Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes.

Prostate cancer is the most common cancer among American and European men. Nervous system affection caused by local tumor growth or osseous metastases are the main causes of neurological symptoms in prostate cancer patients. Prostate cancer is rarely reported in association with paraneoplastic neurological syndromes (PNS). We have, therefore, studied clinical and paraclinical findings of a series of patients with prostate cancer and PNS, and reviewed cases reported in the literature. Case histories of 14 patients with definite PNS from the PNS Euronetwork database and from the authors' databases were reviewed. A PubMed literature search identified 23 patients with prostate cancer and PNS. Thus, a total of 37 case histories were reviewed with respect to syndrome type, cancer evolution, paraclinical investigations, antibody status, treatment and outcome. The three most frequent isolated PNS were paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis (PEM)/limbic encephalitis and subacute sensory neuronopathy (SSN). Onconeural antibodies were detected in 23 patients, in most cases the Hu antibody (17 patients, 74 % of all antibody-positive cases). Other well-characterized onconeural antibodies (Yo, CV2/CRMP5, amphiphysin, VGCC antibodies) were found in a minority. PNS was diagnosed prior to prostate cancer diagnosis in 50 % of the cases. The association of PNS with prostate cancer is quite infrequent, but clinically important. PNS often heralds prostate cancer diagnosis. Syndromes associated with Hu antibodies predominate. Another tumor more prone to associate with PNS should always be excluded.

Pseudoprogression in high-grade glioma.

Pseudoprogression is a treatment-related effect seen on imaging in high-grade glioma. Enhancement of gadolinium contrast on control MRI can be misinterpreted as tumor recurrence and is also difficult to distinguish from radiation necrosis. Pseudoprogression is seen in up to 30% after standard treatment for glioblastoma multiforme (GBM), which is radiotherapy concurrent with chemotherapy with temozolomide (TMZ) and adjuvant cycles of TMZ. In this article, the current literature on pseudoprogression in high-grade glioma is reviewed by searches in PubMed. We also present two clinical cases, one of which had medullary pseudoprogression. No articles on this subentity of pseudoprogression were found in PubMed. Standard MRI with gadolinium contrast cannot differentiate between pseudoprogression, tumor recurrence and radiation necrosis. More advanced imaging techniques are often not available. Pseudoprogression seems to be related to methylated promoter of the O(6)--methyl-guanine methyl transferase (MGMT) gene, which is associated with improved treatment effect. Discontinuation or change of therapy on the basis of misinterpretation of MRI as disease progression is thus unfortunate. MRI should be interpreted with caution the first 6 months after standard treatment of high-grade glioma. In a GBM patient with contrast enhancement on MRI but few or no new symptoms and/or stable steroid doses, treatment should be continued and control imaging performed after 2-3 months.

Communication and neurology--bad news and how to break them.

How to deliver bad news to patients is a crucial part of medical practice. Many neurological diseases are incurable, progressive and result in physical or cognitive disabilities, which pose special challenges in the process of communication. Information about diagnosis, therapy and prognosis should be given in an appropriate setting and tailored to the patient's needs and cognitive level of functioning. Support and advice to the family and a team-oriented approach in the follow-up of neurological patients are of high importance. Patient autonomy, truth disclosure expectations and the access to other sources of information is important aspects that influence communication. There is a need for a special and continuous focus on communication in the education of neurologists with regard to the specific needs of this field. Attention should be given to the consequences of neurological disease as well as to therapy and prognosis.

Onconeural antibodies in patients with neurological symptoms: detection and clinical significance.

BACKGROUND: Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well-characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS. MATERIALS AND METHODS: Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed. CONCLUSIONS: The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies.

Cost of disorders of the brain in Norway.

BACKGROUND: Little is known about the cost of neurological disorders in Norway. OBJECTIVES: To estimate the cost of disorders of the brain, including the main psychiatric, neurological and neurosurgical conditions in Norway. METHODS: Most of the data are extrapolations from a large European cost study that collected the best available epidemiological and health economical evidence for the year 2004. Some epidemiological data are available from Norway, but very little on costs. RESULTS: Brain disorders seemed to affect 1.5 million Norwegians in 2004, and the total cost amounted to 5.8 billion Euros. The most prevalent disorders are anxiety disorders and migraine, and the most costly are affective disorders, addiction and dementia. Migraine is the most costly of the purely neurological conditions, followed by stroke, epilepsy and Parkinson's disease. The indirect costs account for more than half of the total costs. DISCUSSION: Although the different brain disorders are very dissimilar in appearance, from health economic and public health perspectives, it is relevant to view them as a whole, since many of them share important pathophysiological mechanisms. This means that new insights into one disorder can have relevance for many other disorders. CONCLUSION: As a result of the high impact on individuals and society, more resources should be allocated to treatment and research into brain disorders.

Norwegian neurology: present status and future trends.

Diseases of the nervous system constitute a major cause of morbidity and mortality. The chronic nature of many neurological diseases demands long-term follow-up and good communicative skills. Financial conditions and compensation is closely linked to modern health care and may limit the availability of new therapeutic options. An ageing population and modern lifestyle represent challenges for neurology in the future. The participation in public debate and strategic planning of health services are crucial to improve neurological services on a national and global level. Our focus should be the promotion of special needs of patients with neurological disease.

Autoimmune limbic encephalitis.

Autoimmune limbic encephalitis (LE) can arise both by paraneoplastic and non-paraneoplastic mechanisms. Patients with LE usually have a subacute onset of memory impairment, disorientation and agitation, but can also develop seizures, hallucinations and sleep disturbance. The following investigations may aid the diagnosis: analysis of cerebrospinal fluid (CSF), electroencephalography, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography and neuronal antibodies in the serum and CSF. Neuronal antibodies are sometimes, but not always, pathogenic. Autoimmune LE may respond to corticosteroids, intravenous IgG (IVIG) or plasma exchange. The cornerstone of paraneoplastic LE therapy is resection of the tumour and/or oncological treatment. Several differential diagnoses must be excluded, among them herpes simplex encephalitis.

Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies.

INTRODUCTION: Immunohistochemical studies of paraneoplastic cerebellar degeneration (PCD) are rare, and the findings vary. MATERIALS AND METHODS: We performed morphological and immunohistochemical characterization of the brain, medulla and tumour of two patients with PCD, Yo antibodies and ovarian adenocarcinoma. RESULTS: The cerebellum of both patients had extensive loss of Purkinje cells. Microglia activation and T cells were found in the cerebellum, but B cells or deposits of IgG or complement were not detected. Microglia activation was also present in the brain stem and medulla. T cells were found in the ovarian adenocarcinoma. CONCLUSION: PCD is characterized by loss of Purkinje cells and microglia activation, and the presence of T cells indicates cellular immune reactions in PCD and in ovarian cancer.

A retrospective view on research in neuroscience in Norway.

This brief historical review on neuroscience in Norway shows a comparatively high research activity with many important results. The Norwegian zoologist Fridtjof Nansen, who later became a famous Arctic explorer, was the first to formulate the neuron doctrine. 'The Oslo School of Neuroanatomy' contributed enormously to the understanding of the detailed anatomy and chemistry of the central nervous system. Norwegian neurophysiologists made important findings from studies of hippocampus including the inhibitory basket cell, the LTP phenomenon and the 'hippocampal-slice-technique'. In clinical neuroscience the description of Refsum's disease and studies of myasthenia gravis and multiple sclerosis have been of particular importance. Two of 13 centres of excellence in Norway selected in 2003 were from neuroscience, and The Norwegian Research Council has its own programme for neuroscience. The Norwegian Neurological Association arranges annual meetings to promote interest in neurological research.

Proteasome antibodies in patients with cancer or multiple sclerosis.

Proteasome antibodies were detected by enzyme-linked immunosorbent assay in two of the 45 (4.4%) patients with lung cancer, 0 of the 39 patients with breast cancer and six of the 51 (11.8%) patients with ovarian cancer. Six of the 47 (12.8%) patients with relapsing remitting multiple sclerosis had proteasome antibodies, as well as two of the 100 (2%) blood donors. Significant higher odds ratios compared to the blood donors were found for the patients with ovarian cancer (OR: 6.4; 95% CI: 1.1-68) and multiple sclerosis (OR: 7.1; 95% CI: 1.2-74). There was no association between proteasome antibodies and metastases or onconeural antibodies. The antibodies showed reactivity to 23, 25 and 27 kD proteins of the 20S proteasome using Western blot. The increased prevalence of proteasome antibodies in patients with ovarian cancer or multiple sclerosis may reflect cellular damage and release of intracellular antigens. Whether the antibodies take part in the clearance of released proteasomes and thus participate in the pathogenesis of cancer or autoimmune disease is not known.

Antibodies to CRMP3-4 associated with limbic encephalitis and thymoma.

We present a case with subacute limbic encephalitis (LE) and thymoma. Neither classical onconeural antibodies nor antibodies to voltage gated potassium channels (VGKC) were detected, but the serum was positive for anti-glutamic acid decarboxylase (GAD). The patient serum also stained synaptic boutons of pyramidal cells and nuclei of granule cells of rat hippocampus. The objective of the study was to identify new antibodies associated with LE. Screening a cDNA expression library identified collapsin response mediator protein 3 (CRMP3), a protein involved in neurite outgrowth. The serum also reacted with both CRMP3 and CRMP4 by Western blot. Similar binding pattern of hippocampal granule cells was obtained with the patient serum and rabbit anti-serum against CRMP1-4. The CRMP1-4 antibodies stained neuronal nuclei of a biopsy from the patient's temporal lobe, but CRMP1-4 expression in thymoma could only be detected by immunoblotting. Absorption studies with recombinant GAD failed to abolish the staining of the hippocampal granule cells. Our findings illustrate that CRMP3-4 antibodies can be associated with LE and thymoma. This has previously been associated with CRMP5.

Detection of autoantibodies to the BTB-kelch protein KLHL7 in cancer sera.

The aim of the study was to search for novel targets of autoantibodies in patients with paraneoplastic neurological syndromes (PNS). PNS are mediated by immune reactions against autoantigen(s) shared by the cancer cells and the nervous system. By serological screening of a rat cerebellum cDNA expression library using anti-Hu-positive sera from three patients with paraneoplastic encephalomyelitis (PEM), we identified an open reading frame encoding an isoform of the BTB-kelch protein KLHL7. Immunohistochemical studies demonstrated that the KLHL7 protein is expressed in the nuclei of neurones, but not in other tissues including various cancers. However, the KLHL7 protein was detected in the nuclei of cancer cell lines. Antibodies to KLHL7 were detected by an immunoprecipitation assay in sera from 12 of 254 (4.7%) patients with various cancers and 2 of 170 blood donors (1.2%). None of 50 sera from patients with multiple sclerosis were positive for KLHL7 antibodies. Sixteen patients with classical PNS and anti-Hu or anti-Yo antibodies were also negative for KLHL7 antibodies. Seven cancer patients with KLHL7 antibodies had various signs of neurological disease that could be related to cancer, whereas the remaining five seropositive cancer patients had no clinical signs of possible PNS. The present results indicate that KLHL7 antibodies are associated with various cancers, and in some patients also with neurological disease. Whether KLHL7 antibodies can be used as paraneoplastic markers for PNS remains to be determined.

Autopsy findings in the nervous system and ovarian tumour of two patients with paraneoplastic cerebellar degeneration.

OBJECTIVES: To review autopsy findings in paraneoplastic cerebellar degeneration. MATERIALS AND METHODS: We report the autopsy results of two individuals with paraneoplastic cerebellar degeneration and ovarian cancer. RESULTS: Both patients had extensive loss of cerebellar Purkinje cells and general activation of microglia in the central nervous system, as well as signs of immunactivation in the medulla. CONCLUSION: The immunoactivation in PCD is widespread and involving more than the cerebellum.

Yo antibodies in ovarian and breast cancer patients detected by a sensitive immunoprecipitation technique.

Onconeural antibodies are found in patients with cancer and are associated with paraneoplastic neurological syndromes (PNS). The objective of the present study was to assess the frequency of Yo antibodies in ovarian and breast cancer using a sensitive immunoprecipitation technique, and to look for any association of Yo antibodies with neurological symptoms and prognostic factors. A multiwell adapted fluid-phase immunoassay using radiolabelled recombinant cerebellar degeneration related protein (cdr2), produced by coupled in vitro transcription/translation was used for the detection of Yo antibodies. This technique combines high specificity and sensitivity with high sample analysing capacity for the antibody in question. Sera or EDTA-blood from 810 ovarian (n = 557) and breast cancer (n = 253) patients were analysed for Yo antibodies by immunoprecipitation, as well as immunofluorescence and immune blots. Two hundred healthy blood donors and sera from 17 patients with paraneoplastic cerebellar degeneration and Yo antibodies served as controls. Immunoprecipitation was more sensitive in detecting Yo antibodies than immunofluorescence and immune blots. The prevalence of Yo antibodies was 13/557 (2.3%) in ovarian cancer and 4/253 (1.6%) in breast cancer using immunoprecipitation. Yo antibodies were not correlated with specific histological subgroups. The Yo index of ovarian cancer patients in FIGO stage IV was higher compared to FIGO stage I-III. The prevalence of Yo antibodies was 3 times higher in patients with stage III breast cancer than in stage I and II. Only 2/17 (11.8%) patients with Yo antibodies detected during the screen of 810 cancer patients had PNS. The results show that the prevalence of Yo antibodies is low in ovarian and breast cancer. Yo antibodies may be associated with advanced cancer, but less often with PNS.

Pyridoxal phosphatase is a novel cancer autoantigen in the central nervous system.

Autoantibodies against many proteins are common in sera from patients with various types of cancer. These antibodies are sometimes involved in the development of conditions associated with cancer, such as paraneoplastic neurologic disorders. We used a human brain cDNA expression library and serum from a paraneoplastic neurologic disorder patient to search for new autoantigens in the nervous system. Pyridoxal phosphatase was identified as a novel autoantigen. Expression studies showed that pyridoxal phosphatase was strongly expressed in various parts of the central nervous system. Sera contained antibodies against pyridoxal phosphatase in 22 of 243 (9.1%) patients with lung cancer and eight of 113 (7.1%) with other forms of cancer vs two of 88 (2.3%) healthy control subjects. In addition, 2-4% of patients with different autoimmune diseases had autoantibodies against pyridoxal phosphatase. None of the antipyridoxal phosphatase-positive patients were known to have a paraneoplastic neurologic disorder. Hence, autoantibodies against pyridoxal phosphatase correlate with cancer but not necessarily with the subset of patients with paraneoplastic neurological disorders although serum from such a patient was used to screen the cDNA library. This study showed that yet another enzyme involved in pyridoxal 5'-phosphate metabolism is an autoantigen. Thus, pyridoxal 5'-phosphate seems to be a common denominator for autoantigens involved in autoimmune diseases.

Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer.

PURPOSE: Hu antibodies previously have been associated with longer survival of patients with small-cell lung cancer (SCLC). Voltage-gated calcium channel (VGCC) antibodies play a pathogenic role in Lambert Eaton myasthenic syndrome, which is also associated with SCLC. These antibodies may reduce tumor growth in patients with the neurologic disease, but it is not clear whether they provide prognostic information in those without neurologic symptoms. PATIENTS AND METHODS: Two hundred patients with SCLC (age 39 to 79 years; mean, 62.3 years; 129 males and 71 females) receiving chemotherapy were studied for the presence of Hu and VGCC antibodies. Sera were examined for Hu antibodies by an in vitro transcription-translation-based immunoprecipitation technique and by immunohistochemistry/dot blot. VGCC (P/Q subtype) antibodies were detected by radioimmunoassay. Survival analysis was used to analyze the data. Results Hu antibodies were detected in 51 of 200 patients (25.5%) by in vitro transcription-translation-based immunoprecipitation and in 37 of 200 patients (18.5%) by immunohistochemistry or dot blot, whereas VGCC antibodies were detected in only 10 of 200 patients (5%). The presence of Hu antibodies did not correlate with VGCC antibodies, and there was no association between Hu or VGCC antibodies and the extent of disease or survival. CONCLUSION: Hu and VGCC antibodies are found in a proportion of SCLC patients, irrespective of neurologic symptoms, but their presence does not correlate with the prognosis of the SCLC.

Paraneoplastic antibodies against HuD detected by a sensitive radiobinding assay.

Patients with paraneoplastic encephalomyelitis(subacute sensory neuronopathy) (PEM/SSN), most commonly associated with small-cell lung cancer (SCLC), frequently harbor Hu antibodies, which are usually detected by indirect immunohistochemistry or immunoblot. We developed a new radioimmunobinding assay to detect Hu antibodies based on in vitro transcribed and translated (ITT) HuD. High levels of Hu antibodies were detected in all seven PEM/SSN patients tested, but not in any of 15 patients with other paraneoplastic syndromes, 20 patients with Sjögren's syndrome, 20 patients with miscellaneous tumors and 99 of 100 blood donors. One of the blood donors had low levels of Hu antibodies. The radiobinding assay detected Hu antibodies in 45 of 191 (24%) patients with SCLC, in comparison with immunofluorescence and immuno dot blot, where only 34 of 191 (18%) were detected. All patients with Hu antibodies detected by immunofluorescence and immuno dot-blot were also positive by the radioimmunobinding assay. The results demonstrate that this assay is very specific and sensitive for the detection of Hu antibodies.

[Peripheral neuropathy in cancer]. / Perifer nevropati ved kreft.

Neuropathy is a quite common finding in cancer patients. If the cancer is known, the main clinical problem is often whether the symptoms and signs are caused by metastasis or recurrence, or if the neuropathy can be related to effects of the oncological treatment. In addition to the clinical findings, radiological and neurophysiological examination can often be of considerable diagnostic help. Peripheral neuropathy may also be the first manifestation of the cancer, as in paraneoplastic neuropathies. Detecting the tumor in these cases may improve the oncological prognosis, as the neuropathy often precedes tumor symptoms by several years. A determined approach in searching for an occult cancer is necessary. The neuropathic symptoms are seldom life-threatening. However, the neuropathy may cause distressing symptoms, and symptomatic treatment and rehabilitation is often required.

Neuropathy and malignancy: a retrospective survey.

Peripheral neuropathy is a common condition with a variety of causes. In some cases the neuropathy is the first symptom of an underlying malignancy. The frequency of occult cancer in patients with neuropathy is of importance in planning the investigations and follow-up of these patients. This retrospective study examined the incidence of cancer-related neuropathy among patients originally diagnosed with idiopathic peripheral neuropathy. Between 1981-1995 our department discharged 187 patients with the diagnosis of idiopathic peripheral neuropathy. Their names were cross-matched with the Norwegian Cancer Registry, and the medical records of the patients with known cancer were reviewed. In 14 patients (7.5%) we found cancer as the probable cause of the peripheral neuropathy originally classified as idiopathic. In eight of the patients the neuropathic symptoms preceded the tumour. In six cancer was already diagnosed when the neuropathic symptoms developed, but in three of these the neuropathy heralded a tumour recurrence. Idiopathic progressive neuropathy should always raise the suspicion of an underlying malignancy, especially if there are atypical accompanying symptoms and signs.

[The POEMS syndrome--a rare multiorgan disease]. / POEMS-syndromet--en sjelden multiorgansykdom.

POEMS syndrome is a rare multisystemic disorder characterized by a variable constellation of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. The syndrome is believed to be immune-mediated and is probably related to the pathological monoclonal component caused by a myeloma or a plasmocytoma. The treatment is aimed at the underlying plasma cell dyscrasia. We have studied three patients with this rare syndrome. This article presents the clinical picture of each one and a survey of the literature.