Safety and efficacy of autologous hematopoietic stem-cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis.

BACKGROUND AND PURPOSE: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. METHODS: Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow-up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. RESULTS: A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. CONCLUSIONS: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy.

A correlation between epilepsy and cellular redox imbalance has been suggested, although the mechanism by which oxidative stress (OS) can be implicated in this disorder is not clear. In the present study several oxidative stress markers and enzymes involved in OS have been determined. In particular, we examined the levels of 4-hydroxy-2-nonenal protein adducts (HNE-PA), a by-product of lipid peroxidation, and the activation of NADPH oxidase 2 (NOX2), as cellular source of superoxide (O(2)(-)), in surgically resected epileptic tissue from drug-resistant patients (N=50). In addition, we investigated whether oxidative-mediated protein damage can affect aquaporin-4 (AQP4), a water channel implicated in brain excitability and epilepsy. Results showed high levels of HNE-PA in epileptic hippocampus, in both neurons and glial cells and cytoplasmic positivity for p47(phox) and p67(phox) suggesting NOX2 activation. Interestingly, in epileptic tissue immunohistochemical localization of AQP4 was identified not only in perivascular astrocytic endfeet, but also in neurons. Nevertheless, negativity for AQP4 was observed in neurons in degeneration. Of note, HNE-mediated post-translational modifications of AQP4 were increased in epileptic tissues and double immunofluorescence clearly demonstrated co-localization of AQP4 and HNE-PA in epileptic hippocampal structures. The idea is that sudden, disorderly, and excessive neuronal discharges activates NOX2 with O(2)(-) production, leading to lipid peroxidation. The resulting generation of HNE targets AQP4, affecting water and ion balance. Therefore, we suggest that seizure induces oxidative damage as well as neuronal loss, thereby promoting neuronal hyperexcitability, also affecting water and ion balance by AQP4 modulation, and thus generating a vicious cycle.

Papillary glioneuronal tumor: case report and review of literature.

Papillary glioneuronal tumor (PGNT) is a recently described central nervous system neoplasm that mostly occurs in the supratentorial system, adjacent to the lateral ventricles. In 2007, WHO classified PGNT as grade I neuronal-glial tumor because of the characteristic papillary architecture and bipartite (astrocytic and neuronal/neurocytic) cell population. As a newly established entity of mixed glioneuronal tumor family, PGNT attracted extensive attention recently. In our report we discuss the clinical, neuroradiological and surgical features. The final result is compared with literature data.

A rare localization of cerebral venous sinus thrombosis. Case report.

In this work the Authors report their experience on the treatment of a case of cavernous venous sinus thrombosis. The diagnosis is clinical and neuroradiological, CT, MRN, cerebral angiography and orbital venography have aided in establishing the diagnosis during life. Very interesting is the therapeutic approach.

Internal haemorrhagic pachymeningiosis: specific disease or complication of chronic subdural hematoma? Report of five cases surgically treated and literature review.

BACKGROUND: Internal haemorrhagic pachymeningiosis (IHP) is a rare disease characterized by a fibrous thickening and inflammatory infiltration in dural space mimicking chronic subdural hematoma. The pathogenesis of IHP is not entirely clear yet and treatment is still controversial. OBJECTIVE: We want to emphasize the importance of differentiating pachymeningiosis from chronic subdural hematoma as distinct pathological entities. PATIENTS AND METHODS: The records of five selected cases of IHP histologically confirmed were reviewed, focusing onset, neuroimaging, surgery and outcomes. CONCLUSIONS: IHP is most likely underestimated. Only through multidisciplinary approach it is possible to plane the proper therapeutic strategy. The diagnosis of IHP is confirmed by definitive histology but in some cases is possible with intraoperative frozen section.

The role of laboratory medicine in a value-based healthcare system: the example of heart failure patient management in the Italian context.

OBJECTIVE: As of today, healthcare systems worldwide face severe challenges that undermine their sustainability. The value-based healthcare (VBHC) approach has been proposed as a strategic and methodological framework to ensure the delivery of the best patient outcomes with economic efficiency. Through the illustrative example of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) for heart failure (HF) patient management in the context of the Italian National Healthcare system, this article explores the role that in vitro diagnostics (IVDs) can play in enabling value-based care models. SUBJECTS AND METHODS: 14 healthcare professionals representing the relevant professional figures involved in HF patient management met to revise the current HF patient journey and design a new care pathway that, leveraging on BNP/NT-proBNP, reflects the VBHC principles. RESULTS: The literature recognizes the dosage of BNP/NT-proBNP as the gold stan-dard for diagnosing HF. However, as of today, these IVDs are not employed at their full potential regarding HF patient management. A new patient journey is proposed so that patients are diagnosed early and properly monitored in the aftermath of hospitalization, improving outcomes at contained costs. CONCLUSIONS: As testified by the example of HF patient management in Italy, laboratory medicine can represent a lever for adopting value-based care models. Still, large-scale adoption of VBHC will call for structural reforms that revise how healthcare delivery is organized, measured, and reimbursed.

Operative case of Langerhans'cell histiocytosis of the skull with dural invasion. An immunohystochemical study of ki-67 expression of eosinophilic granuloma: case report and review of the literature.

Eosinophilic granuloma (EG), Letterer-Siwe disease and Hand-Schuller-Christian disease are collectively called Langherans-cell histiocytosis (LCH). While the latter two are systemic diseases, the former is a localized form of histiocytosis. Solitary EG of the skull are rare lesions characterized by a natural history not well defined yet. In this context, we report a case of a 23-year-old male suffering for a recurrent and progressive right parietal headache. On computed tomography (CT) it was observed an ostelytic lesion which on magnetic resonance imaging (MRI) appeared as an hyperintense soft mass on both T1 and T2 weighted images. The lesion showed a marked and heterogeneous enhancement after gadolinium administration. The surgical excision was complete and the severe headache disappeared. Immunohistochemical analysis of the specimen indicated an eosinophilic granuloma characterized by Ki-67 nuclear antigen expression with a labeling index of 20%. In the pertinent literature we have found two aggressive cases of EG showing the Ki-67 expression with a respectively 6.2% (occipital bone granuloma) and 10% (parietal bone granuloma) labeling index. That high proliferative activity suggests a local Langherans' cell proliferation along with an exuberant inflammatory response and also explains the aggressive clinical course and the rapid expansion of the lesion observed in some rare cases of solitary EG. This is the third case-report of calvarial EG characterized by Ki-67 nuclear antigen expression.

Schwannoma of median nerve at the elbow. Case report and short review of the literature.

The Authors present a case of rare elbow localization of schwannoma of the median nerve, in 42 year old woman. The surgical treatment and the short follow-up are presented.

Therapeutic strategy of late cerebral radionecrosis. A retrospective study of 21 cases.

AIM: Late cerebral radiation necrosis (LCR) is a serious complication of radiation treatment for brain tumors. This study investigates the diagnosis and management of patients with late clinical and neuroradiological cerebral radionecrosis after primary removal of brain neoplasm. The authors discuss the clinical features and long-term outcome of 21 patients with late cerebral radionecrosis and emphasize the importance of surgical and medical therapy. METHODS: Twenty-one patients with brain tumor treated by surgical resection or brain biopsy alone after radiotherapy during follow-up developed radionecrosis. The magnetic resonance imaging (MRI), surgical and clinical findings of these patients with radionecrosis are reviewed. RESULTS: MRI showed radionecrosis in 21 patients, 9 of which had undergone craniotomy for lesion removal. CONCLUSION: Late radionecrosis is infrequent following radiation therapy and may simulate tumor recurrence on MRI scans. From the authors' experience it is evident that, once begun, radiation treatment of neoplastic lesions can lead to complications such as late cerebral radionecrosis which often require surgical treatment. As correct diagnosis is necessary for appropriate treatment, a fair balance needs to be struck when considering ionizing radiation, medical therapy, surgery and diagnostic imaging.

Passage of mannitol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients.

AIM: Widespread use of mannitol to reduce brain edema and lower elevated ICP in brain tumor patients continues to be afflicted by the so-called rebound phenomenon. Leakage of mannitol into the brain parenchyma through an altered BBB and secondary reversal of osmotic gradient is considered the major cause of rebound . This has only been demonstrated experimentally in animals. As a contribution to this issue we decided to research the possible passage of mannitol into the brain after administration to 21 brain tumor patients. METHODS: Mannitol (18% solution; 1 g/kg) was administered as a bolus to patients (ten had malignant glioma, seven brain metastases and four meningioma) about 30 minutes before craniotomy. During resection, a sample of the surrounding edematous white matter was taken at the same time as a 10 ml venous blood sample. Mannitol concentrations were measured in plasma and white matter by a modified version of the enzyme assay of Blonquist et al. RESULTS: In most glioma patients, mannitol concentrations in white matter were 2 to 6 times higher than in plasma (mean 3.5 times). In meningioma and metastases patients plasma concentrations of mannitol were higher than white matter concentrations except in three cases with infiltration by neoplastic cells. CONCLUSIONS: The results of our study show that even after a single bolus, mannitol may leak through the altered BBB near gliomas, reversing the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting rebound of ICP.

Chronic subdural hematoma: comparison of two surgical techniques. Preliminary results of a prospective randomized study.

AIM: The optimal treatment for chronic subdural hematoma (CSDH) is not yet well defined and research for efficient surgical solutions continues. Burr hole craniotomy (BHC) is a common treatment and twist drill craniostomy (TDC) is a less invasive alternative. A closed-system drainage with subdural expansion catheter and suction reservoir can be used to enhance the TDC procedure. METHODS: We report preliminary results of a prospective study comparing BHC and TDC with suction drainage, in a series of 47 patients randomized into two treatment groups. One group of 22 patients underwent TDC with closed-system drainage and suction reservoir (14 men, 8 women, mean age 78.7 years). Another group of 24 patients underwent BHC with subdural irrigation and closed drainage (16 men, 8 women, mean age 76.3 years). Neurological status was assessed by Markwalder's Grading Scale on admission and at follow-up. All patients underwent computed tomography (CT) before surgery, within 4 days after it, and 1 and 2 months later. RESULTS: Preoperative clinical and radiological data were similar in the two groups. Operating times were shorter in the TDC group, while drainage time was shorter in the BHC group (P<0.0001). Length of hospitalization was similar. Recurrence rate, mortality, and neurological recovery were similar, with non significant differences in favor of the TDC group. After 2 months, CT showed complete regression of subdural effusion in 66.6% of cases in the TDC group and in 31.8% in the BHC group (P<0.05). CONCLUSIONS: Preliminary results indicate TDC and BHC as at least equally effective, however TDC favors faster regression of residual subdural effusion, is a faster procedure, and seems to be associated with fewer recurrences. If confirmed at the end of the study, these results could indicate TDC with suction as the elective surgical treatment for CSDH.

Preliminary results of a soft novel lumbar intervertebral prothesis (DIAM) in the degenerative spinal pathology.

The authors report a series of 43 patients suffering from lower limb pain, almost constantly associated with chronic or acute backpain, treated by microsurgical nerve root decompression and by implantation of a soft intervertebral prothesis (DIAM). Satisfying results were obtained in 97% of cases, inducing the authors to consider the device a reliable tool for curing low-back pain and sciatica. Selection criteria are exposed and discussed.

Wrist median nerve motor conduction after end range repeated flexion and extension passive movements in Carpal Tunnel Syndrome. Pilot study.

Carpal Tunnel Syndrome (CTS) can be due to a variety of different pathological conditions. These etiological and epidemiological differences may explain the non-homogeneous response to ordinary conservative therapeutical options observed in this syndrome. The aim of our study was to investigate on the possibility of identifying different sub-groups of patients among conservatively treatable CTS with different susceptibility to physiotherapeutic treatments. We decided to utilize an objective approach measuring some median motor nerve function parameters. Short term variations of Compound Motor Action Potential (CMAP) from the thenar eminence were compared in two groups of 55 hands (CTS patients and normal controls) after performance of two different types of end range passive movement. We found a different distribution of CMAP amplitude modifications within a sub-group of patients that suddenly improved more than the controls after two series of 10 end range passive flexions or after two series of ten end range passive extensions. Amplitude changes proved to be much more useful than latency variation studies in the provocative test neurophysiological approach. The method we propose appears to be useful for better surgical indication and/or for improvement of conservative therapeutic choice.

Lumbar disc hernia secondary to gunshot injury.

The authors present a case of injury to the 4th lumbar root secondary to a gunshot wound. The lesion was not directly related to the traumatic action of the projectile, but was caused by the compressive action of disc material forced into the vertebral canal as a result of the destructive effects of a 7.65 caliber bullet.

Homocystinuria with transverse sinus thrombosis.

A case of cerebral venous thrombosis caused by undiagnosed homocystinuria is reported. The pitfalls regarding the diagnosis of a potentially medically treatable condition are discussed. Cerebral venous thrombosis in children has a variable type of onset and a multiplicity of causes. This type of pathology, although not frequent, is more common than previously thought. Among the different etiologies, undiagnosed homocystinuria is not routinely considered. We report a case of venous thrombosis of the left transverse cerebral sinus in a girl with drug-resistant partial epilepsy and homocystinuria. This diagnosis was considered and confirmed after the appearance of acute cerebral symptoms caused by venous thrombosis.

Intraspinal hemangiopericytomas. Report of two cases and review of the literature.

A description of two cases of intraspinal hemangiopericytoma is given, which join the 30 reported to date. The clinical features of this tumor rarely found in the CNS are compared with those of the same oncotype found at other sites. Surgical treatment is necessary, accompanied by radiotherapy. Spinal tumor embolization preoperatively is of benefit.

Delayed neurological bladder after cervical trauma.

We report a case of neurological bladder (upper motor neuron type) which appeared after a few years after vertebral trauma with retrodislocation of C6. We presumed that there was a traumatic and spondylosic etiopathogenesis of the disturbance. Surgery was done following the surgical techniques used in spondylogenetic myelopathies and there was an immediate improvement of the urinary disturbance.

Oculocerebral perforating trauma by foreign objects: diagnosis and surgery.

Two unusual cases of perforating oculocerebral trauma by foreign bodies treated surgically are reported. Both were caused by industrial accidents. In the first a nail shot from a nail gun ricocheted off the target and crossed the right eyeball and the posterior wall of the orbit, lodging in the homolateral temporal lobe. In the second case a metal fragment expelled by an agricultural machine penetrated the left maxillary sinus, crossed the floor of the orbit, the eyeball and the roof of the orbit and lodged in the homolateral frontal lobe. After accurate neuroradiological examination the patients were operated using simultaneous transcranial and transorbital access. In our opinion this is the only approach which can minimize the risk of infection which is so dangerous in this type of trauma. The functional and aesthetic results, which were very satisfactory in both cases, seem to confirm the correctness of this approach.

Aspecific inflammatory lesion (histiocytosis?) simulating intramedullary astrocytoma. Case report.

We report an exceptional case of aspecific inflammatory lesion of the thoracic spinal cord simulating an intramedullary glial tumor. Patient history was characterized by progressive spastic paraparesis with urinary incontinence; MR imaging (T4-T5) showed an enhancing intrinsic mass lesion. Myelotomy enabled partial resection of grayish astrocytoma-like tissue. Only light microscope examination was possible and disclosed aspecific inflammatory tissue composed of eosinophils, lymphocytes and histiocytes. After the operation, the patient improved promptly and no further therapy was administered. Control MRI after four months, one year and two years showed complete disappearance of the intramedullary mass lesion and the patient remained clinically stable with no other signs of disease. Since electron microscopic as well as immunohistochemical studies were not available, a definitive histological diagnosis was not possible. However on the basis of some clinical similarities with cases of isolated histiocytosis X of the CNS reported in the literature, we suggest that a diagnosis of isolated intramedullary eosinophilic granuloma could be reasonable.

Neurinoma of the cauda equina misdiagnosed as prolapsed lumbar disk. Report of three cases.

The authors report three cases of neurinoma of the cauda equina initially misdiagnosed as prolapsed lumbar disk. Computed Tomography failed to reveal the tumour, while showing evidence of disk-degenerative patology and being thus misleading. Similar cases are reported in literature. After a thorough analysis of the causes of such an apparently gross error, it is concluded that the main source of pitfalls arises from neglecting those typical clinical features differentiating prolapsed disk from oncogenetic sciatica. When oncogenetic sciatica is suspected Computed Tomography is inappropriate and even misleading, while the elective investigation is Magnetic Resonance.