Multifocal Leukoencephalopathy Research Articles

P028 Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus

Abstract Background/Aims Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that develops following the reactivation of the John Cunningham virus (JCV) that in rare circumstances can occur in autoimmune disorders such as systemic lupus erythematosus (SLE). We present a 75-year-old female with SLE who had been treated with immunosuppressive therapy (mycophenylate and steroids) for one year. Methods A 75 year-old female presented with sub-acute deterioration of physical and cognitive function over the course of a few months including memory loss, ataxia, dysgraphia, word finding difficulty, confusion, low mood and reduced oral intake. Neurological examination revealed receptive and expressive aphasia, gaze fixation, unilateral weakness, brisk reflexes with positive plantar reflex and rigidity. A diagnosis of PML was made due to the detection of JC virus in the cerebrospinal fluid (234 copies/ml) and brain MRI findings consistent with the disease. Haematology results showed a profound lymphopenia (0.1x109 ). Mycophenolate was held and she was commenced on increasing doses of Mirtazapine up to 45mg. Clinical review at four months found marked improvement in her cognitive and physical abilities. Repeat CSF analysis found JC virus to be undetectable. Results PML has a 20-fold greater incidence in SLE when compared with the general population. Lymphopenia is a common finding in patients with SLE and has been found to correlate with both the risk and severity of opportunistic infections. The cause of this can be multifactorial and immunosuppressive drugs are often implicated however SLE in isolation can cause severe CD4+ lymphopenia leading to an increased risk of PML reactivation. This case demonstrates the importance of monitoring lymphocyte counts in SLE. Current guidance suggests adjusting regimes of immunosuppressive therapy if lymphocyte counts fall below 1x109 however further guidance on its management may be warranted. The heterogenous manifestation of SLE can make differentiating between the neurological syndromes associated with rheumatic disease and PML challenging. Given the management of PML is vastly different to that of SLE in regards to introduction or withdrawal of immunosuppressive therapies, there should be a high index of clinical suspicion in the early stages of investigation. In vitro studies have explored the possibility of mirtazapine (a 5-HT2A antagonist) providing a low-risk treatment option for those with SLE and this warrants further research into its efficacy in treating or preventing PML in this cohort. Our patient had improved symptomology after cessation of mycophenolate and the commencement of Mirtazapine. Conclusion PML is a rare complication of SLE but should be considered in patients admitted with neuropsychiatric presentations, the use of Mirtazapine may provide a low-risk treatment strategy. Disclosure D. Babla: None. Y. Suleman: None. A. Whittington: None. S. Hamdulay: None.

Genesis of Antibiotic Resistance (AR) LXXXVIII: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: “Hypnotic Trance Ameliorate Turbulence to Laminar Flow (Homeostasis)”: A Neuropsychiatric Basis

An effort is made to substantiate that vascular abnormalities (fluid dynamic/mechanical properties) could be restored to homeostasis by an appropriate hypnotic trance. Clinical Background:Sepsis: Clinical data/Record(observation): decreased capillary density ref Fig 4 c., PMID: 34055944, hypovolemia, endothelial dysfunction, increased WBC accumulation, thrombi deposition, altered CCP, NFP gradient, shunting, degradation of endothelial glycocalyx, vascular hyper permeability (PMID: 23566729; PMID: 20179590; PMID: 24067428), as an indicator of sepsis progress to septic shock. Neuropsychiatry diagnostic index: HAND (HIV associate neurodegenerative disorder), PTSD, psychosis, depression, mania, ANI, MND, HIV associated dementia (HAD), possible multifocal leukoencephalopathy (CMV origin, Toxoplasmaencephalitis, diffused myelin pallor, opportunistic infections, and neurosyphilis (Jarisch Herxheimer reaction). Geometry: Part I: RBC, Platelets, WBC: p47‐56; Part II: blood velocity, and function, Table 2.1; 2,2; 2.3; p63; ISBN 9780128024089; Governing Equations: Part A: CD, https://www.grc.nasa.gov/www/k‐12/airplane/shaped.html;; Part B: Keulegan – Carpenter Number equation: □=Vm/ƒoscD; Clinical Data: Hemodynamics Hypnotic Trance:Before hypnotic induction: 120.65 mmHg / 79.84 mmHg (Derived →PP= 41 mmHg Normal;Derived →MAP=93mmHg); After hypnotic induction: 115.92 mmHg /76.16 mmHg; (Derived →PP= 40 mmHg Normal;Derived →MAP= 89 mmHG)).Heart rate before hypnotic induction: 86.16 / beats per minute (Derived →CO= 86.16/ beats per minute x 70ml/min=6029.8 ml/min); After hypnotic induction, to 78.89 beats per minute (Derived →CO=78.89/ beats per minute x 70 ml/min=5522.3ml/min). (Kurnia S, et.al., (2021). Blood Pressure Control and Heart Rate: Effectiveness Brief Hypnotic Induction Methods on Adults. 10.2991/assehr.k.210423.004). Spirometry (Homeostasis): VT: 500 ml; IRV: 3100 ml; ERV: 1200 ml; VC: 4800 ml; RV: 1200 ml; A respiratory rate of 12 breaths/ minute, the minute ventilation = 12 x 500 = 6000 ml. alveoli alveolar ventilation (volume of air/min that actually reaches the alveoli) = 12 x 350 = 4200ml. Clinical correlation:The basis for correlating the sepsis, neurological(physiological/psychiatric) and hypnotic trance is that the hypnotic trance subject recovers to homeostasis provided abreaction not encountered by the subject as much as the sepsis, neurological ‐ physiological/psychiatric patients with appropriate Dx, and Tx. Taken together, it is suggested that a decrease in capillary density observed in sepsis and en route to septic shock is a transient phenomenon implicit of a reversible loss of hemodynamic function, for patients Txwith SSSP‐ERP‐EGDT similar to that of SSSP‐2 NCT0166370. Such patient cohort could possibly be reverted to sustain homeostasis in a patient‐specific hypnotic suggestion(s), re‐alert concluding with a reassuring‐post hypnotic trans conversation (devoid of abreaction).

Letter to: neurological manifestation of coeliac disease: many immunological markers suggesting a further expression of gluten-induced secondary autoimmunity.

To The Editor [1] I read with great interest the very interesting review article by Osman et al who addressed the issue of neurological manifestations of coeliac disease (CD), with particular emphasis on gluten ataxia and immunological injury (1). They have reviewed in detail the most relevant studies addressing the relationship of CD with cerebellar ataxia (CA) and immunopathology of enteric CD in comparison to neuronal pathology. The role of gluten-free diet (GFD) with special emphasis on its effect on improving symptoms of ataxia was also reviewed. This topic is of great relevance since neurological manifestations can occur in about 10% of CD patients with CA, peripheral neuropathy, seizures, headache, cognitive impartment and various neuropsychiatrist disorders representing potentially extraintestinal manifestations of CD, as properly stated by the authors. Although I consider this review to be of significant interest and very up-to-date, I feel that some issues would have deserved more emphasis owing to their clinical relevance. In particular, when the Author discussed the potential spectrum of neurological manifestations occurring in CD patients, they omitted to mention multiple sclerosis, multifocal leukoencephalopathy, chorea, and attention/memory impairment, all of which are well known to be other neurological disorders potentially associated to CD (2). Of major interest, I would also like to point out that among the autoantibodies potentially detectable in CD patients with neurological manifestations, other than anti-ganglioside antibodies, it is worth mentioning also anti-neuronal antibodies to central/enteric nervous systems detected by indirect immunofluorescence as previously reported (3-5). These antibodies can be considered markers of neurological manifestations as they have been reported in more than 60% of CD patients with neurological manifestations and therefore should be included in the immunological assessment of CD patients due to their major clinical significance. Received: 24 June 2020 Accepted: 29 August 2020 Reprint or Correspondence: Markus Wilhelmi, MD Medical Clinic I, Gastroenterology and Hepatology, Nutritional Medicine, University Hospital, Frankfurt, Germany. E-mail: dr.markus.wilhelmi@gmail.com ORCID ID: 0000-0003-0121-0627

Clinical characteristics and T-lymphocyte subsets in 48 acquired immune deficiency syndrome patients with cytomegalovirus infections

Objective: To investigate the clinical features and T lymphocytes subsets in patients with acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) infection. Methods: A total of 48 hospitalized patients with human immunodeficiency virus (HIV)-1/AIDS and CMV infections were recruited at Peking Union Medical College Hospital from Jan 2010 to Aug 2017. Their clinical features and immune function were retrospectively analyzed. Patients with only HIV/AIDS in previous study were recruited as controls. Results: All 48 patients were at C3 stage, including 36 men and 12 women. Five of them were younger than 30 years old, 33 cases within 31-50 years old, and 10 cases older than 50 years old. Thirty-five patients had CD(4)(+)T lymphocytes ≤ 50 cells/μl, 7 cases with CD(4)(+)T cells 51-100/μl, 3 cases with 101-200 cells/μl, and 3 cases over 200 cells/μl. As to CMV infections, there were 31 cases of CMV viremia, 1 case of CMV encephalitis, 1 case of CMV enteritis, 5 cases of CMV pneumonia, and 9 cases of CMV retinitis. Other opportunistic infections were also common including 16 cases of pneumocystis pneumonia, 9 cases of tuberculosis, 5 cases of syphilis, 18 cases of digestive tract fungal infections, 8 cases of pulmonary fungal infections, 2 cases of EB virus infections, 2 cases of HIV encephalopathy/progressive multifocal leukoencephalopathy (PML), 3 cases of cryptococcal meningitis, 1 case of toxoplasma infection. In group of both CMV and HIV/AIDS infections, 100% patients had inverted CD(4)(+)/CD(8)(+) ratio. The immune activation marker CD(8)(+)CD(38)(+)/CD(8)(+) was higher (61.6%-98.8%) with a median value of 91.2% in 40 patients. HLA-DR(+)CD(8)(+)/CD(8)(+), another marker for T cell activation, was 25.5%-98.0% in 44 patients with a median value of 60.3%. Thirty-six patients had both immune activation markers positive. There was no significant difference in counts of B cells, natural killer cells, CD(4)(+) T cells, CD(8)(+) T cells and immune activation subsets stratified by gender and age (P>0.05). Meanwhile, neither serum HIV viral load nor serum CMV viral load was correlated with HLA-DR(+)CD(8)(+)/CD(8)(+), CD(8)(+)CD(38)(+)/CD(8)(+), CD(4)(+)T cell counts, and CD(4)(+)/CD(8)(+) ratio in the CMV and HIV/AIDS co-infection group (all P>0.05), while HIV viral load in HIV/AIDS only group was significantly correlated with HLA-DR(+)CD(8)(+)T/CD(8)(+), CD(38)(+)CD(8)(+)/CD(8)(+), CD(4)(+) T cell counts, CD(4)(+)/CD(8)(+) ratio (r=0.473, 0.575, -0.767 and -0.678, respectively, all P<0.05). Conclusions: CMV infections develop in HIV patients with advanced stage. CMV infection can cause life-threatening multiple organ lesions, especially in those with CD(4)(+) T cells less than 100 cells/μl. It is of great importance to screen CMV-IgM, pp65 antigen, CMV DNA to make early diagnosis and treatment.

Neurological manifestations of atypical celiac disease in childhood.

Various typical and atypical neurological manifestations can be seen as the initial symptoms of celiac disease (CD). We suggest that gluten toxicity is the most suspicious triggering risk factor for probable pathophysiological pathways of neurological involvement in atypical CD. The medical charts of 117 patients diagnosed with atypical CD were retrieved from a tertiary center in Ankara, Turkey. Eight patients reported as having neurologic manifestations as initiating symptoms were evaluated in detail. The initial neurological manifestations of CD in our study included atypical absence, which was reported first in this study, generalized tonic-clonic seizures, complex partial seizures, severe axial hypotonia and down phenotype, multifocal leukoencephalopathy, mild optic neuritis, attention deficit hyperactivity disorder, and short duration headaches. Seizures mostly emphasizing atypical absence could be the initial presentation manifestation of CD, first described in this literature. Gluten toxicity could be one of the most powerful triggering factors for developing epilepsy in CD. Learning disorders such as attention deficit hyperactivity disorder, short duration headaches, mild optic neuritis, encephalopathy, and DS could also be the initial neurological manifestations of atypical CD. A gluten-restricted diet may improve neurological complaints, epileptic discharges, and neuropsychiatric symptoms. All we found may be a small part of the full range of neurological disorders of unknown origin related to CD. Clinical suspicion should be the rule for accurate diagnosis of the disease.

Short Course of Bendamustine and Rituximab Followed By 90Y-Ibritumomab Tiuxetan in Patients with Chemotherapy-Naive Follicular Lymphoma (FOL-BRITe): Final Report of Response Rates and Progression Free Survival

Background:Y90-Ibritumomab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has not been reported. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. This analysis focuses on the long-term outcomes and safety of untreated follicular lymphoma patients treated with a short induction course of BR for 4 cycles followed by consolidation with 90YIT.Methods:Patients greater than 18 years with chemotherapy-naïve FL (grade 1-2 and 3a) requiring treatment were eligible. All patients had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375 mg/m2. One week later, bendamustine 90 mg/m2 was administered on days 1 and 2, and rituximab 375 mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Patients were restaged 4-6 weeks after the last dose of BR. Patients were eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was given 6-12 weeks after completion of the last cycle of BR. The primary endpoint is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response.Results:From October 2010 to May 2014, forty-four patients were enrolled in this study (NCT01234766). 39 patients initiated treatment, and 5 were screen failures. Median age was 57 years [range 31-75]. The study enrolled FLIPI low (18%), intermediate (44%), and high (38%) risk patients; 33 of 39 (85%) were Grade 1-2 and 6 (15%) were Grade 3a.Twenty-two of 39 patients achieved CR/CRu (56%) and 16 of 39 patients had a PR (41%) for an overall response rate (ORR) of 97%. One patient had stable disease (SD). Four patients were not randomized to receive 90YIT: one in CR and one in PR were unable to receive 90YIT due to thrombocytopenia, one only achieved SD after BR, and one declined treatment. Thirty of 35 evaluable patients were in CR/CRu (86%), 4 remained in PR (11%) after 90YIT and one progressed during 90YIT, for an ORR of 97%. The number of patients in PR after BR who reached CR/CRu immediately after 90YIT were 10 of 16 (63%). Three (19%) additional patients converted to CR/CRu during follow-up, the latest occurring 16 months after 90YIT.After a median follow up of 30 months, 25 patients (71%) remain in CR/CRu, 10 patients (29%) have progressed/relapsed with a 24-month PFS of 80% (95% CI 63-90) [Figure]. The median PFS was not reached.Grade 3-4 hematologic toxicities during the 90YIT period included: neutropenia (34%), leukopenia (37%), thrombocytopenia (40%), lymphopenia (15%), and anemia (6%). There were no incidences of febrile neutropenia. One patient developed JC Virus/Progressive Multifocal Leukoencephalopathy, 13 months after receiving the last dose of rituximab and 90YIT on study. One patient developed chronic myeloid leukemia 11 months after, one patient developed acute myeloid leukemia 15 months after, and one patient developed uterine cancer 52 months after all study treatment. One patient died to progression of the lymphoma, 35 months after treatment. There have been no reported cases of myelodysplasia.Conclusions:In this 2.5 year report of patients that received BR followed by 90YIT, the CR/CRu rate of patients completing all study therapy is 71% and the 24-month PFS is 80%. There is a high rate of conversion in partial responders to CR/CRu (81%), some occurring more than one year after treatment with 90YIT. The durable PFS is comparable to what is reported in the FIT trial (Morschhauser et al. JCO 2013) and the phase II Spanish intergroup study (Canales et al. ASH 2013). BR followed by 90YIT is a well-tolerated regimen for follicular lymphoma with high response rates that is a safe and highly effective as first-line therapy. Long-term safety reflects the natural history of patients with indolent lymphomas. [Display omitted] DisclosuresLansigan:Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding.

P38: Susac syndrome in a chronic cocaine abuser: A synergistic role of levamisole?

Introduction Cocaine abuse may be complicated by degenerative central nervous system (CNS) disorders such as leukoencephalopathy. The possibly synergistic role of adulterants, like levamisole, is also currently debated. We describe a recent case of massive CNS injury consistent with a Susac syndrome in a heavy chronic cocaine abuser. We discuss the possible combined role of cocaine-levamisole exposure in the pathogenesis of CNS lesions. Case observation A 22-year-old man, who was heavily abusing from cannabis (> 10 yrs) and cocaine (> 5 yrs), was admitted with headache, ataxia, and right-sided paresthesias. CSF analysis revealed hyperproteinorrachia (2,49 g/l) and brain MRI showed multiple small foci of T2/FLAIR hypersignal intensity within the white matter and the grey nuclei, mainly corpus callosum consistent with an inflammatory process. The diagnosis of multiple sclerosis was evoked. Despite steroids pulse therapy, the neurological condition rapidly worsened (encephalopathy, quadriparesia). Occlusion of branch retinal arteries was noted at fundoscopy. Follow-up brain MR examinations were consistent with a Susac syndrome (hyperintense lesions of the central fibres of the corpus callosum). Hearing loss could not be demonstrated at brainstem auditory evoked potentials. Despite maximal immunosuppressive therapy (steroids, cyclophosphamide), the patient remained in a minimally conscious state and he died three months later from septic complications. In order to explore toxic etiologies, the detection of cocaine (C), benzoylecgonine (B) and levamisole (L) was obtained in a hair sample. Starting from the root, the following concentrations were found (pg/mg): 0-1 cm, C 49, B Discussion Susac syndrome is a rare neurological disorder that is characterized by the clinical triad of encephalopathy, branch retinal artery occlusions and hearing loss. Lesions typically involve the central fibres of the corpus callosum, with a relative sparing of the periphery. This is an autoimmune microangiopathy triggered by an unknown antigen, with a large female prevalence. The role of some etiologic agents is still debated: viral infections, idiopathic vasospasm... Toxic causes have not been specifically investigated. Among them, the role of cocaine, mainly with levamisole adulteration is debated. Cocaine use has been less frequently associated with leukoencephalopathy than heroin, and widespread confluent vacuolar degeneration of the white matter is typically observed. On the other hand, levamisole exposure alone has been reported to induce in some individuals multifocal and symmetrical demyelinating changes, disseminated mostly in subcortical white matter and periventricular areas. In the present observation, adulteration of cocaine by levamisole was demonstrated by hair testing. However, the MRI pattern appeared different from that of multifocal inflammatory leukoencephalopathy. Triggering Susac-like syndrome by toxic agents such as the combination of cocaine + levamisole has yet not been reported in the literature, but is suggested by the herein reported observation.

The diagnostic role of diffusion tensor imaging in multifocal inflammatory leukoencephalopathy

Multifocal inflammatory leukoencephalopathy (MIL) is a rare syndrome that can occur in patients with colon cancer after chemotherapy with 5-fluorouracil (5-FU) and levamisole. Histologic diagnosis by brain biopsy is most effective, but there can be high surgical risks and technical limitations. Therefore, we introduce a noninvasive diagnostic technique using diffusion tensor imaging (DTI) for patients suspected to have MIL. A 45-year-old woman had been treated for 12 weeks with levamisole and 5-FU for adenocarcinoma of the cecum, when she complained of ataxia, diplopia and left ptosis. Brain MRI showed a nodular enhancing lesion in the left midbrain, using gadolinium enhanced T1-weighted imaging, and scattered multiple white matter lesions throughout the cerebral hemisphere. Instead of a brain biopsy, DTI was performed that revealed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) in the left midbrain lesion compared with the right midbrain denoting demyelination. Levamisole and 5-FU were discontinued, and she received intravenously 1 g of methylprednisolone daily for 5 d. After five weeks, follow-up DTI showed an increased FA and decreased RD, signifying the reversibility. DTI therefore may provide valuable information on diagnosing MIL and assessing the treatment response.

Late Onset CNS Immune Reconstitution Inflammatory Syndrome in an Immunocompetent Patient

Immune reconstitution inflammatory syndrome (IRIS) refers to the presence of paradoxical clinical deterioration attributable to immune system recovery during highly active antiretroviral therapy (HAART). We present an immunocompetent patient with multifocal leukoencephalopathy on HAART, with central nervous system (CNS) IRIS pathology of unknown infectious etiology. CNS IRIS pathology should be suspected in patients on longstanding HAART without immune reconstitution, presenting with unexplained leukoencephalopathy.

Sequential Autologous Followed by Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) From HLA-Matched Related or Unrelated Donors Improves Outcomes of Patients (pts) with Bulky Lymphoma or Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 2365Large lymph node size or chemo-refractoriness limited the success of nonmyeloablative allogeneic HCT in eradicating CLL or lymphoma. We explored an approach of combining the cyto-reductive effect of high dose chemo/radiation therapy and autologous HCT with the graft-versus-tumor effect of nonmyeloablative allogeneic HCT for pts with rapidly progressive/refractory CLL or lymphoma. Between 4/2000 and 3/2010, 45 pts with advanced indolent (16%) or aggressive (54%) non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL, 18%), or CLL (11%) ineligible for myeloablative allogeneic HCT due to age and/or comorbidities were treated with the sequential approach. Autologous HCT alone was thought to be insufficient for disease control. Pts received high-dose therapy and autologous HCT followed [at a median of 65 (range 39–128) days] by nonmyeloablative conditioning and related (n=28) or unrelated donors (n=17) allogeneic HCT. Median pt age was 49 (range 20–71) years and number of prior regimens was 4 (range 1–12). Thirty-four percent of pts had disease responsive to the last chemotherapy before autografting [30% partial (PR) and 4% complete remission (CR)] while 44% and 22% had refractory and progressive disease, respectively. Most pts had aggressive disease (72%). Conditioning for autografts consisted of BEAM (49%) or Cyclophosphamide/12 Gy TBI±VP16 (51%). After auto-grafting, 58% of pts had CR/PR (29%/29%), 36% had responses <PR, 3% had relapse, and 3% had refractory disease. Conditioning for allografts consisted of 2 Gy TBI alone (53%) or combined with FLU (47%), 90 mg/m2. Pts received G-CSF mobilized allogeneic peripheral blood mononuclear cells. All 45 pts had sustained donor engraftment. Incidences of grades II, III, and IV acute and of chronic GVHD were 46%, 16%, 0%, and 52% respectively. With median follow up of 51 (range 5–116) months, the overall response rate was 60% (46% CR). Eighteen pts died, 12 from progression/relapse, 3 from pulmonary complications, 1 from GVHD, 1 from sepsis, and 1 from multi-focal leuko-encephalopathy. Estimated 5-year rates of non-relapse mortality, relapse, overall, and progression-free survivals from the time of autografting were 15%, 44%, 55%, and 42% respectively. Pts with CLL or indolent NHL had rates of relapse and PFS of 11% and 68% compared to 47% and 37% for those with aggressive NHL and 69% and 31% for those with HL, respectively. No statistical significant differences in outcomes were detected for lymph node size (Figure), disease status at allografting, donor type, conditioning regimens for autografts or allografts, HCT-comorbidity index scores, or time between autologous and allogeneic grafting (Table). Sequential Auto-Allo HCT resulted in relatively low NRM with median survival not yet reached among pts with rapidly progressive lymphoma/CLL. This sequential transplant approach overcame the previously reported high relapse risk of bulky lymphadenopathy. [Display omitted] Disclosures:Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.

Frozen section discrepancy in the evaluation of nonneoplastic central nervous system samples

Frozen section (FS) for intraoperative evaluation of central nervous system (CNS) lesions provides the neurosurgeon with a rapid preliminary pathologic diagnosis. Diagnosis of nonneoplastic lesions is particularly challenging in this venue. To highlight common diagnostic pitfalls, we sought to identify discrepancies between FS and final diagnoses among nonneoplastic CNS samples via a retrospective review of 303 FS cases encountered from 1997 to 2006. Thirty-nine (12.9%) discrepant diagnoses were identified, of which 27 were clinically suspected tumors. Final diagnoses in the discrepant group included the following: inflammatory lesions (n = 8, 20.5%), malformation of cortical development-cortical dysplasia (n = 5, 12.8%), gliosis (n = 5, 12.8%), vascular malformations (n = 5, 12.8%), demyelination/progressive multifocal leukoencephalopathy (n = 3, 7.7%), infarct (n = 3, 7.7%), hemorrhage/blood clot (n = 3, 7.7%), and no pathologic changes (n = 3, 7.7%). The remaining 4 (10.2%) discrepant cases involved one case each of amyloid angiopathy, nonspecific vasculopathy, vasculitis, and meningioangiomatosis. Nonneoplastic lesions are often more challenging than neoplastic lesions at FS, particularly because they are less commonly sampled for FS and, therefore, less familiar to pathologists.

Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors

The replication of BK virus (BKV) and JC virus (JCV) is linked to polyomavirus-associated nephropathy, hemorrhagic cystitis, and multifocal leukoencephalopathy in immunodeficient patients, but the behavior of these viruses in immunocompetent individuals has hardly been characterized. We used EIA to study samples obtained from 400 healthy blood donors aged 20-59 years for BKV- and JCV-specific antibodies against virus-like particles. We also studied BKV and JCV loads in plasma and urine among these individuals by use of real-time polymerase chain reaction. IgG seroprevalence was 82% (328 of 400 donors) for BKV and 58% (231 of400) for JCV. As age increased (age groups were divided by decade), the seroprevalence of BKV decreased from 87% (87 of 100) in the youngest group (aged 20-29 years) to 71% (71 of 100) in the oldest group (aged 50-59 years) (P = .006), whereas the seroprevalence of JCV increased from 50% (50 of 100) in the youngest group to 68% (68 of 100) in the oldest group (P = .06). Asymptomatic urinary shedding of BKV and JCV was observed in 28 (7%) and 75 (19%) of 400 subjects, respectively, with median viral loads of 3.51 and 4.64 log copies/mL, respectively (P < .001). Unlike urinary BKV loads, urinary JCV loads were positively correlated with IgG levels. The shedding of JCV was more commonly observed among individuals who were seropositive only for JCV, compared with individuals who were seropositive for both BKV and JCV, suggesting limited cross-protection from BKV immunity. Noncoding control regions were of archetype architecture in all cases, except for 1 rearranged JCV variant. Neither BKV nor JCV DNA was detected in plasma. Our study provides important data about polyomavirus infection and replication in healthy, immunocompetent individuals. These data indicate significant differences between BKV and JCV with respect to virus-host interaction and epidemiology.

X-linked Hyper-IgM Syndrome Associated With a Rapid Course of Multifocal Leukoencephalopathy

To report an exceptional association between X-linked hyper-IgM syndrome and progressive multifocal leukoencephalopathy. Clinical, immunological, and histological analysis. Patient A 19-year-old male patient with X-linked hyper-IgM syndrome developed typical signs and symptoms of progressive multifocal leukoencephalopathy. The serum level of IgA was decreased; the serum level of IgM was slightly increased; and the serum level of IgG was normal as a result of monthly infusions of immunoglobulin. The expression of CD40 ligand on T cells was markedly reduced in the patient. Magnetic resonance imaging indicated confluent lesions involving the majority of the right hemisphere with a mass effect. The patient died after 6 weeks despite combined antiviral treatment. Progressive multifocal leukoencephalopathy may follow a rapid course in patients with X-linked hyper-IgM syndrome because of global defects of cellular and B cell responses.

Neurologische Komplikationen entzündlicher intestinaler Erkrankungen: Zöliakie, Morbus Whipple, Morbus Crohn und Colitis ulcerosa

A number of neurological symptoms have been described as complications of inflammatory bowel disorders such as coeliac disease, Whipple's disease, Crohn's disease and ulcerative colitis. The neurology of coeliac disease includes disorders of the central nervous system encompassing cerebellar ataxia, epilepsy, myoclonus, dementia and multifocal leukoencephalopathy. Peripheral neuropathies, of axonal and demyelinating types, and myopathies have also been reported. The pathomechanisms are more related to immunological-inflammatory processes than to a malresorptive vitamin deficiencies. While CNS symptoms of coeliac disease show a poor response to gluten restriction, peripheral symptoms may respond to elimination of gluten from the diet. There are few reports of a successful corticosteroid treatment in patients showing inflammatory findings in the CSF or bioptic material. Whipple's disease is caused by the gram-positive bacillus Tropheryma whipplei. Patients with a central nervous system manifestation of Whipple's disease may develop a variety of symptoms including dementia, supranuclear gaze palsy, movement disorders, hypothalamic dysfunction and myorhythmia. The CNS-infection is diagnosed by PCR of the CSF. Long-term antibiotic treatment is required, and relapses may occur after withdrawal of antimicrobial therapy. Crohn's disease and ulcerative colitis are complicated by various forms of polyneuropathies, and arterial and venous cerebrovascular diseases. In most cases with neurological complications of inflammatory gastrointestinal diseases an immune mediated inflammatory process is suspected to be the underlying pathomechanism.

The neurology and neuropathology of coeliac disease.

A number of neurological syndromes have been described in association with coeliac disease. These include disorders of the central nervous system encompassing epilepsy, myoclonus, ataxia, internuclear opthalmoplegia, multifocal leukoencephalopathy and dementia. Most of these associated conditions show a poor response to gluten restriction. Peripheral neuropathies, of axonal and demyelinating types, have also been reported and may respond to elimination of gluten from the diet. The mechanism underlying these processes remains obscure but may be immunological or related to trace vitamin deficiencies. Controversially, it has also been claimed that occult coeliac disease accounts for a substantial proportion of patients with neurological dysfunction of unknown cause. Some authorities recommend that cryptogenic ataxias and neuropathies should be routinely screened for the presence of gluten-sensitivity but this remains contentious and has not been universally accepted. This review will attempt to review the clinical and pathological findings in this condition and speculate on pathogenesis and directions for future research.

Multifocal Demyelinative Leukoencephalopathy Associated with 5-Fluorouracil and Levamisole

(2000). Multifocal Demyelinative Leukoencephalopathy Associated with 5-Fluorouracil and Levamisole. Acta Oncologica: Vol. 39, No. 1, pp. 117-120.

Survival after AIDS diagnosis in a cohort of hemophilia patients. Multicenter Hemophilia Cohort Study.

We studied factors affecting survival after the diagnosis of AIDS in a cohort of 1253 patients with hemophilia. The nature of the AIDS-defining condition was found to be as important as age at seroconversion and CD4+ lymphocyte level in predicting survival. A multivariate analysis yielded estimates of median survival for groups defined by age at seroconversion (0 through 15, 16 through 69), CD4+ lymphocyte count (<100 cells/microl versus > or = 100 cells/microl), and 10 AIDS-defining disease groups. Estimates of median survival after a single AIDS-defining condition ranged from 3 to 51 months, depending on the diseases. Median survival after a second AIDS-defining condition was about 1.5- to 2.0-fold shorter than after an initial, isolated AIDS-defining condition. HIV-related neurologic disease (i.e., AIDS dementia complex or multifocal leukoencephalopathy) was a notable exception. It correlated with the shortest estimates of median survival (3 to 9 months), and this poor prognosis was no worse for patients who had a second AIDS-defining condition. The results of this analysis were consistent in most respects with other published analyses of factors affecting survival. These findings may be useful in the clinical care of persons with AIDS and in estimating the number of persons alive who have had a particular AIDS-defining disease.

Neuroradiology case of the day. Multifocal inflammatory leukoencephalopathy due to treatment with 5-fluorouracil and levamisole.

Neuroradiology case of the day. Multifocal inflammatory leukoencephalopathy due to treatment with 5-fluorouracil and levamisole.

Multifocal Leukoencephalopathy: Occurrence During 5-Fluorouracil and Levamisole Therapy and Resolution After Discontinuation of Chemotherapy

We report the fourth case of cerebral demyelinating disease associated with 5-fluorouracil and levamisole hydrochloride therapy for adenocarcinoma of the colon. The initial manifestations included subacute progressive decline in mental status, ataxia, dysarthria, and diplopia. Magnetic resonance imaging of the head demonstrated multifocal enhanced lesions in the white matter. The patient experienced improvement, without corticosteroid treatment, from 2 weeks to 4 months after cessation of chemotherapy.

The influence of the ground substance on the extracellular water of normal and edematous human brain: focal edema and the demyelinating diseases, including multiple sclerosis.

The presence of a ground substance in brain provides a mechanism by which edema localized to one region of the white matter might occur without spreading diffusely into the adjacent tissues. The most common such localization is the sparing of the arcuate white matter when the deeper white matter is markedly edematous. This may be related to the higher concentration of mucopolysaccharides in the former. Petechial hemorrhages in the white matter may be surrounded by a zone free of edema, although the hemorrhagic zone itself is almost certainly edematous. This, and the presence of a central zone within some of the petechiae forming a ring hemorrhage may reflect the influence of the ground substance. Focal lesions of the dorsum of the corpus callosum and similar lesions of the basal surface of the pons, these probably due to traumatization by the contiguous falx or arteries, are characterized by myelin loss and axon preservation, a characteristic of edema; the surrounding tissues are not edematous. Severe hypertension is sometimes associated with the presence of clusters of focal perivenous demyelinating lesions in the white matter, the axons being preserved. These resemble the lesions of acute disseminated encephalomyelitis and may be due to edema; they are surrounded by nonedematous white matter. It is suggested that the same concept may apply to the focal demyelinating lesions of acute disseminated encephalomyelitis, multifocal leukoencephalopathy, central pontine myelinolysis and of multiple sclerosis, i.e. the "true" demyelinating diseases, just as has already been suggested for diffuse sclerosis.