure 1B). Outcome differences between risk factor defined subgroups decreased after PFS1 and later PFS milestones (Figure 1B).The outlook of PCNSL patients treated with HD-MTX-based therapy improves significantly given a progression-free survival of one year, after which baseline adverse risk factors lose prognostic impact over time. However, in contrast to systemic DLBCL, survival does not normalize to the background population even after several years without PFS event. By the time of the ASH, updated results that include patients from the population-based lymphoma database in British Columbia (Canada) will be presented. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pulmonary artery involvement in Behçet׳s syndrome: Effects of anti-Tnf treatment

ObjectivesAnti-TNF agents are being increasingly used in patients with Behçet׳s syndrome (BS) when conventional immunosuppressives fail. However, experience with anti-TNF treatment on pulmonary artery involvement (PAI) of BS is limited. MethodsA chart review revealed 13 patients with PAI (all men) treated with anti-TNF agents (12 infliximab and 1 adalimumab) following an inadequate response to immunosuppressives for 12.2 ± 9.5 SD months and 2 male patients who developed PAI while receiving infliximab for large vein thrombosis for 10 months and for parenchymal central nervous system involvement for 2 years, respectively. ResultsThe first patient developing PAI while receiving infliximab responded to cyclophosphamide and prednisolone but the second died with hemoptysis within 1 month. At the end of the survey, 6 of the 13 patients with PAI were continuing these agents for 25.5 ± 16.2 SD months with good response, 4 stopped anti-TNF treatment after a mean of 23 ± 9.8 SD months after achieving clinical and radiologic response and 1 patient with good response went to another center after receiving infliximab for 10 months and the remaining 2 experienced serious infections (lung tuberculosis and aspergillosis) necessitating early withdrawal. Two patients relapsed within 3 years after stopping anti-TNF agents and concomitant azathioprine. One developed mesenteric vein thrombosis necessitating bowel resection and the second developed new PAI that was controlled with cyclophosphamide and prednisolone after short courses of infliximab, adalimumab, and canakinumab. ConclusionAnti-TNF treatment seems to be effective for refractory PAI of BS but may not prevent its development. Relapses can be seen after withdrawal. Caution is required for their serious adverse effects.

A case of Behcet's disease posted for surgery: Anaesthetic implications.

Sir, Behcet's disease, a multi-systemic inflammatory process of unknown aetiology is characterised by relapsing episodes of oral aphthous ulcers, genital ulcers, skin lesions and ocular lesions, first described 1937.[1] It is associated with involvement of the cardiovascular system, lungs, central nervous system (CNS), vessels and synovial surfaces. There are very few reports of patients with this disease posted for surgery. A 22-year-old male presented with complaints of swelling in the left scrotal region over the past few months. He gave a history of joint pain and swelling. Diagnosed as a case of ulcerative colitis with multiple strictures years back, he was operated for the same thrice under general anaesthesia. Later he developed oral and penile ulcers, was diagnosed as Behcet's syndrome and started on tablet prednisolone 10 mg, tablet mesalazine 400 mg once daily and tablet colchicine 5 mg twice daily. On examination, he had mild pallor (haemoglobin - 9 g/dl). Mouth opening was one finger breadth [Figure 1] with Mallampati class IV. Ulceration of the oral mucosa, acneiform skin lesions and genital scarring was noted. Echocardiography and magnetic resonance imaging of the brain were normal. The morning dose of oral prednisolone was continued and nil by mouth status and written informed consent confirmed. The patient was posted for hydrocoele and incisional hernia repair under spinal anaesthesia. An intravenous (IV) line was secured using 20 gauge cannula in a single prick and Ringer lactate solution was started. Injection hydrocortisone 50 mg and ondansetron 4 mg were given IV. Subarachnoid block was performed. 3 cc of bupivacaine 0.5% with 30 μg of injection clonidine was administered resulting in a block uptoT6. Pulse rate, blood pressure, respiration, electrocardiogram and oxygen saturation were monitored throughout. Surgery was completed uneventfully.Figure 1: Restricted mouth openingDiagnostic criteria for Behcet's disease as suggested by Mason and Barnes include: Major criteria-buccal ulceration, genital ulceration, eye lesions and skin lesions. Minor criteria-gastrointestinal lesions, cardiovascular lesions, thrombophlebitis, arthritis, CNS lesions and family history. Diagnosis of the disease is made only if three major or two major and two minor criteria are present.[2] Male sex and younger age group are associated with a more severe disease.[1] Since Behcet's disease is an inflammatory process, chronic use of anti-inflammatory and anti-neoplastic drugs is common.[3] Our patient was on tablet mesalazine and tablet colchicine. Mesalamine is a 5-amino salicylic acid based agent indicated for the treatment of ulcerative colitis. Nephrotoxicity can be seen with these compounds. Immunosuppressants reduce the activity of the immune system, thus interrupting the inflammation process that causes symptoms of Behcet's disease. Colchicine, an anti-inflammatory medication is found to be beneficial here. It may lead to haematologic, renal and musculoskeletal side effects on long-term therapy. Thus, a complete haemogram with blood cell count and renal function tests should be obtained pre-operatively. Chronic corticosteroid use can cause suppression of the adrenocortical response leading to cardiovascular collapse intra and post-operatively. Thus, supplemental corticosteroids are necessary on the day of surgery. Since these patients are prone to develop inflammatory skin lesions ultimately leading to ulcer formation, puncture of the skin and mucous membranes should be minimised. IV line should be secured with caution. General anaesthesia should proceed only after a thorough airway examination. Difficult airway could result from active oropharyngeal ulceration or scarring leading to limited mouth opening.[2] When considering awake intubation, anaesthesia of the airway should include topical application of local anaesthetics, not injectable airway blocks because of potential compromise of the airway from an inflammatory response to the local injection. In extreme cases, lesions can severely reduce the lumen of oropharynx and tracheostomy might be necessary for urgent surgery.[2] For elective procedures, awake fibreoptic intubation is usually preferred. The use of laryngeal mask airway can lead to aggravation of the oropharyngeal lesions. Repeated attempts at laryngoscopy and intubation should be avoided as tissue trauma can lead to further development of aphthous ulcers.[4] Regional anaesthesia is less ideal as puncture of the skin or mucous membranes is very likely to result in inflammation and nodular formation. Dangerous parenchymal CNS involvement affecting the brainstem, spinal cord and cerebral hemispheres and non-parenchymal manifestations including intracranial hypertension, aseptic meningitis, cranial neuropathy and cerebrovascular disorders are contraindications for the neuraxial block.[5] However, we preferred spinal anaesthesia considering that CNS involvement was ruled out and the problems associated with difficult airway were far more severe. Clonidine was added to prolong the duration of the neuraxial block. The main pre-operative anaesthetic concerns in Behcet's disease are therefore scarring of oral mucosa leading to difficult airway, inflammatory involvement of the organ systems, inflammatory response to skin prick and chronic immunosuppressant therapy which could cause renal and haematopoietic side effects. The case was successfully managed after a thorough knowledge of the disease and the anaesthetic implications involved.

Neuro-Behçet Disease Presenting With Acute Psychosis in an Adolescent

Behçet disease is a systemic vasculitis of unknown etiology that can affect the neurologic system. Neuro-Behçet disease is not well defined in children and adolescents, and the diagnosis is difficult to make in this population as they often present with insufficient symptoms to meet diagnostic criteria. Psychiatric symptoms as the initial manifestation of neuro-Behçet disease has rarely been reported. We describe a 17-year-old boy who presented with acute psychosis and was subsequently diagnosed with neuro-Behçet disease. A rare combination of both cerebral venous thrombosis and parenchymal central nervous system involvement was identified by neuroimaging. Although treatment guidelines for neuro-Behçet disease are limited, the patient made demonstrative clinical and radiographic improvement with a combination of corticosteroids, anticoagulation, and immunosuppressants, including a tumor necrosis factor-α (TNFα) blocking agent.

Nervous System Lyme Disease: Diagnosis and Treatment

The tick-borne spirochete responsible for Lyme disease is highly antibiotic-sensitive. Treatment related misconceptions can be attributed to confusion in three principal realms: (1) the appropriate approach to diagnosis (who should be treated); (2) necessary and appropriate treatment; and (3) what actually constitutes nervous system infection and to what extent this mandates different treatment. Contrary to often-repeated assertions, laboratory-based diagnosis-in the appropriate setting-is as valid as it is in most other serologically diagnosed infections. Treatment is highly effective in the vast majority of patients, including those with nervous system disease. Nervous system infection, most typically meningitis, cranial neuritis, radiculoneuritis, and other forms of mononeuropathy multiplex, is highly antibiotic responsive. The encephalopathy that can be seen in some patients with active infection represents the same phenomenon that occurs in patients with many other inflammatory disorders, is not evidence of central nervous system (CNS) infection, and does not require any different, more prolonged, or more intensive treatment. In patients with infection not involving the CNS, oral treatment with amoxicillin, cefuroxime axetil, or doxycycline for 2-4weeks is almost always curative. Despite historic preferences for parenteral treatment with ceftriaxone, cefotaxime, or meningeal dose penicillin, patients with the forms of nervous system involvement listed above are highly responsive to oral doxycycline. Parenteral regimens can be reserved for those very rare patients with parenchymal CNS involvement, other severe forms of infection, or the approximately 5% of patients who fail to respond to oral regimens.

Secondary infiltration of the central nervous system in patients with diffuse large B-cell lymphoma

ObjectiveTo investigate the incidence and risk factors of infiltration of the central nervous system after the initial treatment of diffuse large B-cell lymphoma in patients treated at Santa Casa de Misericórdia de São Paulo. MethodsA total of 133 patients treated for diffuse large B-cell lymphoma from January 2001 to April 2008 were retrospectively analyzed in respect to the incidence and risk factors of secondary central nervous system involvement of lymphoma. Intrathecal prophylaxis was not a standard procedure for patients considered to be at risk. This analysis includes patients whether they received rituximab as first-line treatment or not. ResultsNine of 133 (6.7%) patients developed central nervous system disease after a mean observation time of 29 months. The median time to relapse or progression was 7.9 months after diagnosis and all but one patient died despite the treatment administered. Twenty-six (19.5%) patients of this cohort received rituximab as first-line treatment and nine (7.1%) received intrathecal chemoprophylaxis. Of the nine patients that relapsed, seven (77.7%) had parenchymal central nervous system involvement; seven (77.7%) had stage III or IV disease; one (11.1%) had bone marrow involvement; two (22.2%) had received intrathecal chemoprophylaxis; and 3 (33.3%) had taken rituximab. In a multivariate analysis, the risk factors for this infiltration were being male, previous use of intrathecal chemotherapy and patients that were refractory to initial treatment. ConclusionCentral nervous system infiltration in this cohort is similar to that of previous reports in the literature. As this was a small cohort with a rare event, only three risk factors were important for this infiltration

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) is effective therapy for patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) involvement

Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

Behçet’s Disease

Neurologic involvement in Behçet's disease (BD) is seen in about 5% to 10% of all BD patients. Clinical and imaging data suggest that neurologic involvement in BD presents in two major forms. The first, central nervous system (CNS) parenchymal involvement with a predilection to brainstem-diencephalic regions, is seen in the majority of patients with neuro-BD (NBD). The second form is cerebral venous sinus thrombosis (CVST), which is seen in up to 20% of cases. BD is very rare in children, but when it does occur, the patterns are reversed: most children with NBD present with CVST. Other syndromes such as spinal cord involvement, arterial CNS involvement, optic neuritis, aseptic meningitis, and peripheral neuropathies may be seen, but are rare. Venous sinus thrombosis in BD has a significantly better neurologic prognosis than parenchymal CNS involvement. There is no Class I evidence regarding treatment of parenchymal CNS involvement or CVST in BD. Current treatment applications are based largely on expert opinion; none are evidence-based. Acute parenchymal CNS involvement should be treated with high-dose intravenous methylprednisolone (IVMP), 1g per day, for 5 to 10days, followed by either a prolonged oral taper or intermittent IVMP pulses with a low oral dose between the pulses, over 6months. After treatment of the acute attack, long-term maintenance with immunosuppressive agents should be considered in patients with parenchymal CNS involvement, as this form may follow a relapsing or secondary progressive course and may result in significant physical and cognitive deficits leading to severe neurologic disability. A number of randomized controlled studies have tested treatments for systemic manifestations of BD. Colchicine was found to be effective for mucocutaneous symptoms, thalidomide was found to be effective in erythema nodosum-like skin lesions, azathioprine and cyclosporine were shown to be effective in BD uveitis, and cyclophosphamide was shown to be effective for major vascular involvement. More recently, interferon alfa and anti-TNF agents were also shown to be effective in BD uveitis. Although randomized controlled studies have not been performed in NBD, the most widely used long-term therapeutic agent is azathioprine. Recent observations suggest that the addition and long-term use of azathioprine in NBD could be associated with a more favorable course. A growing number of case reports in recent years suggest that anti-TNF agents may be an effective alternative in NBD, but current experience with these agents is limited. CVST in BD is also treated with steroids. The addition to glucocorticoids of anticoagulation, including short-term fractionated heparin, is controversial, as these patients have a higher probability of harboring pulmonary or other aneurysms, which may be associated with an increased risk of bleeding. Long-term oral anticoagulation is unnecessary. Interestingly, the prognosis of CVST due to BD seems to be much more favorable than the prognosis of CVST due to other causes, with much less tendency for venous infarcts and seizures. However, as recurrences may occur, long-term treatment with azathioprine is recommended.

18F]Fluorothymidine PET imaging in the diagnosis of leptomeningeal involvement with diffuse large B-cell lymphoma

The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement

AbstractAbstract 1358Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures:No relevant conflicts of interest to declare.

Les manifestations neurologiques de la maladie de Behçet : étude de 67 patients

Neurological manifestations of Behçet disease (BD) are polymorphic and serious. The purpose of this study was to analyze the clinical patterns and outcome of neurological involvement in BD. The medical records of patients with neurological manifestations of BD were reviewed retrospectively. All patients fulfilled the International Study Group Criteria for the Diagnosis of BD. Patients with headache and normal findings (neurological examination, cerebrospinal fluid, computed tomography scan, magnetic resonance imaging) were excluded. Sixty-seven patients had clinical evidence of neurological involvement. There were 53 men and 14 women. A male/female sex ratio was 3.78. The average age of onset of neurological involvement was 31.5. The meningoparenchymal (MP) central nervous system involvement was found in 83.58%. The most common findings were pyramidal signs. Eleven patients (16.41%) without parenchymal central nervous system involvement were noted. In this group, there were six cases of intracranial thrombosis, one case of intracranial aneurysm and four cases of idiopathic intracranial hypertension. Other clinical features were reported: extrapyramidal signs and isolated spinal cord involvement. The course of disease was favorable in 70% of cases, and unfavorable in 30%. Clinical patterns of neurological involvement in BD are various and particularly serious in the MP group.

Safety and Efficacy of Intrathecal Liposome-Encapsulated Cytarabine for Central Nervous System (CNS) Prophylaxis in Adult Patients with Burkitt and Atypical Burkitt Lymphoma Treated with the R-CODOX-M/R-IVAC (Magrath) Regimen: Results of a Phase II Study.

Abstract 3716Poster Board III-652 IntroductionIntrathecal (IT) chemotherapy is an integral component of treatment for Burkitt lymphoma (BL), together with intensive systemic chemotherapy including blood brain barrier crossing agents such as high dose cytarabine (Ara-C) and methotrexate (MTX). However, the optimal IT treatment is yet to be established. Since cytotoxic concentrations of conventional IT agents (Ara-C and MTX), are maintained in the cerebrospinal fluid (CSF) for only a few hours, repeated lumbar punctures are necessary which may turn cumbersome for patients (pts) and pose technical difficulties in some instances. The availability of a sustained-release formulation of Ara-C (liposome-encapsulated Ara-C; Depocyte®) may offer the opportunity of reducing the total number of IT administrations by maintaining/enhancing, the efficacy of CNS prophylaxis. In this regard, a single 50 mg IT injection of Depocyte is able to achieve cytoxic concentrations of free-Ara-C in the CSF for 10-14 days. We report the results of a prospective phase II study aimed at evaluating the safety/activity profile of IT Depocyte in pts with BL and atypical (a)BL. Patients and MethodsThe study was designed to assess, in untreated pts with BL and aBL, the safety and feasibility of a 50% reduction (from 8 to 4) of the number of IT injections required by substituting IT Ara-C (4 doses) and MTX (4 doses) with 4 administrations (50 mg) of IT Depocyte. IT injections were planned on days (d) 1 or 2 of each rituximab (R)-CODOX-M courses and on d 8 of each R-IVAC course. Pts with aBL received 2 additional R-CODOX courses without any further IT therapy. Primary study endpoints were safety, Depocyte-related extra-hematologic adverse events ≥G3, and CNS failure, i.e. progression/relapse at leptomeningeal and/or parenchymal sites; secondary endpoints included event- and disease-free survival (EFS, DFS). ResultsA total of 30 HIV negative pts (15 BL and 15 aBL) were enrolled and treated with a dose-modified Magrath regimen (Lacasce, 2004). The median age of pts (M/F: 22/8) was 53 years (r, 25-78), 10 pts (33%) were considered as a low risk (LR) category by displaying ≥ 3 of the following factors: normal LDH, WHO PS 0-1, Ann Arbor stage I-II, and ≤ 1 extra nodal sites. All remaining cases (67%) were considered as high-risk (HR). At diagnosis, 3 pts (10%) had a positive CSF for lymphoma, 6 (20%) had bone marrow involvement and 12 (40%) bulky (>10 cm) disease. Each pt received a median of 4 (r, 1-6) IT injections of Depocyte at the a median day of 0.5 (r, -1 to 1) for R-CODOX-M1 (course1), 4.0 (r, -2 to 17) for R-IVAC1 (course 2), 1 (r, -1 to 1) for R-CODOX-M2 (course 3) and 6.5 (r, -3 to 14) for R-IVAC2 (course 4). On a total of 111 applications, the following IT injection-related adverse events (NCI-CTCAE v 3.0) of G1-G2 severity were recorded (pts experiencing toxicity): headache 26.6%, nausea 6.6%, vomiting 3.3%, fever 10%, lumbar pain 10%, fatigue 26.6%, somnolence 6.6% and sinus bradycardia 3.3%. A G3 headache episode, accompanied by a transient loss in visual acuity, led to refusal of further IT Depocyte by a single pt. At 51 mo.s, the EFS was 70% with a DFS of 90% at a median observation of 24 mo.s (r, 1-49). Among the 27 complete responders, no isolated leptomeningeal relapses occurred. In particular, none of the 3 responders with CSF involvement at presentation, displayed any form of CNS progression (leptomenigeal and/or parenchymal). In contrast, a parenchymal CNS involvement, with a negative CSF, was observed, at 4.0 mo.s, as a part of the systemic progression in a single pt (3.3%) with chemorefractory aBL. This pt presented with unfavorable features (hi-LDH, stage IVB, PS 2, bulky retroperitoneal adenopathy and 4 extra nodal sites including liver, pancreas, kidney and spleen) and skipped both the first IT and systemic MTX administrations. ConclusionsWithin the limits of a single arm study, our results show that substitution of 8 IT injections (Ara-C/MTX) with 4 IT administrations of Depocyte within the R-CODOX-M/IVAC regimen is feasible and devoid of severe and/or life-threatening/invalidating neurotoxicity. The CNS progression/recurrence rate was at least super imposable to historical results (CNS relapse rate: 6% to 11%) achieved by the Magrath regimen including double-agent IT treatment. Based on these results, it appears that Depocyte can be safely incorporated into the Magrath regimen to provide adequate single-agent CNS prophylaxis with a reduced burden of IT applications. Disclosures:Off Label Use: Liposome-encapsulated Ara-C for CNS prophylaxis. Vitolo:Mundipharma: Lecture fees. Pinto:Mundipharma: Lecture fees.

Cerebral venous thrombosis in Behçet's disease

To analyze the clinical findings, treatment, outcome, and prevalence of cerebral venous thrombosis (CVT) in a large cohort of patients with Behçet's disease (BD) from a single center. We reported a series of 64 consecutive patients with CVT who fulfilled the international criteria for BD. Multivariate analysis was performed to define factors that affect prognosis. Among a cohort of 820 patients with BD, CVT was present in 64 (7.8%). Compared with BD patients without CVT, those with CVT had lower parenchymal central nervous system involvement (4.7% versus 28.7%; P = 0.0001) and higher extraneurologic vascular lesions (62.5% versus 38.8%; P = 0.03). Up to 90% of patients responded to anticoagulation therapy without severe hemorrhagic complications. Neither steroid nor immunosuppressant use provided better outcome. Severe visual loss due to optic atrophy was the main complication of CVT, being found in 15% of patients. In multivariate analysis, papilledema (odds ratio [OR] 7.1, 95% confidence interval [95% CI] 1.6-31.9) and concurrent prothrombotic risk factors (OR 4.6, 95% CI 1.1-20.2) were independently associated with the occurrence of sequelae. Factors associated with relapse of thrombosis were concurrent prothrombotic risk factors (hazard ratio [HR] 4.9, 95% CI 1.5-15.4) and a peripheral venous thrombosis (HR 2.8, 95% CI 0.7-10.5). After a mean +/- SD followup of 8.2 +/- 6.9 years, 4 deaths unrelated to CVT were noted. CVT in patients with BD may result in serious neurologic outcomes. Anticoagulation represents a safe and effective therapy. Extensive investigation of prothrombotic disorders should be considered.

Manifestations neurologiques de la maladie de Behçet

Neurological involvement is well described in Behçet's Disease (BD), with variable prevalence of 5.3 to 30p.cent. The purpose of this retrospective study was to analyze the clinical patterns of neuro-Behçet (NB) and to compare them with different clinical features of 925 BD registered in the same period and the literature. All patients of NB fulfilled the International Study Group Criteria for the diagnosis of BD. 93 patients with headache, without other neurological symptoms were excluded. The findings were supported by cerebrospinal fluid, computed tomography scan, magnetic resonance imaging and angiography. NB was present in 16.64p.cent of BD. A sex ratio male/female: 4.31. The mean age of patients with NB was 31.76 years. The average age of onset of NB was 29.83. The mean duration of the NB disease was 3.81 years. The findings were categorised in 2 main types: parenchymal and non-parenchymal involvement. Some patients had features of both types (mixed patterns). 94 patients (61.03p.cent) presented with parenchymal central nervous system (CNS) involvement. The most common findings were pyramidal signs, cranial nerve palsies, pseudobulbar syndrome and cerebellar signs. 27 patients (17.53p.cent) without parenchymal CNS which were divided into: intracranial hypertension in 24 patients (15.58p.cent) presenting headache, vomiting and bilateral papilloedema; cerebro-arterial involvement in 3 cases (one of them had cerebrovascular aneurysms). Mixed patterns were observed in 9 cases. Erythema nodosum and vascular involvement were more frequent in intracranial hypertension than in BD. Other clinical features were reported: pure meningeal pattern in 15 cases, pure peripheral nervous system involvement in 4 cases, isolated cranial nerves in 8 cases, chorea in one patient and pseudotumor of cervical medulla in other patient. 6 cases of juvenile BD and one case of familial Behçet were observed. 133 patients were treated (86.36p.cent). Mean duration of treatment was 7.46 month. We used corticosteroids, immunosuppressive agents (cyclophosphamid, azathioprine, chlorambucil) and anticoagulant in intracranial hypertension. The course of disease was good in only 54.13p.cent of cases, and was bad in 18.79p.cent. NB occurred frequently in men and is more serious especially in parenchymal CNS involvement: 7 deaths (6 from parenchymal CNS).