Italian recommendations for Lambert-Eaton myasthenic syndrome (LEMS) management.

Lambert-Eaton myasthenic syndrome (LEMS) is a pre-synaptic disorder of the neuromuscular and autonomic transmission mediated by antibodies to voltage-gated calcium channels at the motor nerve terminal. LEMS is a quite rare and probably under-diagnosed disease: the onset may be slow and clinical signs are typically fluctuating, thus adding to the delay in diagnosis. LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50-60% of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer; the onset of neurological symptoms generally precedes tumour detection. A careful screening for the early detection of the possible associated cancer is a crucial step for optimal disease management. The Italian Working Group on Myasthenic Syndromes developed diagnostic and therapeutic algorithms that could serve in routine clinical practice as tools for a patient-tailored approach.

Double step paraneoplastic brainstem encephalitis: a clinicopathological study.

A case of brainstem encephalitis in a man positive for both anti-Hu and anti-Ri antibodies is reported. This case had an unusual double step evolution and progressive involvement of different CNS subdivisions at MRI. Brainstem encephalitis developed abruptly, mimicking a posterior vascular deficit with vertigo and dizziness. These symptoms transiently remitted completely after a few days to relapse acutely 1 month later with sudden loss of consciousness, followed by confusion, disorientation, dysarthria, dysphagia and reduced thermic sensation on the right side. Within another few days, the patient developed acute respiratory failure and died some weeks later. MRI was negative at the beginning but later showed a progressive ascending involvement of the brainstem and thalamus. At autopsy, this picture corresponded to lymphocytic infiltration, preferentially B cells into the perivascular spaces and T cells in the brainstem parenchyma, confirming that T cells could be the effector of cytotoxicity, probably in the presence of cooperation with B cells that were well represented in this setting.

Anti-Hu-associated brainstem encephalitis.

OBJECTIVE: A series of patients with anti-Hu-associated brainstem encephalitis is reviewed to better define the clinical presentation and to improve its recognition. METHODS: Data were collected from 14 patients diagnosed by members of the Paraneoplastic Neurological Syndromes Euronetwork, and eight patients from the literature who presented with isolated brainstem encephalitis and had anti-Hu antibodies. RESULTS: The median age of the 22 patients was 64 years (range 42-83), and 50% were men. All patients developed a subacute neurological syndrome, in days or weeks. Brain MRI was always normal. Mild cerebrospinal fluid pleocytosis was reported in only two patients. The following syndromes were identified on admission: A medullary syndrome was seen in 11 (50%) patients. Seven of them presented with dysphagia, dysarthria and central hypoventilation. The other four in addition of bulbar symptoms, without central hypoventilation, presented pontine manifestations. Six (27%) patients developed a pontine syndrome with paresis of the VI or VII cranial nerves, nystagmus, usually vertical, and gait ataxia. There was a rapid downward progression to the medulla in all patients. Five (23%) patients presented a ponto-mesencephalic syndrome with uni- or bilateral palsy of the III and VI cranial nerves and gait ataxia, but rapidly progressed to complete gaze paresis and medullary dysfunction. CONCLUSIONS: The study confirms the predominant medullary involvement but also shows that half of the patients present with clinical features that indicate an upper, mainly pontine, dysfunction before downward progression.

Opsoclonus-myoclonus syndrome as a paraneoplastic manifestation of renal cell carcinoma. a case report and review of the literature.

Opsoclonus is a rare but distinctive disorder of ocular motility, characterized by irregular, continual and conjugated chaotic saccades of the eyes. It is increased with eye closure and fixation, and it persists during sleep. Opsoclonus appears more commonly in children and in half of such cases in association with neuroblastoma. In adults the most frequent causes are idiopathic (50%) and paraneoplastic (20%). Among the second group, different types of tumors involving a wide variety of organs have been reported. Opsoclonus when accompanied by other symptoms of central nervous system involvement (head, appendicular myoclonus and truncal ataxia) constitutes a clinical picture, known as opsoclonus-myoclonus syndrome. We report the case of a young patient affected by renal cell carcinoma associated with opsoclonus-myoclonus syndrome which did not respond to medical therapy but dramatically improved after cancer ablation.

Patients with amyotrophic lateral sclerosis and cancer do not differ clinically from patients with sporadic amyotrophic lateral sclerosis.

We examined whether patients with both amyotrophic lateral sclerosis (ALS) and cancer differ from classical ALS patients, and whether motor neuron disease responds to oncological therapy. We analyzed clinical and immunological features of 14 patients (9 men, 5 women; mean age 65.3 years) with pure/definite ALS and cancer. Patients with solid tumor cancer and definite ALS were selected according to the E1 Escorial criteria; cases with ALS plus were excluded. Four patients had breast cancer, three lung adenocarcinoma, and three bowel tumor; hepatocarcinoma, kidney cancer, and mesothelioma were observed in one case each, and in one patient the primary tumor was unidentified. Patients' sera were examined for antinervous system antibodies by means of immunohistochemistry and western blot analysis. Of five patients who underwent surgical therapy, two worsened during the procedure, while the other three had no benefit. The remaining two patients did not improve after chemotherapy and radiotherapy. In none of our cases did the oncological disease progress. Death was a consequence of ALS in all eight patients who died. Median survival was 18 months and did not differ from that of 28 ALS patients matched for age, sex, and onset features (bulbar or spinal). Anti-nervous system antibodies were never detected. We conclude that our group of pure ALS patients with cancer do not significantly differ from patients with classical ALS. They usually die as a consequence of the motor neuron syndrome in the absence of cancer progression. To date we have not observed any response of ALS to antitumor therapy.

Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study.

A retrospective clinical and pathological study of 4 patients who developed the syndrome of radiation induced dementia was performed. All patients fulfilled the following criteria: (1) a history of supratentorial irradiation; (2) no evidence of symptomatic recurrent tumor; (3) no other cause of progressive cerebral dysfunction and dementia. The clinical picture consisted of a progressive "subcortical" dementia occurring 3-12 months after a course of cerebral radiotherapy. Examination revealed early bilateral corticospinal tract involvement in all patients and dopa-resistant Parkinsonian syndrome in two. On CT scan and MRI of the brain, the main features consisted of progressive enlargement of the ventricles associated with a diffuse hypodensity/hyperintensity of the white matter best seen on T2 weighted images on MRI. The course was progressive over 8-48 months in 3 patients while one patient had stabilization of his condition for about 28 years. Treatment with corticosteroids or shunting did not produce sustained improvement and all patients eventually died. Pathological examination revealed diffuse white matter pallor with sparing of the arcuate fibers in all patients. Despite a common pattern on gross examination, microscopic studies revealed a variety of lesions that took two basic forms: (1) a diffuse axonal and myelin loss in the white matter associated with tissue necrosis, particularly multiple small foci of necrosis disseminated in the white matter which appeared different from the usual "radionecrosis"; (2) diffuse spongiosis of the white matter characterized by the presence of vacuoles that displaced the normally-stained myelin sheets and axons. Despite a rather stereotyped clinical and radiological course, the pathological substratum of radiation-induced dementia is not uniform. Whether the different types of white matter lesions represent the spectrum of a single pathological process or indicate that the pathogenesis of this syndrome is multifactorial with different target cells, remains to be seen.

A prospective study of cognitive functions following conventional radiotherapy for supratentorial gliomas in young adults: 4-year results.

PURPOSE: To evaluate the effects of limited field conventional cerebral radiotherapy (RT) on cognitive functions of adults. METHODS AND MATERIALS: A prospective neuropsychological study was performed on 17 patients who underwent conventional limited field RT for a low-grade glioma or for a good-prognosis anaplastic glioma. Results were compared with 14 control patients with low-grade gliomas who did not receive radiotherapy. RESULTS: A transient significant decrease of performances for the Reaction Time test was observed at 6 months in the irradiated group with return to baseline values 12 months post-RT. Subsequently, no other significant changes were observed over a 48-month follow-up period in the irradiated and nonirradiated groups. Nonetheless, when the scores of each patient were considered over time instead of the mean values of the group, one irradiated patient (5.8%) experienced progressive deterioration while two irradiated patients (11.7%) experienced long-lasting improvement. Individual changes did not occur in the control group. CONCLUSION: This study suggests that a transient early delayed drop of neuropsychological performances at 6 months is frequent following limited field conventional RT, but the risk of long-term cognitive dysfunction after irradiation is low, at least in the first 4 years after RT and when it is administered alone in young adults.

Prognostic factors in adult medulloblastoma. A clinico-pathologic study.

AIMS AND BACKGROUND: Medulloblastoma in adults is a rare tumor. The small number of cases in the reported series has not permitted a definite assessment of the prognostic role of clinical, pathologic and cell kinetics factors. The largest series of medulloblastoma in adults treated in a single institution is herein reported. METHODS: The clinical, therapeutic, pathologic and proliferation features of medulloblastoma in 44 adult patients (> 18 years) were analyzed retrospectively with regard to postoperative survival. The proliferation potential of each tumor was evaluated by the immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) and Ki-67, clone MIB-1, in paraffin sections. RESULTS: The overall 5- and 10-year survival rates were 40% and 35.6%, respectively. Significant factors in predicting a longer postoperative survival were: age < 37 years, decade of management (1977-1990), radiotherapy (50-55 Gy on the posterior fossa and 30-35 Gy on the spinal cord) and nuclear isomorphism. When corrected for adequacy of radiotreatment, desmoplastic type and differentiation were significantly correlated with a shorter survival. The PCNA-labelling index (LI) ranged from 34.5 to 82.2%, the MIB-1-LI ranged from 9.6 to 64.7%. No association was found between PCNA- or MIB-1-LI values and microscopic features, or between LI values and prognosis. CONCLUSIONS: Contrary to a general assumption, desmoplastic medulloblastoma and differentiated medulloblastoma are negative prognostic factors in adequately radiotreated adult patients. This may possibly be referred to lower radiosensitivity of these tumor variants. The LI with PCNA or Ki-67 is of no help in identifying aggressive tumors.

Proliferating cell nuclear antigen (PCNA) in low-grade astrocytomas: its prognostic significance.

AIMS AND BACKGROUND: A clear line cannot be drawn between well-differentiated and anaplastic astrocytomas, and a subset of low-grade tumors, histologically indistinguishable from the others, behaves similarly to anaplastic astrocytomas. The proliferative index could aid in the identification of this subgroup, for which a different therapeutic approach would be indicated. METHODS: We immunohistochemically evaluated the proliferating cell nuclear antigen (PCNA) expression in 77 well-differentiated astrocytomas, since PCNA has been considered a good proliferation marker. The prognostic significance of PCNA labeling index (LI) was assessed in univariate and multivariate analysis, taking into consideration some clinical and histologic factors known to affect prognosis. RESULTS: PCNA immunostaining identified a subgroup of tumors, characterized by a LI > 5%, with a median survival close to that observed in anaplastic astrocytomas. The survival table of such a group was significantly different from that of the group with a lower LI (p = 0.0009). Multivariate analysis confirmed that PCNA-LI is an independent prognostic factor (p = 0.001). CONCLUSION: These data suggest that PCNA immunostaining can be a useful tool to define the prognosis of low-grade astrocytomas on routine biopsy material.

Is polar spongioblastoma a tumor entity?

The distribution of cells in a parallel fashion with palisades of nuclei is common in neuroepithelial tumors. The authors have selected 16 such tumors from their series for study, as examples of different neuroepithelial oncotypes containing palisades of nuclei: three ependymomas, three hemispheric pilocytic astrocytomas, three oligodendrogliomas, three medulloblastomas, three cerebellar astrocytomas, and one central neuroblastoma. In two additional tumors, affecting a 12-year-old girl and a 51-year-old woman, this feature was present in the entire surgical specimen and the diagnosis was consistent with a polar spongioblastoma. This diagnosis applies in the literature to rate tumors of childhood and adolescence, both malignant and with embryonal features. In one specimen, a clear ependymomatous feature was found in a remote area of the tumor and in the other there were ultrastructural characteristics of neuroblastoma. Nuclear palisades can be found as local architectural features in many neuroepithelial tumors. The rare tumors diagnosed as polar spongioblastoma, according to published criteria, correspond to ependymomas and neuroblastomas. Polar spongioblastoma does not exist as a tumor entity.

Proliferating cell nuclear antigen expression in brain tumors, and its prognostic role in ependymomas: an immunohistochemical study.

Proliferating cell nuclear antigen (PCNA)/cyclin is currently often investigated immunohistochemically in tumors as a marker of cell proliferation, but many problems remain open concerning its reliability as a prognostic factor. PCNA has been studied in a series of 123 brain tumors using the monoclonal antibody PC10. A clear intra- and inter-tumor variability of PCNA-positive nuclei has been found, but taking into account the tumor areas with the highest number of positive nuclei, a positive correlation between this number and the histological malignancy of tumors has been demonstrated. The staining intensity of nuclei was variable; very-intensely positive nuclei, counted separately, are hypothesized to represent nuclei in S-phase of the cell cycle. In ependymomas the investigation included a quantitative statistical analysis. The number of PCNA-positive nuclei correlated with cell density and mitotic index, but only very intensely positive nuclei showed a significant statistical correlation with survival. In spite of the many possibilities of wrong interpretation of PCNA expression, the most important of which is its deregulation, the method is useful in the practice for prognostic purposes. Its important advantages are the possibility of a retrospective application and a visual analysis of the proliferation potential of tumors.

Medullomyoblastoma: report of two cases.

Two cases of medullomyoblastoma in children are described. The muscular component showed different features in the two cases and were associated with neuronal differentiation. Morphological, immunohistochemical, and electron microscopical findings are presented. The origin of the muscular component is discussed in relation to the findings in other cases of the literature. Both differentiation from primitive neuroepithelial cells and derivation from ectomesenchyme are considered.

Ependymoma: internal correlations among pathological signs: the anaplastic variant.

In a series of 298 cases of ependymoma, survival analysis identified some prognostic histological factors but failed to demonstrate a worse survival for the anaplastic variant diagnosed with the common criteria used for assessing anaplasia in primitive brain tumors. This finding suggests that either anaplastic ependymoma does not exist, or that the established criteria are not useful in its identification. To solve these problems, the association of histological, immunohistochemical, and ultrastructural signs in 173 intracranial cases was investigated and analyzed by means of contingency tables. Many signs had only focal distribution. Some signs, meaningful for anaplasia, such as very high cell density and number of mitoses, were found to be associated, whereas other signs usually considered indicative of anaplasia, such as endothelial hyperplasia, glomeruli, and necrosers, were not. In addition, pseudorosettes, mesodermic areas, and incomplete formation of perivascular pseudorosettes were signs associated with very high cell density and number of mitoses. Distribution of glial fibrillary acidic protein and vimentin, as well as other immunohistochemical and ultrastructural features, were not helpful, with the exception of microsettes found by electron microscopy. Our conclusion is that the anaplastic variant of ependymoma is recognizable only when some histological prognostic factors, such as cell density and number of mitoses, are maximally expressed.

Relationship between glial reaction to a stab wound and tumor development after receiving transplacental ethylnitrosourea in the rat.

Fisher 344 rats born from mothers treated with ethylnitrosourea (ENU) 50 mg/kg intravenously were injured at the 1st and 2nd month of extrauterine life by a transcranial stab. The wound affected cerebral cortex, white matter and basal ganglia. The animals were killed 15 and 45 days and 5 months after injury and cell reaction was studied histologically and immunohistochemically. Bromodeoxyuridine (BrdUrd) was administered 1 h before sacrifice and the labeled cells were evaluated. In ENU-treated rats injured at 1 month of age only minor differences were found in comparison with injured controls. In ENU rats injured at 2 months of age and killed 15 days later, a higher number of BrdUrd-labeled cells was found in comparison with controls; 45 days after injury the cell reaction acquired the aspect of a microtumor, however, no microtumor unrelated with the needle track was present. In ENU rats killed 5 months after the injury, there was no difference between injured and not injured ENU-treated rats, as far as the aspect and the number of tumors were concerned. The tumor phenotype was, thus, anticipated by the cell response to trauma in ENU rats. The interpretation is that the additional cell division, in response to trauma, anticipate not only the phenotypic, but also the cell kinetics changes, as indicated by BrdUrd labeling.

Vascular response to irradiation in malignant gliomas.

The vascular response to irradiation was studied in peritumoral cortex and tumor areas in 9 autopsied cases of glioblastoma multiforme and in 10 biopsies of reoperated cases. The study was carried out by histological, immunohistochemical and electron microscope procedures. Hyaline thickening of the vessel walls with deformation and impoverishment of endothelial nuclei are the most striking features. Formation of large PAS-positive areas from the confluence of thickened vessel walls and development of a fibroblastic proliferation follow. Fibroblastic areas may entrap tumor glial cells. In PAS-positive areas a special population resembles myofibroblasts of tissue scars. Electron microscope reveals the production of collagen fibrils in and outside vessel walls. The presence of collagen III and IV is in line with the present interpretation of the mesodermic component.

Brain tumors of childhood: nosological and diagnostic problems.

Brain tumors containing undifferentiated cells were selected from a series of 504 childhood brain tumors; 117 were analyzed. Most tumors were medulloblastomas, followed by cerebral neuroblastomas, pineocytomas-blastomas, ependymoblastomas, and polar spongioblastomas. Of each oncotype, the main histological features were evaluated, including differentiation and the most important prognostic factors. The terminology and different tumor entities are discussed in light of the recent PNET system. The usefulness of its application is evaluated in relation to prognosis.

The vascular response to tumor infiltration in malignant gliomas. Morphometric and reconstruction study.

Neo-vascularization and endothelial hyperplasia have been shown to be very active in malignant gliomas. In this contribution the vascularization of the cortex infiltrated by malignant gliomas is morphometrically studied and the endothelial proliferations are immunohistochemically investigated and reconstructed by a three-dimensional computer-assisted procedure. Vessel density increases after tumor infiltration in some cases only. The diameter of vessels increases and so does the number of nuclei/vessel after the complete invasion of the cortex when vascular glomeruli develop. In completely infiltrated cortex with development of glomeruli and circumscribed necroses, vessel density is very low. No neoformation of vessels takes place before the complete infiltration of the cortex by the tumor. The hyperplastic formations, usually arranged parallel to the deep or outer cortical layers, take origin from the radially penetrating vessels from the meninges and their lateral branching. The hyperplasia deforms the vascular network, making it often inadequate to supply tumor cells. Immunohistochemically, the cells composing the hyperplastic structures are variably positive for factor VIII/RAg and, at a lesser extent, for alpha-smooth muscle actin. The poorness of the vascular network in many instances of completely infiltrated cortex is responsible for the development of circumscribed necroses.