Tamir Ben-Hur

Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel

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Publications (160)717.12 Total impact

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    ABSTRACT: Importance Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases.Objective To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS.Design, Setting, and Participants In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells.Interventions Patients were administered a single dose of MSC-NTF cells.Main Outcomes and Measures The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale–Revised score and the respiratory function.Results Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale–Revised score in the IT (or IT+IM)–treated patients was reduced (from −5.1% to −1.2%/month percentage predicted forced vital capacity, P < .04 and from −1.2 to 0.6 ALS Functional Rating Scale–Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale–Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression.Conclusions and Relevance The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials.Trial Registration clinicaltrials.gov Identifiers:NCT01051882 and NCT01777646
    No preview · Article · Jan 2016
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    ABSTRACT: Objective: To describe the clinical presentation and unique neurologic manifestations of sandfly viruses (SFVs) in the Jerusalem area. Methods: We identified all patients with acute seroconversion to SFV at the Hadassah-Hebrew University Medical Centers during the years 2008-2013 and retrospectively collected and analyzed the clinical and imaging data. Results: Nine patients (ranging from 1.5 to 85 years old) were identified. Presentation included acute neurologic disease, mostly with fever, change in consciousness and behavior, seizures, headache, meningitis, limb paresis, or myelitis. Eight patients had clinical signs of meningitis, meningoencephalitis, or encephalitis alone. Four patients had myelitis. MRI identified pathologic symmetrical changes in the basal ganglia, thalami, and other deep structures in 5 patients, and additional myelitis of the spine was noted on imaging in 3 patients. Seven patients had long-term follow-up: 4 completely recovered and 3 had remaining neurologic sequelae, among them 1 with permanent severe brain damage. Conclusion: Neurologic involvement associated with acute SFV infections is considered to be benign. However, in this series, all 9 patients presented with significant neurologic pathology associated with a unique finding of myelitis and symmetrical basal ganglia, thalami, or white matter involvement. Thus, acute SFV infection should be included in the differential diagnosis in febrile onset of neurologic manifestations and neuroradiologic changes.
    Full-text · Article · Dec 2015
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    ABSTRACT: Although antibodies to aquaporin-4(AQP4) are strongly associated with Neuromyelitis optica (NMO), the sole transfer of these antibodies is not sufficient to induce an NMO-like disease in experimental animals and T-cells and complement are also needed. Initial data indicating the presence of T-cell responses to AQP4 in patients with NMO, have beeen recently reported.
    No preview · Article · Dec 2015 · Multiple Sclerosis and Related Disorders
  • Yoav Y. Pikkel · Tamir Ben-Hur · Ruth Eliahou · Asaf Honig
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    ABSTRACT: Background: Meningitis and meningoencephalitis pose major risks of morbidity and mortality. Objectives: To describe 20 years of experience treating infections of the central nervous system in Israel Defense Force (IDF) soldiers, including the common presentations, pathogens and sequelae, and to identify risk groups among soldiers. Methods: All soldiers who were admitted to the Hadassah University Medical Center (both campuses: Ein Kerem and Mt. Scopus) due to meningitis and meningoencephalitis from January 1993 to January 2014 were included in this retrospective study. Clinical, laboratory and radiologic data were reviewed from their hospital and army medical corps files. Attention was given to patients’ military job description, i.e., combat vs. non-combat soldier, soldiers in training, and medical personnel. Results: We identified 97 cases of suspected meningitis or meningoencephalitis. Six were mistakenly filed and these patients were found to have other disorders. Four soldiers were diagnosed with epidural abscess and five with meningitis due to non-infectious inflammatory diseases. Eighty-two soldiers in active and reserve duty had infectious meningitis or meningoencephalitis. Of these, 46 (56.1%) were combat soldiers and 31 (37.8%) non-combat; 20 (29.2%) were soldiers in training, 10 (12.2%) were training staff and 8 (9.8%) were medical staff. The main pathogens were enteroviruses, Epstein- Barr virus and Neisseria meningitidis. Conclusions: In our series, soldiers in training, combat soldiers and medical personnel had meningitis and meningoencephalitis more than other soldiers. Enteroviruses are highly infectious pathogens and can cause outbreaks. N. meningitidis among IDF soldiers is still a concern. Early and aggressive treatment with steroids should be considered especially in robust meningoencephalitis cases.
    No preview · Article · Nov 2015 · The Israel Medical Association journal: IMAJ
  • Avital Luz · Nina Fainstein · Ofira Einstein · Tamir Ben-Hur
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    ABSTRACT: Toll-like receptor 2 (TLR2) is expressed on immune cells in the periphery and the CNS and mediates both innate and adaptive immune responses. Recent studies have implicated TLR2 in systemic pathogenesis of adaptive immunity in experimental autoimmune encephalomyelitis (EAE). In addition, TLR2 is expressed on oligodendrocyte progenitor cells and its activation inhibits their differentiation and myelination. We investigated the roles of CNS TLR2 activation in mediating neuro-inflammatory responses in intact versus EAE animals. We examined the effects of intra-cerebro-ventricular (ICV) injection of Zymosan, a TLR2 agonist, on naive versus EAE animals. The neuro-inflammatory response was characterized by immune-fluorescent staining for IBA-1+ microglia/ macrophages and CD3+ T cells, and by semi-quantitative real time PCR for TLR2 and immune cytokines. The nature of the immune cells isolated from EAE brain tissue was assessed by their proliferative response to the PLP peptide autoantigen. Survival and clinical scores were monitored; demyelination and axonal loss were quantified by gold-black and Bielschowsky stains. Our findings showed that Zymosan injection in naïve mice induced a massive neuro-inflammatory response without any clinical manifestations. In EAE mice, ICV Zymosan induced a severe acute toxic response with 80% mortality. Surviving animals returned to pre-injection clinical score, and their course of disease was not altered as compared to control EAE group. Demyelination and axonal loss were not affected by ICV Zymosan injection. Quantification of immune response in the brain by real time PCR, immunofluorescent stains and proliferative response to PLP peptide suggested that TLR2 activation induces innate but not adaptive immune response. We conclude that EAE mice are hypersensitive to CNS TLR2 activation with a severe toxic response. This might represent the susceptibility of multiple sclerosis patients to even trivial infections. As CNS TLR2 activation does not alter the clinical and pathological course of EAE, it implies that CNS TLR2 activation affects the innate but not adaptive brain immune responses. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Sep 2015 · Experimental Neurology
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    ABSTRACT: A marker for diagnosis of Parkinson's disease (PD), which reflects on the occurrence of peripheral pathogenic mechanisms, would potentially improve therapy. The significance of α-Synuclein (α-Syn) expression in red blood cells (RBC) is currently unclear. Here we investigated whether RBC's-expressed α-Syn may associate with PD. To this aim, we determined the levels of total and proteinase K-resistant α-Syn in samples of packed red blood cells (PRBCs). Twenty-one individuals with PD at various disease stages and 15 healthy controls, with similar demographic features, were recruited to this study. α-Syn levels were determined by their biochemical property to bind phospholipids, using a phospholipid-ELISA assay. A significantly lower ratio of total-to-proteinase K-resistant α-Syn levels was detected in PD patients than in the healthy control group. However, there was considerable overlap between the two groups. Suggesting a need for additional markers to be tested in combination with α-Syn levels. To the best of our knowledge, this is the first evidence for an association between RBCs-expressed α-Syn and pathogenic mechanisms involved in PD.
    Full-text · Article · Jun 2015 · Scientific Reports

  • No preview · Article · Jun 2015 · Cytotherapy
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    ABSTRACT: The intrinsic abilities and limits of the nervous system to repair itself after damage may be assessed using a model of optic chiasmal compression, before and after a corrective surgical procedure. Visual fields (VFs), multifocal visual evoked potentials (mfVEP), retinal nerve fiber layer (RNFL) thickness, and diffusion tensor imaging were used to evaluate a patient before and after removal of a meningioma compressing the chiasm. Normally sighted individuals served as controls. The advantage of each modality to document visual function and predict postoperative outcome (2-year follow-up) was evaluated. Postsurgery visual recovery was best explained by critical mass of normally conducting fibers and not associated with average conduction amplitudes. Recovered VF was observed in quadrants in which more than 50% of fibers were identified, characterized by intact mfVEP latencies, but severely reduced amplitudes. Recovery was evident despite additional reduction of RNFL thickness and abnormal optic tract diffusivity. The critical mass of normally conducting fibers was also the best prognostic indicator for functional outcome 2 years later. Our results highlight the ability of the remaining normally conductive axons to predict visual recovery after decompression of the optic chiasm. The redundancy in anterior visual pathways may be explained, neuroanatomically, by overlapping receptive fields.
    No preview · Article · May 2015 · Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society
  • N Raz · As Bick · T Ben-Hur · N Levin
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    ABSTRACT: Neuronal loss following damage is often greater than expected from the severity of injury to the nerve itself. The visual pathways, which comprise a well-defined system, and optic neuritis (ON), which is usually a discrete event, make a fine model to study this phenomenon. Understand the effect of focal optic nerve demyelination on neighboring white matter. Diffusion tensor imaging and probabilistic tractography were used to identify and characterize the optic tracts and radiations of 17 ON and matched controls. Data were correlated with retinal nerve fiber layer (RNFL) thickness. Patients' optic tracts exhibited reduced axial diffusivity, which correlated with RNFL thickness values. Patients' optic radiations demonstrated intact axial diffusivity but reduced fractional anisotropy and elevated radial diffusivity, which could be explained by intra-bundle lesions. No correlations were found between diffusivity measurements in patients' optic tracts and radiations; or between RNFL thickness and optic radiations' diffusivity. Following ON, chronic axonal loss develops distally in the optic tracts, demonstrating Wallerian degeneration. Degeneration did not proceed to the optic radiations, opposing anterograde trans-neuronal changes. DTI in ON provides fine in-vivo human model for studying histological abnormalities in normal appearing white matter, localized in close proximity to damaged bundle. © The Author(s), 2014.
    No preview · Article · Nov 2014 · Multiple Sclerosis
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    ABSTRACT: Background: Screening of putative autoimmune targets in multiple sclerosis (MS) revealed a proportion of patients carrying antibodies (Abs) against KIR4.1, a potassium channel that shares functional properties with AQP4. Both are localized at the perivascular astrocytic processes. Aims: To measure anti-KIR4.1 Abs in the serum of MS and neuromyelitis optica (NMO) patients, and to identify the clinical and laboratory characteristics of patients harboring anti-KIR4.1 Abs. Methods: We measured anti-KIR4.1 Abs in serum, using the peptide KIR4.1 (83-120) enzyme-linked immunosorbent assay (ELISA). Results: Serum levels of anti-KIR4.1 Abs were significantly higher in MS and NMO patients than in healthy controls (HCs); with Abs detected in 21 of 80, 10 of 45, and 2 of 32 individuals, respectively (MS versus HC, p < 0.05). The level of anti-KIR4.1 Abs was significantly higher during MS relapse, versus remission (p = 0.04). The clinical characteristics of our study patients did not vary based on KIR4.1 positivity. Conclusions: Anti-KIR4.1 Abs were found in similar proportions of patients with MS and NMO, at a significantly higher level than observed in HCs; consequently, the presence of Abs does not discriminate between these demyelinating diseases. However, anti-KIR4.1 Ab levels differed in MS patients during relapse and remission; as such, they may represent a marker of disease exacerbation.
    No preview · Article · Nov 2014 · Multiple Sclerosis
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    Shikma Keller · Pablo Roitman · Tamir Ben-Hur · Omer Bonne · Amit Lotan
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    ABSTRACT: Anti-NMDA receptor (NMDAR) encephalitis is a recently identified autoimmune disorder with prominent psychiatric symptoms. Patients usually present with acute behavioral change, psychosis, catatonic symptoms, memory deficits, seizures, dyskinesias, and autonomic instability. In female patients an ovarian teratoma is often identified. We describe a 32-year-old woman who presented with acute psychosis. Shortly after admission, she developed generalized seizures and deteriorated into a catatonic state. Although ancillary tests including MRI, electroencephalogram, and cerebrospinal fluid (CSF) analysis were unremarkable, the presentation of acute psychosis in combination with recurrent seizures and a relentless course suggested autoimmune encephalitis. The patient underwent pelvic ultrasound which disclosed a dermoid cyst and which led to an urgent cystectomy. Plasmapheresis was then initiated, yielding partial response over the next two weeks. Following the detection of high titers of anti-NMDAR antibodies in the CSF, the patient ultimately received second line immunosuppressive treatment with rituximab. Over several months of cognitive rehabilitation a profound improvement was eventually noted, although minor anterograde memory deficits remained. In this report we call for attention to the inclusion of anti-NMDAR encephalitis in the differential diagnosis of acute psychosis. Prompt diagnosis is critical as early immunotherapy and tumor removal could dramatically affect outcomes.
    Full-text · Article · Oct 2014

  • No preview · Article · Oct 2014
  • Nina Fainstein · Avital Luz · Ofira Einstein · Tamir Ben-Hur

    No preview · Article · Oct 2014
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    Yacov Ezra · Marc Gotkine · Sylvie Goldman · Haim · Moshe Adahan · Tamir Ben-Hur
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    ABSTRACT: Conclusions 1. HR was a more popular choice among patients. 2. Patients choosing HR reported greater amelioration than those choosing AMT. 3. Patients choosing HR were found to have greater treatment compliance. 4. HR practiced by a neurologist is feasible in a standard neurological outpatient clinic. Diagnosis and Treatment choice: hypnosis vs. Amytriptilline Amytriptilline Increase daily dose every 3 weeks, from 10mg to 25mg to 50mg. Hypnosis: Three consecutive appointments: 1 st : evaluation + Rx 2 nd : Rx and tape-recording 3 rd : Acquisition of rapid trance achievement Results 98 patients were enrolled, 92 agreed to receive prophylactic therapy. 53 (57.6%) patients chose HR of which 36 (67.9%)initiated this treatment, 39 (42.4%) chose AMT of which 25 (64.1%) initiated therapy. 74%of the patients in the HR group and 58% of patients in the AMT group had a 50% reduction in the frequency of headaches (P=.16). At the end of the study , 26 patients who tried HR compared with 10 who tried AMT continued receiving their initial treatment.
    Full-text · Conference Paper · Sep 2014
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    Mikhal E. Cohen · Nina Fainstein · Iris Lavon · Tamir Ben-Hur
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    ABSTRACT: Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal Cell-Derived Factor-1α, Monocyte Chemo-attractant Protein-1 and Hepatocyte Growth Factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE.
    Full-text · Article · Sep 2014 · Stem Cell Research
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    ABSTRACT: Unlabelled: Neurodegenerative diseases generate the accumulation of specific misfolded proteins, such as PrP(Sc) prions or A-beta in Alzheimer's diseases, and share common pathological features, like neuronal death and oxidative damage. To test whether reduced oxidation alters disease manifestation, we treated TgMHu2ME199K mice, modeling for genetic prion disease, with Nano-PSO, a nanodroplet formulation of pomegranate seed oil (PSO). PSO comprises large concentrations of a unique polyunsaturated fatty acid, Punicic acid, among the strongest natural antioxidants. Nano-PSO significantly delayed disease presentation when administered to asymptomatic TgMHu2ME199K mice and postponed disease aggravation in already sick mice. Analysis of brain samples revealed that Nano-PSO treatment did not decrease PrP(Sc) accumulation, but rather reduced lipid oxidation and neuronal loss, indicating a strong neuroprotective effect. We propose that Nano-PSO and alike formulations may be both beneficial and safe enough to be administered for long years to subjects at risk or to those already affected by neurodegenerative conditions. From the clinical editor: This team of authors report that a nanoformulation of pomegranade seed oil, containing high levels of a strong antioxidant, can delay disease onset in a mouse model of genetic prion diseases, and the formulation also indicates a direct neuroprotective effect.
    Full-text · Article · Aug 2014 · Nanomedicine: nanotechnology, biology, and medicine
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    Arnaud Saj · Noa Raz · Netta Levin · Tamir Ben-Hur · Shahar Arzy
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    ABSTRACT: Patients with conversion disorder generally suffer from a severe neurological deficit which cannot be attributed to a structural neurological damage. In two patients with acute conversion paraplegia, investigation with functional magnetic resonance imaging (fMRI) showed that the insular cortex, a limbic-related cortex involved in body-representation and subjective emotional experience, was activated not only during attempt to move the paralytic body-parts, but also during mental imagery of their movements. In addition, mental rotation of affected body-parts was found to be disturbed, as compared to unaffected body parts or external objects. fMRI during mental rotation of the paralytic body-part showed an activation of another limbic related region, the anterior cingulate cortex. These data suggest that conversion paraplegia is associated with pathological activity in limbic structures involved in body representation and a deficit in mental processing of the affected body-parts.
    Full-text · Article · Jun 2014
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    ABSTRACT: Our goals were to explore whether performing computerized tomography angiography (CTA) prior to administration of tissue plasminogen activator (tPA) delays treatment and impacts outcome in patients with proximal middle cerebral artery occlusions (pMCAO). Patients with pMCAO with a National Institutes of Health Stroke scale (NIHSS) score >10 were identified from a prospective Stroke Registry. Patients underwent multi-parametric imaging studies whenever possible. Patients who underwent CTA were compared to those who only had non-contrast CT scan. Disability was measured with the modified Rankin Scale. Logistic regression was used to determine outcome modifiers. We included 73 patients (median age 73years, 52% men) with moderate-severe stroke (median admission NIHSS 14). Of those, 44 underwent CTA and 29 did not. There were no differences between the groups in risk factor profile or baseline characteristics including stroke severity and door to needle, door to imaging or imaging to treatment times. At 90days post-stroke there were no statistically significant differences in outcomes between the groups. On multivariate analysis, performing CTA had no impact on the chance of obtaining favorable outcome. In conclusion, CTA does not have a major impact on outcome in patients with pMCAO treated with tPA. Therefore, performing CTA should be considered on an individual basis prior to administration of tPA.
    No preview · Article · May 2014 · Journal of Clinical Neuroscience
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    ABSTRACT: Objective: Transient global amnesia (TGA), an abrupt occurrence of severe anterograde episodic amnesia accompanied by repetitive questioning, has been known for more than 50 years. Despite extensive research, there is no clear evidence for the underlying pathophysiological basis of TGA. Moreover, there is no neuroimaging method to evaluate TGA in real time. Methods: Here we used resting-state functional magnetic resonance imaging recorded in 12 patients during the acute phase of TGA together with connectivity and cluster analyses to detect changes in the episodic memory network in TGA. Results: Our results show a significant reduction in functional connectivity of the episodic memory network during TGA, which is more pronounced in the hyperacute phase than in the postacute phase. This disturbance is bilateral, and reversible after recovery. Although the hippocampus and its connections are significantly impaired, other parts of the episodic memory network are also impaired. Similar results were obtained for the analysis of the episodic memory network whether it was defined in a data-driven or literature-based manner. Interpretation: These results suggest that TGA is related to a functional disturbance in the episodic memory network, and supply a neuroimaging correlate of TGA during the acute phase.
    No preview · Article · May 2014 · Annals of Neurology
  • Noa Raz · Michal Hallak · Tamir Ben-Hur · Netta Levin
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    ABSTRACT: In order to follow optic neuritis patients and evaluate the effectiveness of their treatment, a handy, accurate and quantifiable tool is required to assess changes in myelination at the central nervous system (CNS). However, standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. We present two visual tests addressing dynamic monocular and binocular functions which may closely associate with the extent of myelination along visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols. In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is critically dependent on motion perception. In the Time-constrained Stereo protocol, spatially disparate images are presented for a limited length of time, challenging binocular 3-dimensional integration in time. Both tests are appropriate for clinical usage and provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along visual pathways. These protocols may be efficient to diagnose and follow optic neuritis and multiple sclerosis patients. In the diagnostic process, these protocols may reveal visual deficits that cannot be identified via current standard visual measurements. Moreover, these protocols sensitively identify the basis of the currently unexplained continued visual complaints of patients following recovery of visual acuity. In the longitudinal follow up course, the protocols can be used as a sensitive marker of demyelinating and remyelinating processes along time. These protocols may therefore be used to evaluate the efficacy of current and evolving therapeutic strategies, targeting myelination of the CNS.
    No preview · Article · Apr 2014 · Journal of Visualized Experiments

Publication Stats

6k Citations
717.12 Total Impact Points

Institutions

  • 1983-2016
    • Hebrew University of Jerusalem
      • • Department of Neurobiology
      • • Hadassah Medical School
      • • Faculty of Medicine
      Yerushalayim, Jerusalem, Israel
  • 1992-2015
    • Hadassah Medical Center
      • • Department of Neurology
      • • Liver Unit
      Yerushalayim, Jerusalem, Israel
  • 2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1998-1999
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France