Paraneoplastic and autoimmune encephalopathies.

Immune-mediated encephalitis is an increasingly recognized cause of neurologic dysfunction including behavioral change, psychosis, movement disorders, seizures, autonomic instability, and coma. Associated antineuronal antibodies are of two main subtypes, those targeting neuronal cell surface antigens, which are pathogenic, and nonpathogenic antibodies targeting intracellular antigens. Antibody identification aids in screening for underlying cancers and prediction of outcome. Cancer is found most commonly with antibodies targeting intracellular neural components. Certain cancers, such as small-cell lung carcinoma, and breast and ovarian cancer are particularly immunogenic. When cancer is detected, oncologic treatment should be followed with immunotherapy. Nonpathogenic antibody disorders respond poorly to treatment, whereas pathogenic antibodies predict a favorable response to immune treatment. If no cancer is identified, then ongoing surveillance is recommended for 5 years after detection of most antineuronal antibodies.

Assessment of gonadal function in boys and adolescents at the diagnosis of neoplastic disease.

OBJECTIVE: We assessed the gonadal function in boys with a newly diagnosed neoplastic disease prior to chemotherapy. Eighty-four boys (48 prepubertal and 36 pubertal) were evaluated, including 50 with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), 10 with Hodgkin lymphoma (HL), and 24 with solid tumors. The control group consisted of 24 healthy prepubertal and 24 pubertal boys. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and testosterone were determined, and testicular volumes were measured. RESULTS: Patients in prepuberty and early puberty (Tanner stages 1-3) diagnosed with ALL/NHL or solid tumor presented normal serum reproductive hormone levels, whereas in ALL/NHL patients in Tanner stages 4-5, the mean values of inhibin B were significantly lower (45.18 +/- 33.85 vs. 153.57 +/- 71.44 ng/L, p = 0.0027). In patients with HL in Tanner stages 4-5, a statistically significant lower mean inhibin B level (100.44 +/- 67.45 versus 153.57 +/-71.44 ng/L, p = 0.0027), higher mean FSH level (6.3 +/- 3.6 versus 4.6 +/- 2.2 mIU/mL, p = 0.05), and higher mean LH level (5.9 +/- 4.0 versus 3.6 +/- 1.8 mIU/mL, p = 0.05) were observed. No statistically significant differences were noted in assessed hormones in patients with solid tumors, independently of Tanner stage. CONCLUSION: Our analysis indicates that adolescents with ALL/NHL and HL prior to treatment, exhibit reduced levels of inhibin B, which indirectly suggests the possibility of spermatogenesis dysfunction.

Reduction in Size of a Large Rathke's Cleft Cyst on Treatment with Low Dose of Corticosteroid.

Rathke's cleft cyst is a non-neoplastic sellar cyst, which is increasingly reported on radiological investigation performed for unrelated intra-cranial pathology. When symptomatic, it is associated with headache, visual symptoms, and pituitary dysfunction. We report a case of an 18 year-old male patient with Rathke's cleft cyst, who presented with failing vision, headache, and hypocortisolism. After defaulting on planned surgery, the patient continued to take a replacement dose of prednisolone for a year. He reported significant improvement in vision and remarkable reduction in cyst size on repeat imaging after a year. Surgery was later performed in view of persisting severe headache. The authors discuss the reduction in cyst size in relation to long-term usage of replacement steroid. They postulate that selected patients with Rathke's cleft cyst with radiological evidence of inflammatory fluid can be given a trial of glucocorticoids and assessed for cyst shrinkage and changes in imaging characteristics.

Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood.

CONTEXT: Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor (ROHHADNET) is a newly described syndrome that can cause cardiorespiratory arrests and death. It mimics several endocrine disorders or genetic obesity syndromes during early childhood and is associated with various forms of hypothalamic-pituitary endocrine dysfunctions that have not yet been fully investigated. OBJECTIVE: The current report aspires to facilitate the earlier recognition and appropriate treatment of the ROHHADNET syndrome when children present with various endocrine manifestations, such as early obesity, growth failure, pseudo-Cushing's syndrome, glucocorticoid insufficiency, congenital hypopituitarism, or adrenal tumors. A more widespread knowledge of the syndrome will help characterize its molecular origin. DESIGN: Endocrine studies were performed in six patients admitted for seemingly common early-onset obesity associated with growth failure in five of them. The six patients later showed distinctive features of the ROHHADNET syndrome. RESULTS: Abnormalities of the pituitary adrenal axis ranged from a true Cushing-like profile (one of six), to glucocorticoid deficiency with normal ACTH (two of six). Complete GH deficiency with low IGF-I was observed in four of six, hypogonadotropic hypogonadism in four of six, hyperprolactinemia in six of six, and various degrees of TSH/T(4) abnormalities in five of five patients. All had increased natremia without diabetes insipidus. Five children had unilateral macroscopic adrenal ganglioneuroma. Two patients died at 8.5 and 12 yr of age. CONCLUSIONS: Various hypothalamic-pituitary endocrine dysfunctions are associated with ROHHADNET, carrying a risk of misdiagnosis until other elements of the syndrome make it more easily recognizable. Given its severity, ROHHADNET syndrome should be considered in all cases of isolated, rapid, and early obesity.

Characteristics of stem cells from human neuroblastoma cell lines and in tumors.

Cellular heterogeneity is a hallmark of human neuroblastoma tumors and cell lines. Within a single neuroblastoma are cells from distinct neural crest lineages whose relative abundance is significant for prognosis. We postulate that a self-renewing multipotent tumor stem cell, which gives rise to diverse cell lineages, is the malignant progenitor of this cancer. To test this hypothesis, we have established 22 cloned, phenotypically homogeneous populations of the three major cell types from 17 neuroblastoma cell lines. In vitro, malignant neuroblastoma stem cells, termed I-type (intermediate type), have distinct morphologic, biochemical, differentiative, and tumorigenic properties. I-type cells express features of both neuroblastic (N) cells (scant cytoplasm, neuritic processes, neurofilaments, pseudoganglia, and granin and neurotransmitter enzyme expression) and substrate-adherent (S) cells (extensive cytoplasm and vimentin and CD44 expression). Moreover, they show bidirectional differentiation to either N or S cells when induced by specific agents. I-type cells are significantly more malignant than N- or S-type cells, with four- to five-fold greater plating efficiencies in soft agar and six-fold higher tumorigenicity in athymic mice. Differences in malignant potential are unrelated to N-myc amplification/overexpression or the ability to digest and migrate through the extracellular matrix. Immunocytochemical analyses of a small series of tumors reveal that frequency of cells coexpressing N and S cell markers correlates with poor prognosis. Thus, I-type stem cells may be instrumental in the genesis and growth of tumors in the patient. Their unique biology deserves attention and further investigation.

Expression and ligand-binding function of the integrin alpha 4 beta 1 (VLA-4) on neural-crest-derived tumor cell lines.

Human neural-crest-derived tumor cell lines, including three neuroblastomas, an astrocytoma, a glioblastoma, a rhabdomyosarcoma and a melanoma were screened for the expression of the integrin alpha 4 beta 1 (VLA-4). The neuroblastomas IMR-32 and SK-N-SH, the astrocytoma 131-INI, the glioblastoma Fogerty and the rhabdomyosarcoma TE-671 expressed alpha 4 beta 1 as determined by cytofluorometry and immunoprecipitation. Another neuroblastoma line, LA-N-1, did not express alpha 4 beta 1. Analysis of immunoprecipitated alpha 4 beta 1 showed that the alpha 4 subunit from the various cell types differed in relative molecular weight (M(r)). The variability in the observed M(r) could be accounted for by differences in the levels of N-linked glycosylation. The observed variability in M(r) did not appear to affect function since intact cells and solubilized alpha 4 beta 1 bound to a synthetic peptide identical in sequence to the CS-1 region of the alternatively spliced IIICS domain of fibronectin, a known alpha 4 beta 1 ligand.

Eicosanoids, but not tachykinins, excite C-fiber endings in rat sciatic nerve-end neuromas.

Normal nociceptors are sensitized by hyperalgesic mediators such as eicosanoids and tachykinins. The possibility that these mediators contribute to hyperalgesic pain associated with neural injury was investigated by examining their effects on the excitability of injured afferent nerve endings. In amounts that sensitize normal nociceptors and are hyperalgesic in normal skin, the eicosanoids prostaglandin I2 (PGI2), and 8(R),15(S)-dihydroxyicosatetraenoic acid (8(R),15(S)-diHETE) both excited some C-fibers in chronic neuromas of rat sciatic nerve. In contrast, the selective tachykinin-receptor agonists septide and senktide did not excite C-fibers. None of the mediators affected A-fibers. We conclude that PGI2 and 8(R),15(S)-diHETE may contribute to post-injury pain and hyperalgesia by an action on injured afferent endings.

Extensive neuronal localization and neurotrophic function of fibroblast growth factor 8 in the nervous system.

Fibroblast growth factor (FGF) 8 has been well established to play a critical role in the early development of the central nervous system (CNS). We report here extensive neuronal localization and neurotrophic function of FGF8 in the nervous system. In sections of mouse embryos at E10.5, FGF8 was immunohistochemically found in neurons at the marginal zones of the CNS and in the dorsal root ganglia (DRG). Neuronal localization of FGF8 was marked at later embryonic stages and in adults, involving most of the central and peripheral neurons, including intermuscular enteric neurons, DRGs, and paraaortic sympathetic ganglia. Functionally, FGF8 promoted neurite outgrowth in human neuroblastoma SK-N-MC cells as well as in rat pheochromocytoma PC12 cells, suggesting that FGF8 acts as a neurotrophic factor. FGF8 also supported neuronal survival and differentiation in cultured human neural progenitor cells. In a cell growth assay, treatment with 50 ng/ml FGF8 on human cultured neuroblastoma SK-N-MC and IMR32 cells attenuated the growth of both. In accordance with these in vitro findings, the immunohistochemical analysis on human neurological diseases showed that FGF8 expression is evident in differentiating histological types of neuroblastoma and ganglioneuroblastoma, and that the levels of FGF8 immunoreactivity in the substantia nigra from Parkinson's disease are significantly lower than those in age-matched controls. Taken together, the present findings strongly suggest that FGF8 acts as a more generalized neurotrophic factor than previously reported.

Variability in the occurrence of ongoing discharges in primary afferents originating in the neuroma after peripheral nerve section in different strains of rats.

Activity in myelinated (A) afferents was recorded proximal to the neuroma 7-14 days after ligation and section of the sciatic nerve in spontaneously hypertensive (SHR), Wistar-Kyoto (WK) and Sprague-Dawley (SD) rats. Ongoing activity was recorded in 83% of nerve filaments in WK and in 89% in SHR rats. In contrast, only 16% of filaments recorded in SD rats had ongoing activity although the silent filaments could be activated by mechanical stimulation of the neuroma. Thus, the ability of the neuroma to generate ongoing activity in rats may be subject to strain-related genetic control.

Neuropathic pain behavior in rats depends on the afferent input from nerve-end neuroma including histamine-sensitive C-fibers.

Sciatic and saphenous neurectomy in rats produces nerve-end neuromas, known to be a source of afferent input. Concurrently rats self-injure the denervated hindpaw ('autotomy'), a behavior related to neuropathic pain in humans. Here we show that surgical resection of the neuromas in various groups of rats, each at a different postoperative time (days 22, 33, 48) suppress autotomy. This recalls the pain relief in humans following resection of painful neuromas. We also show that daily injections of astemizole, a peripheral anti-histamine which blocks histamine H1-receptors, suppress autotomy. Since mostly C-fibers in rat neuroma are sensitive to histamine, these results corroborate the suggestion that autotomy is driven by afferent neuroma input, mainly in histamine-sensitive C-fibers.

Neurologic paraneoplastic syndromes.

Several neurologic paraneoplastic disorders are believed to be caused by an autoimmune reaction against antigen(s) co-expressed by tumour cells and neurons. Of the paraneoplastic syndromes, the evidence for an autoimmune etiology is strongest for the Lambert-Eaton myasthenic syndrome, in which autoantibodies downregulate voltage-gated calcium channels at the presynaptic nerve terminal. For other syndromes, including cerebellar degeneration, multifocal encephalomyelitis, sensory neuronopathy, limbic encephalitis, opsoclonus-myoclonus, stiff person syndrome, and retinal degeneration, the autoimmune theory is supported by the presence of specific antineuronal antibodies. These antibodies serve as a useful diagnostic tool, but their actual role in causing neuronal injury and clinical disease remains unclear. Further understanding of immunopathogenesis awaits successful experimental models. Among different syndromes, a varied proportion of patients shows neurologic improvement with immunosuppressive treatments; it is likely that many patients have already suffered irreversible neuronal injury at the time of diagnosis.

Function-sparing surgery for desmoid tumors and other low-grade fibrosarcomas involving the brachial plexus.

OBJECTIVE: Low-grade fibrosarcomas and desmoid tumors present a surgical challenge in that they have a strong tendency for local invasion, surgical margins are poorly delineated, and complete resections are difficult. Nowhere is this more evident than in those lesions involving the brachial plexus. We review our experience with these difficult lesions. METHODS: From a prospective database of 2900 patients admitted for treatment of sarcoma between 1982 and 1996, we identified 15 patients with involvement of the brachial plexus by a low-grade fibrosarcoma or desmoid tumor. All patients underwent resection, with 13 of 15 receiving adjuvant radiotherapy. The 15 patients had a mean age at initial operation of 47 years. The male-to-female ratio was 8:7. The mean follow-up period was 65 months (median, 53 mo). RESULTS: Gross total resection was achieved in 12 patients (80%), although 11 of these patients had positive surgical margins. Overall, 64% of the tumors have recurred locally. There were no distant metastases, and no patients died as a result of their disease. One patient died as a result of unrelated cancer. An assessment of the functional outcomes revealed seven patients with normal function or mild neurological deficits and eight who were suffering from significant weakness, debilitation, or chronic pain. One patient required forequarter amputation. CONCLUSION: Surgical resection plus postoperative radiotherapy is the treatment of choice for low-grade fibrosarcomas and desmoid tumors involving the brachial plexus. However, aggressive surgical management with the goal of achieving a gross total resection with negative histological margins can produce unnecessary morbidity. Preserving function should be a primary goal of the operations, although this will be associated with residual disease and will risk local recurrence but rarely death resulting from the disease.

Brachial plexus catheter reservoir for the treatment of upper-extremity cancer pain: technical case report.

OBJECTIVE AND IMPORTANCE: Infiltration of the brachial plexus with anesthetics can provide relief of upper-extremity pain from invasive cancer. Because the analgesia is short-lived, however, repeated invasive treatments are necessary. We describe the implantation of a catheter reservoir system, in which anesthetic injections through a subcutaneous port resulted in anesthetic infiltration of the brachial plexus. CLINICAL PRESENTATION: A 47-year-old Hispanic man with squamous cell carcinoma of the larynx had undergone surgical resection, radiation treatment, and chemotherapy. Two years later, he had locally recurrent disease involving the brachial plexus, neck, and chest wall. The patient's pain was minimally responsive to narcotics, which also caused severe nausea and anorexia. TECHNIQUE: The brachial plexus was localized percutaneously with a needle electrode stimulator. Contrast injection under fluoroscopy confirmed entry into the plexus sheath. With use of the Seldinger technique, two Silastic catheters were placed within the brachial plexus and attached with a "Y" connector to a reservoir. The patient experienced complete relief of upper-extremity pain after a test injection with xylocaine. Thereafter, serial injections of bupivacaine with triamcinolone at 1-week intervals provided complete pain relief. After the treatments were initiated, the patient reported improved sleep and an improvement in his quality of life. CONCLUSION: A catheter reservoir system for brachial plexus analgesia can provide safe and effective analgesia for upper-extremity pain. This technique negates the need for repeated invasive procedures and avoids the complications of neurolysis.

The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).

Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.

Centrocentral anastomosis of the proximal nerve stump in the treatment of painful amputation neuromas of major nerves.

The term "centrocentral anastomosis" is used to describe the end-to-end connection across interposed nerve grafts between paired fascicular groups of the proximal stump of a severed nerve. In 22 patients harboring a painful terminal neuroma following amputation of a lower limb (20 neuromas on the sciatic nerve and two on the peroneal nerve), a centrocentral anastomosis was performed on the end of the sectioned nerve to treat pain that had not improved with conventional conservative treatment. Follow-up review at 1 year revealed that the typical neuroma pain had disappeared in all cases, although sporadic diffuse pain persisted in four. Where previous phantom sensation was present, no change was observed. The results presented here are consistent with laboratory findings demonstrating the absence of neuroma formation after centrocentral anastomosis. Therefore, this technique is recommended for the treatment of painful amputation neuroma.

Neuroblastoma: a neurochemical approach.

Neuroblastoma is among the most common malignancies of childhood. Despite greatly improved therapy for some pediatric tumors, the prognosis for children with metastatic neuroblastoma has not changed significantly in the past 10 years. With conventional chemotherapy, radiation therapy, and surgery, children with metastatic neuroblastoma have a 20% long-term survival rate. We describe here approaches to neuroblastoma that target its neuronal characteristics. On the one hand, the neurotransmitter receptors on the surface of the neuroblastoma cells and, on the other hand, specific isozymes that distinguish neuroblastoma cells from their normal counterparts are the focus of these experimental therapies. In the former case, specificity for tumor cells is effected by (1) selective protection of normal neuronal elements from toxicity, or (2) selective potentiation of toxicity for neural tumor cells. It is hoped that these strategies will be generalizable to other neural crest-derived tumors.

Spinal cord compression in neuroblastoma.

Twelve of 80 patients suffering from neuroblastoma who were treated during a 21-year period had intraspinal involvement. Mediastinal tumors have a greater tendency to extend to the spinal canal; however, distant spread of the tumor is rare in patients presenting with intraspinal extension. Patients with intraspinal extension also survive longer than those without. Other factors affecting survival are age, stage of disease, duration of neurological symptoms, degree of histologic differentiation, and mode of therapy. In the absence of osseous metastasis, total excision of the primary lesion and its intraspinal components is usually followed by a favorable outcome; residual neurological deficits among survivors, however, are relatively common.

[Genetics and molecular biology of neurinoma and meningioma]. / Génétique et biologie moléculaire des neurinomes et des méningiomes.

Tumorigenesis is caused by abnormal proliferation of cells that escape regulatory mechanisms. Most of the molecular events leading to the formation of tumors are still largely unknown. In this paper, experimental data supporting a causative role for cellular genes, termed oncogenes, in the formation of tumors of the nervous system are reviewed. Two types of oncogenes are described: dominant oncogenes, characterized by the fact that one abnormal copy of the gene is sufficient to induce tumorigenesis, and recessive oncogenes which require the inactivation of both copies of the gene to lead to tumor formation. The role of recessive oncogenes in tumorigenesis of the nervous system is illustrated by molecular studies of meningiomas and neurinomas. The mutation of one, and perhaps two loci on chromosome 22, has indeed been shown to be most probably the causative molecular event in the growth of these two tumors when they occur either in their sporadic form, or in neurofibromatosis type 2. All the available data support the proposition of systematically analyzing a large number of tumors to eventually correlate clinical phenotype and evolution, to the genetic abnormalities observed. Furthermore, the understanding of the normal and pathological function of oncogenes should lead to future therapeutical improvements.

Facial nerve angioma.

Angioma of the facial nerve is a rare benign tumor. Symptoms include progressive or sudden facial paralysis and, often, a facial twitch. Although angiomas have unique features, diagnosis and treatment is similar to that for facial nerve neuroma. Magnetic Resonance Imaging (MRI) with gadolinium infusion and thin-section Computed Tomography (CT) can often identify the lesion. Treatment by total excision and facial nerve grafting can provide a permanent cure with good restoration of facial function. Four cases are discussed.

[The glial fibrillary acidic protein]. / La protéine gliofibrillaire acide.

Since it was discovered, twenty years ago, the glial fibrillary acidic protein has been the subject of more than 500 publications. The huge interest it has raised up is probably due partly to its abundance in the central nervous system and also, above all, to its cellular specificity which makes it the universally recognized marker of astrocytes. It has been used by biologists as a tool to follow the normal or pathological glia cell differentiation in animal models and human pathology, particularly in the fields of neuropathology and neuro-oncology.