Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing–remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2–3%, is still the main problem of this powerful therapy.     

Upper cervical spine fracture: sources of misdiagnosis

PURPOSE: Missing cervical spine fractures during the initial plain film study may lead to severe neurological complications for patients and to medicolegal responsibilities for the physician. The upper cervical spine tract (C1-C2) is considered to be at high risk for misdiagnoses. We decided to investigate the possible causes of mistake in the cases of missed fractures on the initial plain film, performed in the emergency room. MATERIAL AND METHODS: We retrospectively reviewed the radiological reports, the original plain films and the CT findings, of 32 patients with upper cervical (C1-C2) fractures, admitted January 1994 to December 1998. Twenty-eight of these patients (87.5%) had multisystem trauma, 4 (12.5%) had minor craniocervical trauma. None of these patients had neurological signs correlated to the cervical injuries, 30 of them had normal consciousness and reported only neck pain, 2 of them were unconscious for the associated head trauma and were hospitalized in the intensive care unit. All the patients with normal consciousness underwent conventional three-view cervical spine radiography; the two unconscious patients in the intensive care unit were submitted to bedside examination with an anteroposterior and a lateral views of the cervical spine. All patients underwent spiral CT of the upper cervical tract. RESULTS: In 9 of 32 patients (28%) a cervical fracture was missed on the plain film and CT was performed only because of persistent neck pain. We found 2 Jefferson's fractures, 2 type II dens fractures, one type I dens fracture and 4 hangman's fractures. In 8 of the 9 patients (89%) the fracture was potentially unstable. Misdiagnoses resulted from overlapping bone structures (3%), suboptimal film quality (3%), satisfaction of search phenomenon (3%), missed mild tilting of the dens (6%), missed double cortex sign (16%), missed C1-C2 lateral subluxation (6%) and marked osteoporosis (3%). Prevertebral soft tissue swelling was not seen in any of the 9 cases of missed fractures. Considering the group of patients with C1-C2 fractures separately, the false negative rate is 28%, which corresponds to 10.7% of the total number of patients with cervical fractures and dislocations examined during the same period. CONCLUSIONS: Among the causes of false-negative interpretation, osteoporosis, suboptimal film quality due to associated fractures and overlapping bone structures must be considered unavoidable. On the other hand these possibilities should be indicated on the X-ray report because, if painful symptoms persist, a CT exam is strongly advised. Subtle alterations like dens tilting, double cortex sign, lateral subluxation of C1 and prevertebral soft tissue swelling should be regarded as highly suspicious for fracture. Missing these lesions might be considered a true diagnostic mistake with possible legal consequences, which may also expose the patient to the risk of neurological complications. The satisfaction of search phenomenon can be avoided only by trying to use a search pattern for every film, which includes checking all the visible anatomical structures even in the presence of a particularly evident lesion. In all questionable cases or high-risk fracture patients, even with an apparently negative plain film, it is advisable to perform CT instead of additional plain films. Finally, in all the patients treated in the intensive care unit for head trauma, an upper cervical CT scan should be routinely carried out at the same time as the brain scan.     

Dynamics of the reactivity to MBP in multiple sclerosis

Though many lines of evidence support the importance of myelin basic protein (MBP) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), its role in multiple sclerosis (MS) is still debated as well as the significance of epitope spreading in disease progression. We characterised the response to MBP in eight MS subjects and three of these were followed over time. In one case, the follow up lasted over a 6-year period. Clonal expansion, clonal persistence and epitope spreading against other MBP determinants was detected irrespective of disease course. In one patient we identified a novel T-cell receptor variable gene (BV28S2) which may be involved in the selection of MBP determinants, as suggested by experiments performed in the presence of mismatched antigen presenting cells (APC) between two subjects compatible for HLA-DR2 subtype but differing for the epitope recognised. Our findings do not sustain a role for the response to MBP effecting on clinical course and suggest that a novel TCR gene may be involved in the recognition of unusual self antigens.     

Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction

Background and Purpose

Altered glutamate exocytosis and cAMP production in cortical terminals of experimental autoimmune encephalomyelitis (EAE) mice occur at the early stage of disease (13 days post-immunization, d.p.i.). Neuronal defects were paralleled by overexpression of the central chemokine CCL5 (also known as RANTES), suggesting it has a role in presynaptic impairments. We propose that drugs able to restore CCL5 content to physiological levels could also restore presynaptic defects. Because of its efficacy in controlling CCL5 overexpression, desipramine (DMI) appeared to be a suitable candidate to test our hypothesis.

Experimental Approach

Control and EAE mice at 13 d.p.i. were acutely or chronically administered DMI and monitored for behaviour and clinical scores. Noradrenaline and glutamate release, cAMP, CCL5 and TNF-α production were quantified in cortical synaptosomes and homogenates. Peripheral cytokine production was also determined.

Key Results

Noradrenaline exocytosis and α₂-adrenoeceptor-mediated activity were unmodified in EAE mice at 13 d.p.i. when compared with control. Acute, but not chronic, DMI reduced CCL5 levels in cortical homogenates of EAE mice at 13 d.p.i., but did not affect peripheral IL-17 and TNF-α contents or CCL5 plasma levels. Acute DMI caused a long-lasting restoration of glutamate exocytosis, restored endogenous cAMP production and impeded the shift from inhibition to facilitation of the CCL5-mediated control of glutamate exocytosis. Finally, DMI ameliorated anxiety-related behaviour but not motor activity or severity of clinical signs.

Conclusions

We propose DMI as an add-on therapy to normalize neuropsychiatric symptoms in multiple sclerosis patients at the early stage of the disease.     

Thoracic aortic stents: a combined solution for complex cases.

OBJECTIVES: The combination of endovascular and standard surgical techniques may facilitate the management of complex aortic disease although the long-term durability of this approach needs to be confirmed. DESIGN: A retrospective review of our experience in the treatment of patients with complex aortic pathology using a combined endovascular and surgical approach. MATERIALS AND METHODS: Between 1998 and 2001, 27 patients with thoracic aortic aneurysm underwent stent-graft implantation. Eight required combined endovascular and surgical procedure because of complex pathology. In 3 cases, combined repair was carried out for a concomitant abdominal aortic aneurysm or aorto-iliac-femoral occlusive disease. In the other 5 cases, vessel relocation was performed to obtain safe landing zones: left subclavian artery to left carotid artery translocation in 3 patients, celiac trunk to superior mesenteric artery translocation in one and aorto-celiac-mesenteric bypass grafting in one. RESULTS: One of the 8 patients died on 12th post-operative day of intestinal bleeding and bowel infarction. No neurological sequelae were reported. The other patients are currently well at 11 months mean follow-up time. CONCLUSIONS: Simultaneous surgical and endovascular procedure is a feasible and may be a valuable adjunct to the treatment of complex aortic and peripheral vessel anatomy.     

Demyelination and axonal damage in a non-human primate model of multiple sclerosis

The demyelinating plaque is the paradigmatic lesion of multiple sclerosis (MS), but only recently attention has been given to axonal damage and to its role in the pathophysiology of disease. Albeit the possible relevance of axonal loss in MS and its experimental models, the amount and timing of axonal sufferance has been addressed only in experimental autoimmune encephalomyelitis (EAE) of rodents. In this report we observed that, in the marmoset model of EAE, axonal damage occurs early during the demyelinating process as assessed by immunoreactivity for amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32 positive) detected mostly in early active lesions compared to late active and normal appearing white matter. The rare occurrence of morphological features of axonal transection, such as APP or SMI-32 positive spheroids and swellings, as well as an increase of neurofilament density in the demyelinated axons without accumulation of electron dense organelles or osmiophilic bodies, at electron microscopy, suggests that early axonal damage may be, at least in part, a reversible process. These findings are of relevance for the development of therapies, which can protect axons and enhance their function and survival.     

Immunological patterns identifying disease course and evolution in multiple sclerosis patients

Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking. We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules in PBMCs from 198 MS patients. The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGF-beta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals. CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients. Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.