BONE TUMORS, INFECTIONS, OSTEONECROSIS

Question 1

Paradigms of Cancer Rehabilitation

Answer 1

Preventive interventions
Restorative interventions
Supportive interventions
Palliative interventions
Palliative interventions

Question 2

Preventive interventions

Answer 2

• lessen the effect of expected
disabilities
• emphasize patient education.
• Improving the patient's physical
functioning and general health
• Psychological functioning

Question 3

Restorative interventions

Answer 3

• Goal is to return patients to previous
levels of physical, psychological,
social, and vocational functioning.
• Postoperative ROM exercises for patients undergoing mastectomy and reconstructive surgery for head and neck cancer represent this category of
interventions.

Question 4

Supportive interventions

Answer 4

• Designed to teach patients to accommodate their disabilities
• To minimize debilitating changes from ongoing disease.
• Supportive efforts include:
- teaching patients how to use
prosthetic devices after
amputation
- Adaptive devices
- Emotional support

Question 5

Palliative interventions

Answer 5

• Interventions and goals focus on
minimizing or eliminating complications and providing comfort and support
• Goals include pain control, prevention of contractures and pressure sores, prevention of unnecessary deterioration from inactivity, and psychological support for the patient

Question 6

Childhood Cancer

Answer 6

• Rare in children
• Leading cause of death by disease
past infancy among children in the
United States
• 2014: 15,780 children and
adolescents ages 0 to 19 years will be diagnosed with cancer & 1,960 will die of the disease in the United States

Clinical Features
• non-specific, therefore a long period
of time may elapse until the tumour is
diagnosed
• Pain, swelling and general discomfort
are the cardinal symptoms that lead to
the diagnosis of bone tumours.
• However, limited mobility and spontaneous fracture may also be
important features.

Etiology
• Inherited mutation
• Genetic mutation
• Ionizing radiation
• Environmental exposure

Pain
• First and most common symp-tom in
nearly all malignant bone tumours {
• If a spontaneous fracture does not occur, the symp- toms usually
commence slowly.
• Patient has tearing neuralgia-like pain,
which may also be interpreted as
"rheumatic pain".
• Intermittent→ at rest→ distubing→
spreading to adjacent structures

Swelling
• 2nd most important symptom
• May frequently be benign and of long
duration and may not be associated
with other complaints
• Swelling is only observed if there is an
extraosseous part of the tumour or the bone is expanded by the tumourous process.

Limitation of movement
• Mobility may be limited in cases of
lesions close to the joint, in tumours such as osteoblastoma, chrondroblastoma, giant cell tumours and all types of sarco- mas. Occasionally it is not the tumour but reactive synovitis in the joint, especially in chondroblastoma, that causes limita- tion of movement and masks the true diagnosis

Question 7

Pathologic Fracture

Answer 7

• Fracture is diagnosed early, as it
causes the patient to seek attention
immediately.
• It may occur with no prior symptoms
at all, as is frequently the case in juvenile cysts and in some non- ossifying b one fibromas
• Rare inciting event in primary bone malignancy

Constitutional Symptoms

1. Weight loss
2. Fever
3. Weakness

Diagnosis
• Combining both radiological and
histological criteria is most
appropriate.
• Based on clinical and radiological
signs, one should first diagnose benign lesions for which a subsequent biopsy may not be necessary. Metaphyseal fibrous defect > Fibrous dysplasia, Osteochondrom
Enchondroma, Simple bone cyst,
Vertebral haemangioma
• Age is useful information:
- before age of 5, a malignant tumour is often metastatic neuroblastoma;
- between 5 and 15 years old, osteosarcoma or Ewing sarcoma; a
- after 40 years, metastasis or myeloma.
- Certain tumours are more common inparticular bones. Adamantinoma, usually found in the adult, selectively involves the tibia and fibula.
- The most common epiphyseal tumour in childhood is the chondroblastoma. Tumour size is useful and easy to use.

A tumour less than 6 cm in greatest dimension is likely benign whereas one
bigger than 6 cm may be benign or malignant. The axis of the lesion is also useful to determine
• The next step is to determine the limits of bone tumor
- Patterns of bone destruction indicates the aggressiveness of the tumor

Question 8

Sarcomas

Answer 8

• Sarcomas are rare (<1% of all
  malignancies) mesenchymal neoplasms that arise in bone and soft tissues
• Usually of mesodermal origin, although a few are derived from neuroectoderm, and they are biologically distinct from the more common epithelial malignancies.
• Affect all age groups;
• 15% are found in children <15 years of age,
• and 40% occur after age 55 years.
• One of the most common solid tumors
  of childhood and are the fifth most common cause of cancer deaths in children.
• Sarcomas may be divided into two groups 1) and those 2) soft tissues.

Question 9

Soft Tissue Sarcomas

Answer 9

• Soft tissues include muscles, tendons,
fat, fibrous tissue, synovial tis-sue,
vessels, and nerves.
• Approximately 60% of soft tissue
sarcomas arise in the extremities, with the lower extremities involved three times as often as the upper extremities.
• MC asymptomatic mass
• Mechanical symptoms referable to
pressure, traction, or entrapment of nerves or muscles may be present
• All new and persistent or growing masses should be biopsied, either by a cutting needle (core-needle biopsy)
• Treatment: Surgery, RT and neoadjuvant chemotherapy

Question 10

Synovial Sarcoma

Answer 10

• High-grade and soft-tissue sarcoma
that
• Frequently is in the vicinity of joints,
tendons or bursae, although it can also be found in extra-articular location
• Most common cause of soft tissue tumor after rhabdomyosarcoma
• Has embryonic similarity to the synovium

Incidence
• Estimated incidence of this tumor in
the general population is 2.75 per
100,000
• 4th most common sarcoma after the
malignant fibrous histiocytoma,
liposarcoma and rhabdomyosarcoma. • Approximately 800 new cases are
diagnosed each year in the US
• Second only to rhabdomyosarcoma in
children

Prevalence
• 1/3rd of synovial sarcomas occur in the
first two decades of life.
• Prevalent in adolescents and adults
between 15 and 40 years of age
• The male:female ratio is 1.2:1, with
males more frequently affected
• Similar incidence in all ethnic groups.
Pathophysiology
• Chromosomal translocation, t(X;18)
(p11;q11)
• SYT-SSX1, SYT-SSX2 or SYT-SS4
- Has been noted in more than 90% of the cases
- SYT-SSX2 and SYT-SSX2 are more common in females
- Fusion of these gene results
to either inhibition of tumor suppressor genes or activation of protooncogenes

Clinical Presentation
• Usually occurs in the first three
decades of life
• Presents as a small nodule that has
increased rapidly in size
• Mass is generally painful and deep
• More commonly found in the knee but
is also found in the hands and feet

Anatomic regions
a. Trunk-Head, neck, thorax, abdomen
and pelvis
b. Distal extermity- Hands, feet and
ankles
c. Proximal extremity- Arms, forearms,
thighs and legs

Question 11

BONE SARCOMAS

Answer 11

• Bone tumors are classified into:
- Primary bone tumors
- Secondary bone tumors
(Metastasis)

• Most are classified according to the normal cell of origin and apparent pattern of differentiation
• Bone sarcomas are rarer than soft tissue sarcomas. Several benign bone lesions have the potential for malignant transformation
• Enchondromas and osteochondromas can transform into chondrosarcoma; fibrous dysplasia, bone infarcts, and Paget’s disease of bone can transform into either UPS or osteosarcoma

Question 12

Benign tumors

Answer 12

• enchondroma, osteochondroma,
chondroblastoma, and chondromyxoid fibroma, of cartilage origin; osteoid osteoma and osteoblastoma, of bone origin; fibroma and desmoplastic fibroma, of fibrous tissue origin; hem- angioma, of vascular origin; and giant- cell tumor, of unknown origin.

Question 13

Malignant tumors

Answer 13

• The four most common malignant
nonhematopoietic bone tumors are osteosarcoma, chondrosarcoma, Ewing’s sarcoma, and UPS.
• Rare malignant tumors include chordoma (of notochordal origin), malignant giant-cell tumor and adamantinoma (of unknown origin).

Question 14

Primary Bone Tumors

Answer 14

Bone-Forming tumors
1. Osteoma
2. Osteoid osteoma and osteoblastoma
3. Osteosarcoma
Cartilage-Forming tumors
1. Chondroma (Enchondroma)
2. Osteochondroma
3. Chondrosarcoma

Question 15

Bone Tumors

Answer 15

• Bone tumors are classified into:
a. Primary bone tumors
b. Secondary bone tumors (Metastasis)
• Most are classified according to the normal cell of origin and apparent pattern of differentiation

Question 16

Osteoma

Answer 16

• Osteoma are benign lesions of bone

that in many cases represent developmental aberrations or reactive growths rather than true neoplasms.

Question 17

Malignant Osteoid

Answer 17

Osteoid
• Unmineralized, organic portion of the
bone matrix that forms prior to the maturation of bone tissue. Osteoblastic differentiation of the primitive transformed cells produces malignant osteoid, which result in the formation of the malignant primary bone tumour known as Osteosarcoma

Osteosarcoma
• Is the most common malignant bone tumor
• arise from primitive mesenchymal bone-forming cells, and its histologic hallmark is the production of malignant osteoid
• Pulmonary metastases
• Arises as solitary lesion in the long bones of the femur

LOCATIONS
a. Femur (42%, 75% of which are in the
distal femur)
b. Tibia (19%, 80% of which are in the
proximal tibia)
c. Humerus (10%, 90% of which are in
the proximal humerus)
d. Skull and jaw (8%)
e. Pelvis (8%) Surgical removal is the
mainstay of treatment
Chemotherapy is generally given to control the disease progress

Signs and Symptoms
• Most common is pain during activity
• Swelling may or may not occur
• Pathologic fractures are rare
• Respiratory symptoms may occur

Treatment
• Neoadjuvant chemotherapy
• Wide resection
• Biopsies
- Open biopsy (preferred to avoid sampling error and to provide adequate tissue for biologic studies)
- Trephine biopsy or core- needle biopsy (preferred for vertebral bodies and many pelvic lesions)
- Fine-needle aspiration (FNA; not recommended)

Question 18

Osteochondroma

Answer 18

Morphology
• Osteochondromas are mushroom
shaped and range in size from 1 to 20
cm.
• The outer layer of the head of the
osteochondroma is composed of benign hyaline cartilage varying in thickness
• Newly formed bone forms the inner portion of the head and stalk, with the stalk cortex merging with the cortex of the host bone.

Chondrosarcoma
• Collective term for a group of tumors
that consist predominantly of cartilage
• Range from low-grade tumors with low metastatic potential to high- grade, aggressive tumors characterized by early metastasis. See
the image below.

Clinical Feature
• Deep, dull, achy pain
• Pain at night
• Nerve dysfunction of the lumbosacral
plexus or the sciatic or femoral nerves,
with pelvic lesions near a neurovascular bundle
• Limitation of joint range of motion and disturbance of joint function
• Pathologic fracture
• Common sites of predilection
• Pelvis and ribs, 45%
• Ilium, 20%
• Femur, 15%
• Humerus, 10%
• Others, 10%

Staging
Stage I (low-grade tumor) - Stage I-A, intracompartmental; stage I-B, extracompartmental
Stage II (high-grade tumor) - Stage II-A, intracompartmental; stage II-B, extracompartmental
Stage III (distant metastasis)
- Determines the Chromosomal Translocation

Treatment
Surgery: primary treatment chondrosarcoma
for any
- Complete, wide surgical excision of the chondrosarcoma is the preferred method
Radiotherapy and chemotherapy play limited roles in primary treatment
- An exception is their use as adjuvant therapy or palliative treatment for tumors in surgically inaccessible areas or diffuse metastasis

Work-up: Imaging Studies

o Plain radiographs
- Snow storm appearance
o Computed tomography
- Used to confirm presence of a mass,
its size and its location
- Non-diagnostic
o Magnetic Resonance Imaging
- Imaging of choice

Laboratories
Cytogenic analysis
- Determines the Chromosomal Translocation

Treatment
• Surgical excision
- Cornerstone of treatment of synovial
cell sarcoma
- Wide excision with negative margins
A. Standard surgical procedure is a wide excision with negative margins
B. Removing the tumor with a rim of normal tissue around
• Tumor free margin of 1-3 cm

Medical Therapy
• Adjuvant chemotherapy and
neoadjuvant chemotherapy
• Chemotherapy remains controversial
• Recommended for patients with tumor
size larger than 5 cm 
• Trials:
- Doxorubicin and cyclophosphamide-based chemotherapy
- Doxorubicin and bolus ifosfamide
- Ifosfamide with loposomal daunorubicin
- GSF: stimulating the bone marrow

Question 19

Giant Cell Tumor

Answer 19

• Most challenging benign tumors
• This is a neoplasm that contains large
numbers of osteoclast like giant cells
admixed with mononuclear cells.
• Although benign, GCTs show a
tendency for:
- significant bone destruction,
local recurrence, and
occasionally metastasis.
• Natural history of GCTs varies widely and can range from local bony destruction to local metastasis, metastasis to the lung, metastasis to lymph nodes (rare), or malignant
transformation
• Lung metastases is rare

Epidemiology
• Female predominance
• 84% of cases occur in patients >19
years

Clinical Presentation
• Most are located within the epiphyses
of long bones, but they often extend
into the metaphysis
• Approximately 50% of GCTs are
located around the knee. The most common locations are the distal femur, the proximal tibia, and the proximal humerus and distal radius

Work Up
•Radiographic ally, giant cell tumors (GCTs) are lucent and eccentrically located within the bone. These lesions can appear aggressive and are often characterized by extensive local bony destruction, cortical breakthrough, and soft-tissue expansion
- MRI: extent of neoplasm
- CT scan: absence of bone

Treatment
• Surgery
• Denosumab
- Treatment for unresected GCT

Prognosis
• Spontaneous malignant transformation of GCT is not uncommon
• Malignant transformation
- has been defined as a
sarcoma associated with a benign typical GCT at presentation or as a sarcoma arising at the site of a preexisting GCT.
- osteosarcoma, fibrosarcoma, or malignant histiocytoma. (see the images below).

Question 20

Ewings Sarcoma

Answer 20

Includes:

1. Ewing sarcoma, A skin tumor, and peripheral primitive neuroectodermal tumors.
2. Ewing sarcoma and the peripheral primitive neuroectodermal: reciprocal translocation between chromosomes 11 and 22

Clinical Features
• Localized pain
• Back pain, which may indicate a
paraspinal, retroperitoneal, or deep
pelvic tumor
• Palpable mass
• Systemic symptoms of fever and
weight loss, which often indicate metastatic disease

Physical Examination
• Careful inspection and palpation of
painful sites
- lesions of the long bones can
present with a pathologic
fracture
• Comprehensive neurologic
examination to evaluate asymmetrical weakness, numbness, or pain; tumors close to bone can result in neuropathic pain
• Skin inspection for petechiae or purpura that may be caused by thrombocytopenia due to clinically significant bone marrow metastases
• Pulmonary auscultation for asymmetrical breath sounds, pleural signs, or rales that may indicate lung metastases

Management
• Chemotherapy with alternating
courses of 2 regimens: (1) vincristine, doxorubicin, and cyclophosphamide; and (2) ifosfamide and etoposide
• Neutrophil support
• Red blood cell and platelet support
• Surgery and/or radiotherapy

Prognosis
• The most significant factor currently known to determine the prognosis in patients with Ewing sarcoma is the presence or absence of metastatic disease.
• Primary site of the tumor also is a prognostic factor, with distal extremities being more favorable than those with central or pelvic sites.
• Age younger than 15 years also seems to be a more favorable prognosis.
• Survival of patients with Ewing
sarcoma depends highly on the initial
manifestation of the disease.
• Approximately 80% of patients present with localized disease, whereas 20% present with clinically detectable metastatic disease, most often to the lungs, bone, and/or bone
marrow
• The overall patient survival rate is
60%; for patients with localized disease, however, the survival rate approaches 70%
• Patients with metastatic disease have a long-term survival rate of less than 25%.

Question 21

Chemotherapeutic Regimen

Answer 21

• Vincristine - Primarily causes neuropathy, including constipation, myalgias, arthralgias, and cholestasis
• Doxorubicin - Causes myocardial dysfunction and pancytopenia
• Cyclophosphamide - Causes pancytopenia and a dosage- dependent hemorrhagic cystitis
• Ifosfamide - Similar to cyclophosphamide, although it is associated with an increased incidence of hemorrhagic cystitis, which requires the use of mesna; patients near the end of therapy occasionally develop the Fanconi syndrome of electrolyte wasting.
• Etoposide - Can result in pancytopenia, as well as anaphylactic reactions, and it is implicated in the development of second malignancies, particularly acute myelogenous leukemia
• Combination chemotherapy - Results, in general, in alopecia, nausea, vomiting, and occasionally diarrhea; increased risk of infection from immune suppression; the nutritional and psychological status of patients undergoing this therapy must be closely monitored; effects of chemotherapy such as organ damage, infertility, and risk of secondary malignancy

Question 22

Metastatic Bone Disease

Answer 22

• Cancer that begins in an organ, such
as the lungs, breast, or prostate, and
then spreads to bone
• More than 1.2 million new cancer
cases are diagnosed each year. Approximately 50% of these tumors can spread (metastasize) to the skeleton.

Pathophysiology
• Cells from the primary site must,
through the process of neovascularization or through migration to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce proteolytic enzymes that disrupt the basement membrane.
• The cells then migrate through the basement membrane and float away in the bloodstream to a distant site. The process through which these tumor cells are attracted to a specific site in the body is not completely clear, though type I collagen, a byproduct of bone resorption, has been shown to be a chemotactic factor that attracts tumor cells to bone.

Most Common Sites
1. Breast, Lung, Thyroid, Kidney, Prostate

Clinical presentation
• Pain: Most common symptom
• Fractures: Pathologic fracture • Anemia

Question 23

Metastatic Bone Disease VS Primary Bone Cancer

Answer 23

The diagnosis of metastatic bone disease should not be assumed unless a patient has a known primary cancer that has previously spread to bone.

Treatment
• Radiotherapy
• Spinal surgery
- Decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine.
- Anterior or posterolateral decompression, combined
with anteroposterior reconstruction, may be used in the following: Diagnostic spinal surgery, Cervical spinal surgery, Thoracic and lumbar spinal surgery
• Monoclonal antibody antineoplastic agents (eg, denosumab)
• Calcium metabolism modifiers/bisphosphonates (eg, pamidronate, ibandronate)

Pathophysiology
• Hematogenous spread
• Spread from a contiguous site
following surgery
• secondary infection in the setting of
vascular insufficiency or concomitant neuropathy.

Question 24

Osteomyelitis

Answer 24

• An infection of bone
- can be caused by various micro-organisms that arrive at bone through different routes.
- Spontaneous hematogenous osteomyelitis may occur in otherwise healthy individuals, whereas local microbial spread mainly affects either individuals who have underlying disease (e.g., vascular insufficiency) or patients who have compromised skin or other tissue barriers, with consequent exposure of bone.
• The manifestations of osteomyelitis are different in children and adults. In children circulating microorganisms seed mainly long bones, whereas in adults the vertebral column is the most commonly affected site.
• The most important aim of the management of either type of osteomyelitis is to prevent progression to chronic osteomyelitis by rapid diagnosis and prompt treatment.
• Can be classified by various criteria, including pathogenesis, duration of infection, location of infection, and presence or absence of foreign material.
• Cierny-Mader staging system classifies osteomyelitis according to anatomic site, comorbidity, and radiographic findings, with stratification of long- bone osteomyelitis

Etiology
• The most common primary foci of
infection are the urinary tract, skin/soft
tissue, intravascular catheterization
• Spread from a contiguous source follows either bone trauma or surgical
intervention.
• Wound infection leading to
osteomyelitis typically occurs after cardiovascular intervention involving the sternum, orthopedic repair, or prosthetic joint insertion. Osteomyelitis secondary to vascular insufficiency or peripheral neuropathy most often follows chronic, progressively deep skin and soft tissue infection of the foot.
• The most common underlying condition is diabetes. In diabetes that is poorly controlled, the diabetic foot syndrome is caused by skin, soft tissue, and bone ischemia combined with motor, sensory, and autonomic neuropathy.

Classification: Duration
• Classification of osteomyelitis
according to the duration of infection although ill-defined is useful because the management of acute and chronic osteomyelitis differs.
• Acute hematogenous or contiguous osteomyelitis evolves over a short period.
• Subacute or chronic osteomyelitis lasts for weeks or months before treatment is started.
- Chronic osteomyelitis develops when insufficient therapy leads to persistence or recurrence, most often after sternal, mandibular, or foot infection.

Question 25

Vertebral Osteomyelitis

Answer 25

Vertebral Osteomyelitis
Also referred to as disk-space
•Most com mon manifestation of hematogenous bone infection in adults.
•Also referred to as disk-space, infection, septic diskitis, spinal spondylodiskitis, osteomyelitis

• Pathogenesis

• This designation reflects a pathogenic process leading to involvement of the adjacent vertebrae and the corresponding intervertebral disk
• Microorganisms invade via the segmental arterial circulation in adjacent endplates and then spread into the disk. Alternative routes of infection are retrograde seeding through the prevertebral venous plexus and direct inoculation during spinal surgery, epidural infiltration, or trauma.
• In the setting of implant surgery, microorganisms are inoculated either during the procedure or, if wound healing is impaired, in the early postoperative period

Signs and Symptoms
• Signs and symptoms of vertebral osteomyelitis are nonspecific. Only about half of patients develop fever >38°C (100.4°F), perhaps because analgesic drugs are frequently used by these patients.
• Back pain is the leading initial symptom (>85% of cases).
- The location of the pain corresponds to the site of infection: the cervical spine in ~10% of cases, the thoracic spine in 30%, and the lumbar spine in 60%.
- One exception is involvement at the thoracic level in two- thirds of cases of tuberculous osteomyelitis and at the lumbar level in only one-third. This difference is due to direct mycobacterial spread via pleural or mediastinal lymph nodes in pulmonary tuberculosis.
•Neurologic deficits, such as radiculopathy, weakness, or sensory loss, are observed in about one-third of cases of vertebral osteomyelitis.

Question 26

Osteomyelitis in Long Bones

Answer 26

• A consequence of hematogenous
seeding, exogenous contamination during trauma or peri- operative contamination during orthopedic repairs.
• Its presentation is either acute (with a duration of days to a few weeks) or chronic.
• Children: hematogenous infection
• Adults: Exogenous infection

Microbiology
• S. aureus is most commonly isolated from adult patients
• In rare cases, mycobacteria or fungal
agents such as Cryptococcus species, Sporothrix schenckii, Blastomyces dermatitidis, or Coccidioides species

Clinical Manifestations
- Pain and low-grade fever.: Leading symptoms
• Infection occasionally manifests as clinical sepsis and local signs of inflammation.
• After internal fixation, osteomyelitis can be classified as acute (≤3 weeks) or chronic.
• Acute long-bone osteomyelitis manifests as signs of surgical site infection and impaired wound healing.
• Acute implant-associated infection may also follow hematogenous seeding at any time after implantation of a device.
• Chronic infections are usually caused by low-virulence microorganisms or occur after ineffective treatment of early- onset infection.

Question 27

Periprosthetic Joint Infection

Answer 27

• Implanted foreign material is highly
susceptible to local infection due to local immunodeficiency around the device.
• Infection occurs by either the exogenous or the hematogenous route.
• More rarely, contiguous spread from adjacent sites of osteomyelitis or deep soft-tissue infection may cause periprosthetic joint infection
• The fact that foreign devices are covered with host proteins such as fibronectin favors the adherence of staphylococci and the formation of a biofilm that resists phagocytosis

Question 28

Foot Osteomyelitis

Answer 28

• Usually occurs in patients with
diabetes, peripheral arterial insufficiency, or peripheral neuropathy and after foot surgery
• Foot osteomyelitis is also seen in patients with isolated peripheral neuropathy and can manifest as implant-associated osteomyelitis in patients without comorbidity due to a deep wound infection after foot surgery
• Foot osteomyelitis is acquired almost exclusively by the exogenous route. It is a complication of deep pressure ulcers and of impaired wound healing after surgery.

Epidemiology
• Incidence of diabetic foot infection is
30–40 cases/1000 persons with
diabetes per year
• The condition starts with skin and soft
tissue lesions and progresses to osteomyelitis, especially in patients with risk factors.
• About 60–80% of patients with diabetic foot infection have confirmed osteomyelitis.
• Diabetic foot osteomyelitis increases the risk of amputation. With adequate management of the early stage of diabetic foot infections, the rate of amputation can be lowered.

Risk Factors
Risk factors for diabetic foot infection are
a. Peripheral motor, sensory, and
autonomic neuropathy
b. Neuro-osteoarthropathic deformities
(Charcot foot;
c. Arterial insufficiency;
d. uncontrolled hyperglycemia;
e. disabilities such as reduced vision f. maladaptive 
Behavior