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

1. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157
What 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 the
disorder. The viral etiology is supported by the presence of viral mRNA in precursor and mature osteoclasts; it is also
supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus
nucleocapsid or matrix genes. However, the viral etiology has been questioned by the inability to culture a live virus from
pagetic 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 Paget's disease in which there appears to be
autosomal dominant transmission with incomplete penetrance. Approximately 20-30% of families have a mutation in the
sequestosome 1 gene. The protein produced by this gene is important in the interleukin-6, tumor necrosis factor and rank
ligand signaling pathways which help regulate osteoclast function. When a mutated sequestosome 1 gene was placed into
the osteoclast precursors of transgenic mice a generalized increase in osteoclast-mediated bone resorption is produced, but
the pathology of Paget's disease is not found. A second gene mutation has been found in the valosine containing protein of a
very rare type of familial Paget's disease in which muscle dysfunction and dementia are prominent features. It appears that
the gene mutations thus far demonstrated in familial Paget's disease are not sufficient to produce the bone lesions, but
probably increase the susceptibility of affected family members to develop the disorder. The interaction of the
paramyxovirus 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 for
men and whites living in Europe, North America, New Zealand and Australia. On the contrary, native populations of
Scandinavia, 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 to
those associated with mental illnesses such as Bipolar disorder and Psychosis. In Paget’s, patients usually presents with signs
and symptoms of dementiaI such as hallucinations, delusions, disordered thinking (as occur in Psychosis), mood/behavioural
changes (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 direct
compression of the cerebral hemispheres via symmetric or asymmetric enlargement of the parietal or frontal bones (frontal
bossing), and increased skull thickness or as a result of hydrocephalus (caused by basilar bone invaginaton)4. These Paget’s
patients suffer progressive mental deterioration, lethargy, memory loss, dull intelligence, and stupor. Secondly, the aetiology
of the Paget’s and its neurological aspects, and these two mental illnesses are somewhat related. For example, it is
theorised that Bipolar disease (BD)is genetically linked since it is more common in people who have blood relatives suffering
I
Dementia is a loss of brain function that occurs with certain diseases. It affects memory, thinking, language, judgment, and behavior
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2. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157
from the disorder5 while some people afflicted by Paget’s is deemed to have familial aetiology that leads to the disease and
is inherited in an autosomal dominant fashion. In addition, some BD patients present with physical changes in the brain as is
similar to those Paget’s patients with mental-illness-like symptoms whose brains are physically injured. Moreover, some
patients with psychosis can acquire the condition if they are infected with the HIV6; on the other hand, the onslaught of
Paget’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 loss
from cochlear nerve damage due to temporal bone involvement whereby the auditory foramen is narrowed; or it can occur
as are result of direct involvement of the bones of the middle ear. A study showed that fractured stapes footplate was linked
as a causative lesion of conductive hearing loss in Paget’s. Extensive bone remodelling around the Cotugno canal was a
frequent finding in this study of these Paget’s patients. The study postulated that sensorineural hearing loss in Paget’s
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3. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157
patients with Paget’s of the temporal bone may, sometimes, be linked to the obliteration of Cotugno’s canal (for inferior
cochlear vein) by remodelling of the bone, thus obstructing the venous drainage of the cochlea, with subsequent effect on
the 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. In
Paget’s, there is abnormal resorption and regrowth of bones that lead to the formation of an excessive amount of blood
vessels (hypervascularity) and this leads to an increase in the demand of blood supply, and hence cardiac output8. In
addition, with Paget’s, there is the formation of multiple functional arteriovenous shunts that leads to increased cardiac
output to suit the adjusted needs of the bones. Decreased peripheral resistance leads to hypotension in the peripheral blood
vessels; thus, the heart has to pump harder to get sufficient blood to the body – explaining the likelihood of cardiac
hypertrophy – and subsequent heart failure in decompensated states e.g. probably due to coronary artery ischemia, in an
effort to rebuild arterial blood pressure that decreased.
Disease Calcium Phosphorus Alkaline Parathyroid Miscellaneous
Phosphatase hormone
Osteoporosis 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 women
Rickets and Decreas decreased Increased or Increased Soft bones
Osteomalacia ed or normal Vitamin D deficiency in children and
normal adults respectively – so decreased
mineralization of bones
Paget’s Normal Normal Increased Normal Abnormal bone architecture – due to
disease (*) (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 osteoporosis8
How 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 to
bridge his symptoms with those seen in Paget’s disease – the classic symptom being his deafness. Beethoven was short
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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 Beethoven's
appearance changed over time. Furthermore, it has been suggested that Paget's disease would explain the composer's
recurrent headaches and progressive deafness which some argue was due to a mixture of nerve deafness (caused by
compression from overgrowth of surrounding bony structures) and bony deafness (caused by Paget's induced otosclerosis).
Also, it has been argued that his recurring abdominal pains were caused by recurrent renal colic secondary to nephrolithiasis
induced by Paget's related hypocalcaemia. Moreover, the post-mortem findings of a narrowed eustachian tube, especially at
the bony part, and a large external auditory meatus was cited by some as further evidence suggestive of Paget's disease9.
But, I believe that Beethoven may not have had Paget's disease for several reasons; but if he did, then it was not severe
enough to cause his deafness, abdominal problems, and death. Firstly, the thickening of his skull was uniform (unlikely in
Paget's disease); secondly, Paget's disease does not cause severe diarrhoea and does not explain Beethoven's early
gastrointestinal symptoms; thirdly, Paget's disease is very rare below the age of 50 years (note that his deafness kicked in at
age 28); and finally, his bones were subjected to X rays analysis that were done to check for Pagetic traits with no positive
results found.
References
1
A Physician's Guide to The Management of Paget's 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.html
2
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/DS01104
4
Favus, M. J., & Vokes, T. J. (n.d.). PAGET’S DISEASE AND OTHER DYSPLASIAS OF BONE. Retrieved October 21, 2012, from
http://www.mhprofessional.com/downloads/products/0071741445/endocrinology_c29_462-474.pdf
5
Bipolar disorder - MayoClinic.com. (2012, January 18). Retrieved October 22, 2012, from www.mayoclinic.com:
http://www.mayoclinic.com/health/bipolar-disorder/DS00356
6
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 Paget's 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/22222574
8
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, from
pmaksimovich.tripod.com: http://pmaksimovich.tripod.com/Varia/English/lvbmed.txt
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5. Title of paper: Paget’s Disease Name of Student: Vidur Singh Registration #: 10/0531/1157
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