skeletal aspects of gaucher disease: radiological findings and

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Skeletal Aspects of Gaucher

Disease:

Radiological Findings and Functional Use

Laura M. ChiangHarvard Medical SchoolDr. Gillian Lieberman

Image obtained from www.ADAM.com

Sept. 22, 2008

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We will begin with an overview of Gaucher disease. Knowledge of the disease on a

cellular level will aid our understanding of how radiology plays a critical role in the

diagnosis and on-going assessment of the skeletal components of Gaucher

disease.

WELCOME TO AN ONLINE TUTORIAL OF THE SKELETAL

ASPECTS OF GAUCHER DISEASE

L. ChiangDr. G. Lieberman

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Gaucher

Disease:A lysosomal

storage disease with a cascade of systemic effects

• Autosomal

recessive inborn error of metabolism

•

Defective ß-glucosidase accumulation of glucocereboside(lipid membrane component) in macrophages

• Macrophage behavior altered Gaucher cells-Increased inflammatory behavior via cytokine release-Increased metabolic activity-Increased secretion of acid hydrolases

Gaucher

cell with classic “tissue paper”

appearance


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Primarily arises because of:1. Space-occupying accumulation and lesions, such as in the marrow canal

Pathologic link between lipid accumulation and altered cellular function remains unclear, however, aberrant behavior disturbs organ functioning by two mechanisms, as described below.

Organ/Systemic Level:

2. Inflammation

PATHOPHYSIOLOGYL. ChiangDr. G. Lieberman

Cellular level:

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PRIMARY ORGANS/SYSTEMS EFFECTED:

Dependent upon the type of Gaucher

disease, the brain may also be effected

SpleenSpleenRES, platelet sequestration

LiverLiverKupffer

cell accumulation

LungLungInfiltration, Pulmonary Arterial HTN

BoneBoneBone

Bone MarrowBone MarrowBone Marrow

daVinci’s

“Vitruvian

Man”


HepatomegalySplenomegaly

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While in this presentation we will focus upon the skeletal aspects of Gaucher

disease, it is

important to consider the other systemic ramifications in assessing bone involvement.

For example, splenectomy

has been associated with increased

bone involvement

and

destruction, as without splenic

sequestration, Gaucher

cells appear to accumulate more in

the marrow cavities.

FOCUSING ON BONE, WITH A RECOGNITION ON THE WHOLE BODY


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GENETICS & TYPING

Autosomal

Recessive

Three main forms

I: Non-

neuropathic

II: Acute, neuronopathic Neuronal damageDeath in early infancy

III: Chronic, neuropathic Neuronal damageDeath in childhood, early adulthood

•1q21•Almost 200 known SNPs•N370S is ~50% of mutations


www.bioethics.org

Our focus

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TYPE I GAUCHER DISEASE

Prevalence: -

1 in 50,000 –

100,000

-

Highly concentrated within the Ashenazi

Jewish

population, where prevalence can be as high as 1 in 500

Variable “penetrance”:

Even amongst monozygotic twins,

presentation is extremely varied in form and severity ? Environmental influence

Lab studies show increased chitotriosidase

Estimated 20,000 individuals in the US


NOW ON TO OUR FOCUS

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Type I Gaucher

Disease:

The role of radiology in diagnosis and disease assessment


Image obtained from www.ADAM.com

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CC/Identifying information:

INDEX PATIENT: HISTORY AND PRESENTATION

• S/p splenectomy

at age 15• Ascites•True and Pseudo-osteomyelitis•Multiple bone infarcts and necrosis, s/p

BKA

Significant for severe hepatomegaly

without jaundice

•Lab work-up: Elevated LFTs

A 43 yo

male with severe R knee pain and a history of Gaucher

disease, as well

as osteomyelitis

and R below knee amputation


Gaucher

bone crises, as will soon be discussed, are painful infarcts which may be at times confused clinically with symptoms of osteomyelitis

PMH:

Recall how splenectomy

increases the likelihood of bone pathology

PE:

Continual infarcts and infection can often lead to amputation

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PATIENT #1: AP RADIOGRAPH OF THE R KNEE


Even without a detailed knowledge of Gaucher

disease,

we can pick out many gross abnormalities of our patient’s knee film.

Can you find some?

Loss of joint space with severe destruction of the distal femoral and proximal tibial

surfaces.

Mottled bone with areas of lucency

and sclerosis.

Complete misalignment of the joint.

PACS, BIDMC

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We will come back later and discuss our patient’s findings in detail later.

For now, let’s take a step back and look at the characteristics of bone and marrow involvement

in Gaucher

and what we expect to see on radiographic imaging.

WHAT ARE TYPICAL GAUCHER FINDINGS?


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Gaucher

Skeletal Disease: A Helpful Subdivision

Bone Marrow Disease Structural Involvement

Avascular

NecrosisDeformityPathological

Fractures

Thrombocytopenia

Focal LocalGeneralized Osteopenia

Infarcts

Sclerosis Cortical Thinning


These are the radiologic findings we will look for on plain films.

Low platelets are a result of decreased production from out-crowding in the marrow, as well as increased destruction in the spleen. (The oft-seen anemia and leukocytosis

are more a factor of splenic

sequestration than marrow infiltration.)

Think VASCULAR Involvement Think FORM

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These two modalities are the mainstays of imaging, with MR being the gold standard of assessing disease severity and plain films used for pathologic assessment

Assessing Bone Disease SeverityMenu of Tests

1. Plain film radiographs

2. MRI a) Semi-

quantitative fat loss scoring

b) Quantitative Chemical Shift Imaging (QCSI)

3. Nuclear medicine: Tc

-99m-

Sestamibi

4. Dual Energy X-ray Absorptiometry

(DEXA)

5. Less frequently used nuclear medicine studies: Bone scans, Xe

uptake


There are other imaging modalities, as well.

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PLAIN FILMS

•

Osteolytic

destruction of both cortical and trabecular

bone is often seen when destruction

exceeds 50% of matrix

•Can also see sclerotic lesions

•

Often useful in advanced disease or as an initial assessment of gross orthopedic pathology

•Should not be sole method of assessing orthopedic involvement


Let’s look at some other patients to view typical findings.

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COMPANION PATIENT #1: HISTORY

A 40 yo

female with Gaucher

disease about to start enzyme replacement therapy with no current MSK complaints, here for a skeletal survey.


CC:

This patient’s films will show us examples of local involvement

(again, think FORM).

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COMPANION PT #1: PLAIN FILM OF THE R DISTAL FEMUR

•Erylenmyer

flask deformities (flared metaphyseal

regions) are

commonly of the distal femur and proximal tibia

Local Involvement

Erlenmeyer Flask

Deformity

http://www.ispub.com/o

stia/index.php?xmlPrinter

=true&xmlFilePath=journa

ls/ijos/vol6n2/synovitis.x

ml

•Results from an impaired remodeling process

Normal comparison

Image courtesy of Dr. Ferris Hall


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COMPANION PATIENT #1: PLAIN FILM OF THE L DISTAL FEMUR

Local Involvement

Cortical Thinning

Image courtesy of Dr. Ferris Hall


Thought to arise from marrow canal expansion and impaied

remodeling.

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Widening of the marrow canal

COMPANION PATIENT #1:PLAIN FILM OF THE PROXIMAL L FEMUR


PACS, BIDMC

Local involvement

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COMPANION PATIENT #2: HISTORY

A 62 yo

woman with known Gaucher

disease now

presents with sudden onset of wrist pain. PCP sends for films to r/o

fracture.

In contrast to patient #1, this patient’s films will show us examples of focal and generalized involvement.

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Avascular

Necrosis

and Collapse of the Lunate

Diffuse osteopenia

COMPANION PATIENT # 2: PLAIN FILMS OF THE R WRIST

Focal and General Changes

Paracrine

effect on osteoblasts

and osteoclasts


PACS, BIDMCAP film Oblique film

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LATER IMAGING OF COMPANION PATIENT #2

Cortical thinning

Osteopenia

Sclerotic lesions 2° to infarcts

R and L lateral plain films of the distal femur and proximal tibia


Images from PACS

**Note that this lesion was read as probable sclerosis, though enchondroma

could not be definitively ruled out. It is crucial to remember that patients with Gaucher

dz

can also manifest other, unrelated bone pathology.

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Sclerosis secondary to bone infarcts

Widening of marrow canal

Erlenmyer

flask

deformity

Hip replacement after numerous fx

COMPANION PATIENT #3: A HOST OF FINDINGS


Images from PACS

Frontal plain film of the R femoral shaft

Compression of the vessels from outside the wall by Gaucher

cells leads to ischemia. (As explained by Dr. Ferris Hall.)

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SEVERE PROGRESSION


PACS, BIDMC

Replaced femoral head

Sclerotic lesions and deformity within the lumbar spine

Cropped plain film AP view of the lumbar spine and pelvis

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COMPANION PATIENT #4

An 18 y.o. man with Gaucher

disease undergoing skeletal survey


Image courtesy of Dr. Hall

AP plain film of the pelvis

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COMPANION PATIENT #4: RAPID DETERIORATION

A mere two years later…massive hip joint degeneration


Image courtesy of Dr. Hall

Loss of joint space

Unlike osteoarthritis, the destruction to the joint space and loss of cartilage is the result of bone death first, which leads to cartilage damage secondarily from a poorly matched femoral head and acetabulum.

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BACK TO OUR ORIGINAL PATIENT

Complete loss of joint architecture

BKA

Sclerotic andlucent areas

No soft tissue gas


Images from PACS, onlineTherefore, less likely to be osteomyelitis.

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**Radiographs are a poor indication of response to

treatment!

LIMITATIONS OF PLAIN FILMS

But what about early disease? Can it be caught before destruction occurs?

PLUS…


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AN IMPORTANT NOTE ON THERAPY

Parental enzyme replacement-

An “ideal”

disease for enzyme replacement

because of phagosome

fusion with the lysosome

-Genzyme, FDA approved1991-Now standard of care

Deficient Lysosome

ß-glucosidase

with terminal mannose

Supplemented, EffectiveLysosome

Mannose receptor

Alternative: Substrate reduction

Rapid response seen in visceral organs

MSK response may be delayed-

Damaged bones may

not heal with enzyme replacement alone


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If plain films are not sensitive enough to detect enzyme therapy response, but therapeutic dosings

are often

based upon bone involvment, how else can bone disease of Gaucher

be assessed?

AN IMAGING AND THERAPEUTIC DILEMMA…


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MAGNETIC RESONANCE

• Useful in quantifying marrow replacement by Gaucher

cells

• Traditionally, femur, spine, and pelvis are imaged

•

T1 weighted MR shows reduced fat signal (decreased signal intensity); T2 shows reduced water signal OR increased inflammation

The gold standard for assessing bone marrow involvement


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1.

Bone Marrow Burden Score:

Semi-quantitative evaluation of

marrow loss; indirectly represents Gaucher

cell invasion-

Higher score (max 15) is indicative of more severe disease

2. QCSI (Dixon):Uses a specific fat-sensitive sequence algorithm to quantify marrow replacement as a “fat fraction”

-Lower score more infiltrationAdvantages: Sensitive modality to determine early therapy responseCaveats: Not widespread, technology not included on standard MR

packages.

MAGNETIC RESONANCE (cont.)


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BONE MARROW BURDEN SCORING

Isotense/Hyperintense

(Normal)0

Slightly hypointense 1

Hypointense 2

*Decreasing fat*Decreasing marrow*Increasing Gaucher

infiltration

T1Fat appears

Hyperintense

•Developed in 2003 as a more easily applied assessment

•Validated to be accurate in representing bone disease severity in comparison with Dixon scoring even with radiologists not specifically trained in Gaucher

disease

•Images of femur and spine assessed and scored

Femur rubric


Table adapted from Maas, et al.

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BONE MARROW BURDEN SCORING: Companion Patient #5

Slightly hypointense

= 1


Image from Maas, et al.

T1 weighted coronal MR of the femur

Mildly reduced marrow intensity in the femoral necks.

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BONE MARROW BURDEN SCORING: Companion Pt. 6

Severe Hypointensity

= 2



T1 weighted coronal MR of the femur

Significant loss of marrow intensity in multiple areas, including the femoral neck, diaphysis

and

distal epiphysis.

36Lateral T1 Weighted MR of Spine

Mild

Severe

Images from Maas, et al.


BONE MARROW BURDEN SCORING: T1 Spinal Images

Lateral T1 Weighted MR of Spine

Mild hypointensity

of the spinal marrow.

Nearly complete lack of marrow intensity.

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Hyperintense 2

Slightly hyperintense 1

Isotense

(Normal) 0

Slightly hypointense 1

Hypointense 2

Mixed type (femur only) 3

T2“Water-Weighted”

Acute inflammation, infarction

Decreased healthymarrow, fibrosis

*Note double-tailed scale**Increased intensity and/or mixed intensity is believed to

represent a more active presentation of destruction.

BONE MARROW BURDEN SCORING: T2 Rubric


Table adapted from Maas, et al.

38Coronal T2 weighted MR of the femurs

Mild Hypointensity

= 1




Mildly reduced fluid intensity in the femoral necks and shaft.

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Mixed type

ACUTE




Coronal T2 weighted MR of the femurs

Significant areas of both increased and decreased fluid intensity throughout the L femur.

Also note distal involvement

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BONE MARROW BURDEN SCORING: OTHER KEY MODIFIERS

Diaphysis 1

Proximal epiphysis 2

Distal epiphysis 3

Femur: Location of Involvement

Lumbar Spine: Infiltration Pattern

Patchy 1

Proximal epiphysis 2

Distal epiphysis 3


Tables adapted from Maas, et al.

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A CRITICISM OF MR ASSESSMENT…

MR assesses reduction in normal marrow presence, not an increase in pathological function

In addition, bone response to enzyme therapy may be slow to visualize

What other imaging modalities exist?


42Images from Mariani, et al.

EARLIER DETECTION: TC-99M SESTAMIBI

-

Mariani, et al. showed high correlation with uptake and disease severity; effective in assessing therapeutic improvement

-

Tc-sestamibi

taken up by cells based upon cellular metabolism, retained in mitochondria (commonly used for myocardial perfusion studies)


E = ExtensionI = Intensity

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Caveats:•Not advised in pediatric patients•Poor resolution•Confounding of bone thickness

•Focus on femur and tibia to avoid diffuse uptake of Tc-sestamibi

in

abdomen, obscuring spine and pelvic involvement

TC-99M-SESTAMIBI: NOTES AND CAVEATS


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DEXADual Energy X-ray Absorptiometry

may be used to

assess for osteopenia, however, it is of little use in pediatric patients.

OTHER IMAGING MODALITIES

Xenon-scanning

Inhaled radioactive agent shows increased uptake in areas of Gaucher

cell activity


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NUCLEAR MEDICINE –

WHOLE BODY BONE SCAN

Bone scan from Patient #1 prior to his amputation

•Can be used to evaluate osteomyelitis

in a patient with Gaucher

disease

•Increased uptake in the L distal tibia and distal condyles

of the the

L

femur


Image courtesy of Dr. Kevin Donohoe

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SUMMARY: PRIMARY ROLES OF RADIOLOGY IN GAUCHER DISEASE MANAGEMENT

1.

Immediate stabilization and diagnosis of structural disease

2.

Assessment of long-term therapeutic goalsa)

Bone marrow burden and response to enzyme replacement

b)

Serial MRs

reveal semi-quant dec

in BMB score w/ tx

3.

Thorough MSK evaluation every 2 years to assess change

4.

MSK events –

fracture, pain, bone crisis, r/o

infarct use of

plain films


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References:


1.

Cox TM, Aerts

JM, Belmatoug

N, et al. Management of non-neuronopathic

Gaucher

disease with special reference to pregnancy, splenectomy, bisphosphonate

therapy, use of biomarkers and bone disease monitoring. J Inherit Metab

Dis

2008;31(3):319-36.2.

Hollak

C, Maas M, Akkerman

E, den Heeten

A, Aerts

H. Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher

disease. Blood Cells Mol Dis

2001;27(6):1005-12.3.

Johnson LA, Hoppel

BE, Gerard EL, et al. Quantitative chemical shift imaging of vertebral bone marrow in patients with Gaucher

disease. Radiology 1992;182(2):451-5.4.

Maas M, van Kuijk

C, Stoker J, et al. Quantification of bone involvement in Gaucher

disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging--initial experience. Radiology 2003;229(2):554-61.5.

Maas M, Hangartner

T, Mariani

G, et al. Recommendations for the assessment and monitoring of skeletal manifestations in children with Gaucher

disease. Skeletal Radiol

2008;37(3):185-8.6.

Mariani

G, Filocamo

M, Giona

F, et al. Severity of bone marrow involvement in patients with Gaucher's

disease evaluated by scintigraphy

with 99mTc-sestamibi. J Nucl

Med 2003;44(8):1253-62.7.

Olsen EO, McHugh K, Vellodi

A. Routine magnetic resonance imaging of the spine in children with Gaucher

disease: does it help therapeutic management? Pediatr

Radiol

2003;33(11):782-5.8.

Raza

S, McHugh K. Unusual radiological manifestations of Gaucher

disease. Pediatr

Radiol

2008;38(3):352.9.

Robertson PL, Maas M, Goldblatt

J. Semiquantitative

assessment of skeletal response to enzyme replacement therapy for Gaucher's

disease using the bone marrow burden score. AJR Am J Roentgenol

2007;188(6):1521-8.10.

Rosenthal DI, Barton NW, McKusick

KA, et al. Quantitative imaging of Gaucher

disease. Radiology 1992;185(3):841-5.11.

Wenstrup

RJ, Roca-Espiau

M, Weinreb

NJ, Bembi

B. Skeletal aspects of Gaucher

disease: a review. Br J Radiol

2002;75 Suppl

1:A2-12.

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Many thanks to:

Gillian Lieberman, MDFerris Hall, MDKevin Donohoe, MDEast Campus Film ServicesMaria LevantakisLarry Barbaras


skeletal aspects of gaucher disease: radiological findings and

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