Brain Trauma Oncology Cancer Cachexia
Cancer cachexia is well known, but still lacks a satisfactory explanation. Many patients experience weight loss, in particular loss of muscle mass.19
Weight loss and sarcopoenia are also increasingly
observed in other generalised diseases, and these may share a common pathway. For cancer patients it has been postulated that reducing or stopping weight loss may yield a better prognosis.20
Enlarged Clinical Spectrum of Clinical Paraneoplastic Neurological Syndromes The PNS database includes the most frequent PNS syndromes and describes large numbers of clinical characteristics for them, enabling clinicians to make judgements based on the results of a large observational study. However, the new recently described surface antibodies will increase its clinical spectrum still further.
Brain Stem Encephalitis and Ventilation Some PNS, particularly those associated with Hu and the new surface antibodies, may have signs of brain stem encephalitis resulting in hypoventilation and even apnoea.21
in patient management and may previously have been overlooked.
The Spectrum of Paraneoplastic Psychiatric and Neurological Symptoms in Limbic Encephalitis The characterisation of psychiatric symptoms22
difficult, if not impossible; however, the pathophysiology of PNS is a clue to viable therapies (see Table 4). Classic immune-mediated diseases such as MG, LEMS and the VGCK antibodies seem to respond well, and this has been confirmed by many observations. It is not yet clear how PNS caused by onconeural antibodies should be treated. Most authors recommend using immunosuppression or modulation soon after onset of the PNS, to prevent further disease progression. High-dose steroids, cyclophosphamide, IVIg and plasmapheresis have been presribed for this purpose, but there is a paucity of clinical data to support their use. The new class of surface antibodies (NMDA, AMPA and GABA) seem to have similar behaviour to the classic immune- mediated PNS and respond to conventional immunomodulatory drugs. Recurrence has, however, been reported with some of them, which is suggestive of an ongoing process. Novel approaches include the use of biological drugs such as rituximab or natalizumab, but no case series have yet been published.
Conclusion This is of practical importance will allow for a
more precise diagnosis based on clinical presentation. The core symptoms of LE are short-term memory loss and confusion (see Figure 1). Several markers based on antibody type exist, and consist of a neurological and a psychiatric presentation.22
In summary,
LE is one disease with several causes and clinical presentations. LE was accurately described in 1960 by Brierley and Corsellis and, concurrently, neuropathological changes also were found predominately in the temporal lobe. Two new aspects have emerged in recent years: LE can have different clinical presentations and can be associated with seizures, hyponatremia, sleep disorders and a variety of other antibody-dependent specificities. Pathogenetically, LE can have several causes, including onconeuronal antibodies (Hu), ion channel antibodies, surface antibodies (NMDA etc), and may not be associated with apparent inflammation.23
Several types of LE
respond to therapy and have in fact become treatable conditions. Therapy
There are several considerations regarding the treatment of PNS. First, the underlying tumour should be treated using surgery, radiotherapy and, frequently, chemotherapy. In what way classic tumour removal improves the condition of patients in the presence of ongoing autoimmune therapy is not clear. Tumour treatment, in particular with chemotherapy, exerts an immunosuppressive effect that may also suppress the PNS. The pathophysiology of PNS differs in the various entities and the underlying neoplasms also differ; in addition PNS are infrequent. Taken together, these factors make conventional studies
1. Henson RA, Urich H, Cancer at the nervous system, Blackwell Scientific Publications, 1982.
2. Darnell RB, Posner JB, N Engl J Med, 2003;349(16): 1543–54.
3. Lennon VA, Neurology, 1994:44;2236–40. 4. Hart IK, et al., Ann Neurol, 1997;41:238–46. 5. Pozo-Rosich P, et al., Ann Neurol, 2003;54:530–3. 6. Kleopa KA, et al., Brain, 2006;129:1570–84. 7. Dalmau J, Rosenfeld MR, Lancet Neurol, 2008;7(4):327–40.
76 8.
In addition to the target-oriented antibodies and onconeuronal antibodies, a new group of surface antibodies has been detected, which are associated with a new spectrum of disease, usually combining neurology and a variety of psychiatric symptoms. Other interesting clinical observations include hypoventilation syndromes in some PNS and the fact that a single syndrome, LE, can be caused by entirely different mechanisms. The key message is that some of the surface antibody syndromes are treatable with immunomodulation and cancer therapy (in cancer-associated types) and may not only improve but even heal the patient. n
Wolfgang Grisold is a Professor and Clinician in the Neurology Department of the KFJ Hospital, an affiliate of the Medical University of Vienna. He is also Chair of the Ludwig Boltzmann Institute for Neuro-oncology in Vienna. His primary fields of interest are neuro-oncology and neuromuscular diseases. In neuro-oncology his main interests are interactions between cancers and the nervous system.
Bruno Giometto is Head of the Department of Neurology at the Ca’ Foncello Hospital in Treviso and the Neuro-Immunology Laboratory of the University of Padova. Dr Giometto has received a grant to co-ordinate the Concerted Action of the European Commission on the Paraneoplastic Neurological Syndrome project, which involves 20 centres in 11 European countries.
Stefan Oberndorfer is a Clinician in the Neurology Department of the KFJ Hospital, an affiliate of the Medical University of Vienna. He is an experienced neuro-oncologist and his interests include brain tumours, the side effects of cancer on the nervous system, in particular metastasis, neurotoxicology and epilepsy and end of life issues in neuro-oncology.
Roberta Vitaliani is a Consultant in the Department of Neurology at the Ca’ Foncello Hospital in Treviso. Her research is focused on paraneoplastic syndromes and neuro-oncology. In 2004–2005 she was a research scholar at the Neuro-oncological Institute at Pennsylvania University. Dr Vitaliani obtained her MD in 1999, her specialisation in neurology in 2005 and her doctoral degree in neuroscience in 2009.
Knowledge of the occurrence and characteristics of PNS has increased and a large European database has added useful information.8
Giometto B, Grisold W, Vitaliani R et al., Arch Neurol, 2010;67:330–5.
9. Graus F, et al., J Neurol Neurosurg Psychiatry, 2004;75: 1135–40.
10. O’Neill JH, et al., Brain, 1988;111:577–96. 11. Titulaer MJ, et al., J Clin Oncol, 2009;27(26):4260–7. 12. Liguori R, et al., Brain, 2001;124:2417–26. 13. Dalmau J, et al., Ann Neurol, 2007:61:25–36. 14. Lai M, et al., Ann Neurol, 2009;65:424–34.
15. Lancaster E, et al., Lancet Neurol, 2010;9:67–76. 16. Irani SR, et al., Brain, 2010:133;2734–48. 17. Lai M, et al., Lancet Neurol, 2010;9:776–85. 18. Poza JJ, et al., Ann Neurol, 1999;45:182–8. 19. Bossola F, et al., Ann Surg Oncol, 2007;14:276–85. 20. Martignoni E, et al., Molecular Cancer, 2003;36:1186–476. 21. Saiz A, et al., J Neurol Neurosurg Psychiatry, 2009;80:404–7. 22. Kayser CG, et al., Am J Psychiatry, 167(9):1039–50. 23. Shinohara T, et al., Neuropathology, 2005;25:353–60.
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