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Title of paper: Paget’s Disease                      Name of Student: Vidur Singh                                    Regis...
Title of paper: Paget’s Disease          Name of Student: Vidur Singh                           Registration #: 10/0531/11...
Title of paper: Paget’s Disease               Name of Student: Vidur Singh                       Registration #: 10/0531/1...
Title of paper: Paget’s Disease                 Name of Student: Vidur Singh                               Registration #:...
Title of paper: Paget’s Disease   Name of Student: Vidur Singh   Registration #: 10/0531/1157                             ...
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A Case of Paget's Disease
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Paget's disease

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A report based on Paget's Disease and its relatedness to Beethoven's clinical manifestations

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Paget's disease

  1. 1. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157What might cause Paget’s Disease? Although the aetiology of Paget’s disease remains blurry, studies thus far have implicated two major causes: viral(paramxyoviridae family e.g measles virus and respiratory syncytial virus) and genetic factors in the pathogenesis of thedisorder. The viral etiology is supported by the presence of viral mRNA in precursor and mature osteoclasts; it is alsosupported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virusnucleocapsid or matrix genes. However, the viral etiology has been questioned by the inability to culture a live virus frompagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget’s disease2. Around 20% of Paget’s patients fall into the category of familial Pagets disease in which there appears to beautosomal dominant transmission with incomplete penetrance. Approximately 20-30% of families have a mutation in thesequestosome 1 gene. The protein produced by this gene is important in the interleukin-6, tumor necrosis factor and rankligand signaling pathways which help regulate osteoclast function. When a mutated sequestosome 1 gene was placed intothe osteoclast precursors of transgenic mice a generalized increase in osteoclast-mediated bone resorption is produced, butthe pathology of Pagets disease is not found. A second gene mutation has been found in the valosine containing protein of avery rare type of familial Pagets disease in which muscle dysfunction and dementia are prominent features. It appears thatthe gene mutations thus far demonstrated in familial Pagets disease are not sufficient to produce the bone lesions, butprobably increase the susceptibility of affected family members to develop the disorder. The interaction of theparamyxovirus and genetic factors is under present study1.Epidemiology aka ‘WHO GETS PAGET’S? On average, Paget’s disease affects older people and is scarce in people under 40 years of age with a predilection formen and whites living in Europe, North America, New Zealand and Australia. On the contrary, native populations ofScandinavia, China, Japan and Africa are rarely susceptible2.Why is it like mental illness, bipolar disease and or psychosis? First off, the clinical presentation of certain neurologically-related manifestations of Paget’s disease is quite similar tothose associated with mental illnesses such as Bipolar disorder and Psychosis. In Paget’s, patients usually presents with signsand symptoms of dementiaI such as hallucinations, delusions, disordered thinking (as occur in Psychosis), mood/behaviouralchanges (as is seen in a BD patient whereby the patient’s mood spans a spectrum from extreme mania to severe depression),depression, and self-imposed social isolation3. This clinical presentation of dementia in Paget’s is either due to directcompression of the cerebral hemispheres via symmetric or asymmetric enlargement of the parietal or frontal bones (frontalbossing), and increased skull thickness or as a result of hydrocephalus (caused by basilar bone invaginaton)4. These Paget’spatients suffer progressive mental deterioration, lethargy, memory loss, dull intelligence, and stupor. Secondly, the aetiologyof the Paget’s and its neurological aspects, and these two mental illnesses are somewhat related. For example, it istheorised that Bipolar disease (BD)is genetically linked since it is more common in people who have blood relatives sufferingI Dementia is a loss of brain function that occurs with certain diseases. It affects memory, thinking, language, judgment, and behavior 1|Page
  2. 2. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157from the disorder5 while some people afflicted by Paget’s is deemed to have familial aetiology that leads to the disease andis inherited in an autosomal dominant fashion. In addition, some BD patients present with physical changes in the brain as issimilar to those Paget’s patients with mental-illness-like symptoms whose brains are physically injured. Moreover, somepatients with psychosis can acquire the condition if they are infected with the HIV6; on the other hand, the onslaught ofPaget’s disease in patients has been theorised to be associated with paramyxoviruses.Why is it like cancer…or not?- Both cancer cancer have new blood vessels formation to cater for the metabolic demands such as increased energy requirement (ATP)8.- With cancer, there are tumor markers present in the blood that are use as prognostic tools for its progression or its responsiveness to chemotherapy; also the levels of such markers are increased in specific cancers. While in Paget’s disease, there are elevations in serum alkaline phosphatase and increased urinary excretion of hydroxyproline that reflects excessive bone turnover.- Paget’s disease may present as a solitary lesion (monostotic) or it may crop up at several sites in the skeletal system (polyostotic) with striking variation at each location. This can be likened to metastasis in cases of malignant tumors whereby a formerly localized tumor spreads to the various parts of the body, but usually include other tissue type apart from that of the original site such as the lungs and lymph nodes; this contrasts with Paget’s disease where the bone tissues are the primary target despite the location of the bones in the body2.- Like cancer, the preliminary underlying pathologic changes in Paget’s disease are usually only found on incidental examinations such as on radiographic exams; this contrasts with the marked clinical findings that pop up when the effects of these pathologic conditions would have become more distinct.- Paget’s is linked to a viral and a genetic aetiology as aforementioned; similarly cancer’s aetiology is linked to viruses (such as HPV in cervical cancer) and genetics (e.g. a mutation in p53 gene), in addition to environmental factors.- Paget’s is hallmarked by increased osteoclastic and osteoblastic activity (of normal bone cells) and not by the rapidly, increasing number of abnormal cells as in cancer. Also, Paget’s is usually non-lethal and has a good prognosis as compared with cancer which usually paints the deadly outlook in affected patients.- Histopathologically, Paget’s is characterized by a mosaic pattern of lamellar bone (like a jigsaw puzzle) due to prominent cement lines that haphazardly anneal units of lamellar bone; likewise, in cancer, there is abnormal growth pattern of cells (cancerous) – termed dysplasia2.Why is it linked to high output heart failure and deafness? Cranial expansion, in Paget’s, may narrow cranial foramina and cause neurologic complications including hearing lossfrom cochlear nerve damage due to temporal bone involvement whereby the auditory foramen is narrowed; or it can occuras are result of direct involvement of the bones of the middle ear. A study showed that fractured stapes footplate was linkedas a causative lesion of conductive hearing loss in Paget’s. Extensive bone remodelling around the Cotugno canal was afrequent finding in this study of these Paget’s patients. The study postulated that sensorineural hearing loss in Paget’s 2|Page
  3. 3. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157patients with Paget’s of the temporal bone may, sometimes, be linked to the obliteration of Cotugno’s canal (for inferiorcochlear vein) by remodelling of the bone, thus obstructing the venous drainage of the cochlea, with subsequent effect onthe function of stria vascularis and spiral ligament7. On the other hand, Paget’s results in high-output cardiac failure due to decreased peripheral vascular resistance. InPaget’s, there is abnormal resorption and regrowth of bones that lead to the formation of an excessive amount of bloodvessels (hypervascularity) and this leads to an increase in the demand of blood supply, and hence cardiac output8. Inaddition, with Paget’s, there is the formation of multiple functional arteriovenous shunts that leads to increased cardiacoutput to suit the adjusted needs of the bones. Decreased peripheral resistance leads to hypotension in the peripheral bloodvessels; thus, the heart has to pump harder to get sufficient blood to the body – explaining the likelihood of cardiachypertrophy – and subsequent heart failure in decompensated states e.g. probably due to coronary artery ischemia, in aneffort to rebuild arterial blood pressure that decreased.Disease Calcium Phosphorus Alkaline Parathyroid Miscellaneous Phosphatase hormoneOsteoporosis Normal Normal Normal or Normal Decreased bone mass – either due to decreased impaired synthesis or increased resorption of bone matrix protein but normal mineralization. Occurs in senile people and postmenopausal womenRickets and Decreas decreased Increased or Increased Soft bonesOsteomalacia ed or normal Vitamin D deficiency in children and normal adults respectively – so decreased mineralization of bonesPaget’s Normal Normal Increased Normal Abnormal bone architecture – due todisease (*) (markedly but increases in both osteoblastic and may depend on osteoclastic activity the phase of the Bone density increases disease) Occurs in people above 40 years of age most of the time Table 1 – Comparing Paget’s disease to osteomalacia, rickets and osteoporosis8How do you see the linkage of Paget’s to Beethoven? It was suggested that Beethoven, who died in 1827, had Paget’s disease, based on several theories that tried tobridge his symptoms with those seen in Paget’s disease – the classic symptom being his deafness. Beethoven was short 3|Page
  4. 4. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157(around 1.65m), had an asymmetrical head, large forehead, over-hanging brows, protruding lower mandible, large hands,and thick fingers. All these observations might have been true to an extent. However, nothing suggests that Beethovensappearance changed over time. Furthermore, it has been suggested that Pagets disease would explain the composersrecurrent headaches and progressive deafness which some argue was due to a mixture of nerve deafness (caused bycompression from overgrowth of surrounding bony structures) and bony deafness (caused by Pagets induced otosclerosis).Also, it has been argued that his recurring abdominal pains were caused by recurrent renal colic secondary to nephrolithiasisinduced by Pagets related hypocalcaemia. Moreover, the post-mortem findings of a narrowed eustachian tube, especially atthe bony part, and a large external auditory meatus was cited by some as further evidence suggestive of Pagets disease9.But, I believe that Beethoven may not have had Pagets disease for several reasons; but if he did, then it was not severeenough to cause his deafness, abdominal problems, and death. Firstly, the thickening of his skull was uniform (unlikely inPagets disease); secondly, Pagets disease does not cause severe diarrhoea and does not explain Beethovens earlygastrointestinal symptoms; thirdly, Pagets disease is very rare below the age of 50 years (note that his deafness kicked in atage 28); and finally, his bones were subjected to X rays analysis that were done to check for Pagetic traits with no positiveresults found.References1 A Physicians Guide to The Management of Pagets Disease of Bone. (n.d.). Retrieved October 21, 2012, from www.paget.org:http://www.paget.org/index.php/healthcare-professionals/pagets-disease-of-bone/126-a-physicians-guide-to-the-management-of-pagets-disease-of-bone.html2 Abbas, A. K., Fausto, N., Mitchell, R., & Kumar, V. (2007). Robbins Basic Pathology, Eighth Edition. Elsevier - Health Sciences Division.3 Mental illness - MayoClinic.com. (2012, September 15th). Retrieved October 21st, 2012, from www.mayoclinic.com:http://www.mayoclinic.com/health/mental-illness/DS011044 Favus, M. J., & Vokes, T. J. (n.d.). PAGET’S DISEASE AND OTHER DYSPLASIAS OF BONE. Retrieved October 21, 2012, fromhttp://www.mhprofessional.com/downloads/products/0071741445/endocrinology_c29_462-474.pdf5 Bipolar disorder - MayoClinic.com. (2012, January 18). Retrieved October 22, 2012, from www.mayoclinic.com:http://www.mayoclinic.com/health/bipolar-disorder/DS003566 Psychosis - PubMed Health. (2012, March 7th). Retrieved October 21, 2012, from www.ncbi.nlm.nih.gov:http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002520/7 Dimitriadis PA, B. D. (n.d.). Hearing loss in Pagets disease: a temporal bone histopathology... [Otol Neurotol. 2012] - PubMed - NCBI.Retrieved October 23, 2012, from www.ncbi.nlm.nih.gov: http://www.ncbi.nlm.nih.gov/pubmed/222225748 Schneider, A. S., & Szanto, P. A. (2008). BRS Pathology, 4th Edition. North America: Lippincott Williams & Wilkins.9 Kubba, A. K., & Young, M. (2001, April 20th). Ludwig van Beethoven: A Medical Biography. Retrieved October 22, 2012, frompmaksimovich.tripod.com: http://pmaksimovich.tripod.com/Varia/English/lvbmed.txt 4|Page
  5. 5. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157 5|Page

A report based on Paget's Disease and its relatedness to Beethoven's clinical manifestations

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