CHAPTER 1

INTRODUCTION

Buerger's disease is also called thromboangiitis obliterans is a rare disease of the

small to medium sized arteries and veins in the arms and legs. Buerger's disease,

is a nonatherosclerotic, segmental, inflammatory disease which is characterized by

highly cellular and inflammatory occlusive thrombus with relative sparing of the

blood vessel wall. Since oxygenated blood cannot get to the tissues, this will

eventually damages or destroys skin tissues and may lead to infection, peripheral

skin ulcers and gangrene along with intractable pain.1

Buerger's disease was first reported by Felix von Winiwarter in 1879 in Austria.

Leo Buerger working at Mount Sinai Hospital in New York, reported the results

of pathologic examination of 11 amputated limbs from young men in whom

progressive veno-occlusive disease resulted in amputations. Buerger termed the

entity ‘Thromboangiitis Obliterans’.1,2

Buerger's disease with the incidence of 1/8000 people, which is much more

common in men with the typical age of onset younger than 40 years than in

women, and is closely associated with heavy cigarette and/or cannabis smoking,

or with tobacco chewing. Buerger's disease appears to be more common in Asians

and in the Middle East example Japan, India and Manipur, and is rare among

African-Americans, and is very rare in children.1

In North America, the prevalence of this disease has declined in the past 30 years

due to a decline in smoking. In other parts of the world, the prevalence of this

disease among patients with arterial occlusive disease varies widely, ranging from

0.5 to 5.6 percent in Western Europe to as high as 45 to 63 percent in India. Of

patients diagnosed with Buerger’s disease, 70 to 91 percent are male and 11 to 30

percent are female. However, there are reports of increasing prevalence of disease

in women, possibly due to the increasing use of cigarettes among women.1,2

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CHAPTER 2

CONTENT

2.1 Etiopathogenesis

The etiology of thromboangiitis obliterans (Buerger’s disease) is not known

although there is a definite relationship to cigarette smoking / tobacco use in

patients with the disease. This implies that tobacco plays a role in the

pathogenesis of the disease or that tobacco is a highly contributive factor at the

very least. Moreover, all types of tobacco have been implicated to the disease. The

specific substance however hasn’t been yet defined.3,4

The role of cannabis (marijuana) was recently reconsidered, resulting in a specific

type of arteritis (cannabis arteritis) which is very similar in term of clinical

features and pathological lesions to Buerger’s disease despite of some

unconvincing differences. This makes the role of cannabis remains controversial.

Attempts to investigate the possibility of autoimmune mechanism have also been

carried out. Hypersensitivity to type I and III collagen associated with the

presence of anti-collagen or anti-elastin antibodies has been shown but these

conditions isn’t specific and haven’t been confirmed. It is also possible that such

conditions occur secondarily to inflammatory modification rather than being the

cause.3

In the initial stages, polymorphonuclear leukocytes infiltrate the walls of small

and medium sized arteries and veins. The internal elastic lamina is preserved and

thrombus may develop in the vessel lumen. As the disease progresses,

mononuclear cells, fibroblast, and giant cells replace the neutrophils. At the later

stages, perivascular fibrosis and recanalization take place. These conditions lead

to the blockage of blood flow to parts of the body (primarily upper and lower

limb) supplied by the affected blood vessel resulting in ischemia. In severe

ischemia, painful ulcerations and gangrene may develop.4

2

2.2 Clinical Manifestation

Buerger’s disease generally begins in young male smokers with hand or foot

ischaemia due to distal small arteries and veins involvement of the limbs.3 The

other clinical manifestation are :

a. Ischaemia of the lower and upper limb

The commonest presenting symptoms are ischaemic manifestations of the

lower limbs. Claudication in the arch of the foot is an early sign and is

suggestive of, or even specific to Buerger’s Disease. This condition is a

manifestation of infrapopliteal vessel occlusive disease. Rest pain

generally occurs on the forefoot, causing continuous pain and obliging

patients to sleep with their legs dangling downwards. The intensity of this

pain often contrasts with the apparently limited, almost benign appearance

of the ischaemic trophic lesions. Superinfection often occurs and the

lesions progress towards necrosis and distal gangrene. And also there will

be involvement of ischaemia of the upper limb in 40-50% patients. The

hands and feet of patients with the disease are usually cool and mildly

edematous.3,5

b. Superficial thrombophlebitis

Superficial thrombophlebitis is observed in 40–60% of cases. This

superficial thrombophlebitis is migratory and recurrent and affects the

3

Figure 1. Healed ischaemic lesions of the forefoot in a young patient with Buerger’s disease1

arms and legs. Migrating phlebitis (phlebitis saltans) in young patients is

therefore highly suggestive of Buerger’s Disease.3,5

c. Paresthesias lower and upper limb

Paresthesias (numbness, tingling, burning, hypoesthesia) of the feet and

hands and impaired distal pulses in the presence of normal proximal pulses

are usually found in patients with the disease.5

d. Systemic sign and symptom

Systemic signs and symptoms are very rare in patients with Buerger’s

Disease. Buerger’s Disease may begin with joint manifestations. Patients

present recurrent episodes of arthritis of the large joints, with transient,

migratory single-joint episodes accompanied by local signs of

inflammation. The wrists and knees are the most frequently involved

joints. The duration of signs and symptoms ranges from 2 to 14 days. The

arthritis is nonerosive. Arthritis disappears definitively with the

appearance of ischaemic signs.3

2.3 Diagnosis

Since the specificity of Buerger's disease is characterized by peripheral ischemia

of inflammatory nature with a selflimiting course, diagnostic criteria should be

discussed from clinical point of view. Several different criteria have been

proposed for the diagnosis of thromboangiitis obliterans. 6

a. Diagnostic criteria of Shionoya (1998)

smoking history;

onset before the age of 50 years;

infrapopliteal arterial occlusions;

either arm involvement or phlebitis migrans;

absence of atherosclerotic risk factors other than smoking.

b. Diagnostic criteria of Olin (2000)

age under 45 years;

current or recent history of tobacco use;

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the presence of distal-extremity ischemia indicated by claudication,

pain at rest, ischemic ulcers or gangrenes and documented by non-

invasive vascular testing;

exclusion of autoimmune diseases, hypercoagulable states and

diabetes mellitus;

exclusion of a proximal source of emboli by echocardiography or

arteriography;

consistent arteriographic findings in the clinically involved and non-

involved limbs.

c. Diagnostic methods

No specific laboratory test for diagnosing Buerger's disease is available.

Unlike other types of vasculitis, in patients with Buerger's disease the

acute-phase reactions (such as the erythrocyte sedimentation rate and C-

reactive protein level) are normal. Recommended tests to rule out other

causes of vasculitis include a complete blood cell count; liver function

tests; determination of serum creatinine concentrations, fasting blood sugar

levels and sedimentation rate; tests for antinuclear antibody, rheumatoid

factor, serologic markers for CREST (calcinosis cutis, Raynaud

phenomenon, sclerodactyly and telangiectasia) syndrome and scleroderma,

and screening for hypercoagulability. Screening for hypercoagulopathy

including antiphosolipid antibodies and homocystein in patients with

Buerger's disease, is recommended. If a proximal source of embolization is

suspected, transthoracic or transesophageal echocardiography and

arteriography should be performed. Angiographic findings include severe

distal segmental occlusive lesions. The more proximal arteries are normal.

The role of modern imaging methods, such as computerised tomography

(CT) and magnetic resonance imaging (MRI) in diagnosis and differential

diagnosis of Buerger's disease still remains unsettled. In patients with leg

ulceration suspected of having Buerger’s Disease, the Allen test should be

performed to assess the circulation in the hands and fingers. 6

5

d. Allen’s Test

In the Allen test, the patient is instructed to make a fist, which will empty

the blood from the hand and fingers (Panel A). The examiner’s thumbs are

then pressed down across the thenar and hypothenar eminences to the wrist

to occlude the radial and ulnar arteries. The patient then opens the hand,

making sure not to overextend the fingers, since this can cause a false

positive result. The pressure on the ulnar artery is then released while the

radial artery is still compressed (Panel B). The hand does not fill with

blood. Note the paleness of the hand on the right compared with the hand

on the left, indicating occlusion of the ulnar artery distal to the wrist

(positive test result). If there is prompt return of color to the hand

(indicating a negative test result), the pressure on the radial artery is

released while the ulnar artery remains compressed.7 An abnormal Allen

test result indicating distal arterial disease and establishing involvement of

the upper extremities in addition to the lower extremities helps

differentiate thromboangiitis obliterans from atherosclerotic disease.5

e. Histopathology

While the clinical criteria of Buerger’s Disease are relatively well defined,

there is no consensus on the histopathological findings. It is particularly

6

difficult to distinguish morphologically Buerger’s Disease from

ateriosclerosis obliterans (ASO). Histopatological findings are also known

to vary according to the duration of the disease. The findings are most

likely to be diagnostic in the acute phase of the disease, most commonly at

biopsy of a segment of a vessel with superficial thrombophlebitis. Other

histopathological phases, such as intermediate (subacute) and endstate

(chronic) phases, have been described. The acute-phase lesions include an

occlusive, highly cellular, inflammatory thrombus with less inflammation

in the walls of the blood vessels. Polymorphonuclear leukocytes,

microabscesses and multinucleated giant cells may exist. When Buerger’s

Disease occurs in unusual locations, the diagnosis should be made only

when histopathological examination identifies the acute-phase lesion. In

the intermediate phase of disease there is progressive organization of the

thrombus in the arteries and veins. When only organized thrombus and

fibrosis are found in the blood vessels, the phase is considered to be end-

stage.6

7

Figure 2. Typical Acute Histologic Lesion of Buerger’s Disease in a Vein with

Intens Thromboangiitis, Showing a Microabscess in the Thrombus and Two

Multinucleated Giant Cells (Arrows) (Hematoxylin and Eosin, x400).7

f. Imaging

Arterial duplex, CT angiography, magnetic resonance angiography, and

digital subtraction angiography are all useful radiological imaging

techniques that show medium and small vessel occlusion, often with

'corkscrew'-shaped collateral vessels (Martorell's sign). An angiogram,

helps to see the condition of arteries. A special dye is injected into an

artery, after which undergo X-rays or other imaging tests. The dye helps to

delineate any artery blockages that show up on the images. Buerger's

disease almost always affects more than one limb, and this test may detect

early signs of vessel damage.3

Characteristic angiographic findings include extensive arterial occlusive

disease accompanied by the development of corkscrew collateral vessels.

More than one limb is usually affected with predominantly the lower

limbs. The small and medium-sized arteries are affected in a segmental

and often bilateral manner. In the legs, infrapopliteal lesions predominate,

affecting one or several vascular beds, but particularly the anterior and

posterior tibial arteries. In the arms, the lesions primarily concern the

radial and cubital arteries, together with the palmar arcades and the digital

arteries.3

Ultrasound is also used as one of the diagnosis of Buerger’s disease. It is

used to identify the site of arterial occlusions.3

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Figure 3. Biopsy of a subcutaneous nodule of superficial thrombophlebitis:

moderate non-specific inflammatory infiltrate mostly located in the thrombus.3

2.4 Differential diagnosis

A clinical diagnosis of Buerger’s disease requires exclusion of disorders that may

mimic the disease. The most important disorder to exclude is atherosclerotic

vascular disease, thromboembolic disease, and autoimmune disease such as

scleroderma or CREST (calcinosis, Raynaud phenomenon, esophagal dysmotility,

sclerodactyly, telanglectasia) syndrome. In most cases the combination of

serological testing, echocardiography and arteriography can exclude these

disorders and help establish the diagnosis of Buerger’s disease.8

A scleroderma or CREST syndrome diagnosis is typically suggested by clinical

presentation, including skin findings. Nailfold capillaroscopy may be performed

and is usually quite distinctive in patients with these disorders. However,

characteristics findings of capillary loop dropout in scleroderma and CREST

syndrome may be observed in some patients with Buerger’s disease. Detection of

serological markers such as anti-ACL-70 or anticentromere antibodies provides

further evidence for scleroderma or CREST syndrome.8

Clinicians should evaluate patients for features of other autoimmune diseases such

as systemic lupus erythematosus, rheumatoid arthritis, and other vasculitides.

Serological markers are often helpful in excluding such disorders. Patients with

antiphospholipid antibody syndrome pose a particular diagnostic challenge

because they may be present in both arterial and venous thrombotic events.

Antiphospholipid antibody syndrome is suggested by detection of lupus type

anticoagulants or presence of elevated titres of anticardiolipin antibodies. Of note,

lupus anticoagulant and anticardiolipin antibodies can be detected in some

patients with Buerger’s disease, but may also indicate an unrelated thrombophilia.

Pathological examination can clearly differentiate between the two disorders

because antiphospholipid antibody syndrome is characterized by the presence of

bland thrombosis, whereas Buerger’s disease results in an inflammatory

thrombus.8

Thromboangitis obliterans (Buerger’s disease) is differentiated from other

vasculitides in that it results in distal extremity ischemia, whereas patients with

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Takayasu’s arthritis or GCA present with more proximal arterial involment.

Arteriographic features of Buerger’s disease are also quite distinctive from that

observed in Takayasu’s arteritis or giant cell arteritis. In addition, vasculitides

such as Takayasu’s arteritis and GCA are typically associated with elevations in

inflammatory markers including erythrocyte sedimentation rate and C-reactive

protein.8

Clinicians evaluating patients with suspected Buerger’s disease should inquire

about possible ergotamine or cocaine abuse, in addition to disorders of repetitive

mechanical trauma such as vibration induced vascular injury and hypothenar

hammer syndrome. Serum ergotamine levels can be obtained to exclude vascular

injury caused by this drug. Because it can mimic Buerger’s disease, all patients

should be questioned about cocaine abuse. A complete toxicology screen is

recommended in patients who present with a history and physical compatible with

Buerger’s disease, especially if they deny tobacco use8.

2.5 Management

a. Pharmacology

The first and foremost treatment for Buerger’s disease is smoke cessation

and behavioural therapy where complete discontinuation of smoking

cigarette and tobacco is advised. As for pharmacological management,

there are certain treatment options.

In acute complaints, vasodilation caused by medicines and medical

procedures appear to have reduced the painful sensation. Prostaglandins

for example Limaprost5 are vasodilators that relieves pain but helps little in

improving the disease’s course.

In chronic cases, treatment with intravenous Iloprost, which is a

prostaglandin analogue, is used. Iloprost dilates systemic and pulmonary

arterial vascular beds, aiding in vasodilation.9 It has been proved to be

effective in improving the symptoms and accelerating the resolutions of

the distal extremity trophic changes, and thus, reducing the rate of

amputations. Intravenous Iloprost also helps to slow down progressive

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tissue loss, in this case, reducing amputation caused by gangrene. The

duration of the treatment is typically 3 days. This is usually repeated every

8 to 12 weeks. Lumbar sympathectomy helps by reducing vasoconstriction

and increases blood flow to limbs and also aids in healing and giving relief

from pain of ischemic ulcers.10 Bypass can sometimes be helpful in treating

limbs with poor perfusion secondary to this disease. Thrombolytic therapy

has shown positive results in treating but is still in the research stage.

The usage of antibiotics, non-steroidal, steroidal, narcotic analgesics,

Calcium channel blockers, anti-inflammatory agents like corticosteroids,

anti-platelet drugs and anti-coagulants to treat ulceration, infection and

inflammation have been proven to be ineffective and in some cases,

dangerous.11However, a few cases have been proven to respond to these

drugs as a pain relief therapy, but only when used in low dosage

intermittent form.

b. Non-pharmacology

The most effective treatment for Buerger’s disease is smoking cessation. It

is therefore essential that patients diagnosed with Buerger’s disease stop

smoking immediately and completely to prevent progression of the disease

and avoid amputation. Smoking as few as 1 or 2 cigarettes daily, using

chewing tobacco or even using nicotine replacements may keep the disease

active.6,5

Given the diffuse segmental nature of Buerger’s disease and the fact that

the disease primarily affects small- and medium-sized arteries, surgical

revascularization for Buerger’s disease is usually not feasible and is

extremely rare.7,5 However supportive care should be directed towards

maximizing blood supply including avoiding vasoconstriction from

exposure to cold or drugs.6 Several strategies are important in prevention

of complications from Buerger’s disease, including the use of well-fitting

protective footwear to prevent foot trauma and thermal or chemical injury

and early aggressive treatment of extremity injuries to protect against

infections.5

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The role of bypass to the distal arteries for patients with Buerger’s disease

remains controversial because of the high incidence of graft failure.

However, if the patient has severe ischemia and there is a distal target

vessel, bypass surgery with the use of an autologous vein should be

considered. Sympathectomy decreases arterial spasm, which is the reason

for assessing this procedure in patients with Buerger’s disease.

Laparoscopic method for sympathectomy has also been used. However,

sympathectomy only seems to provide short-term pain relief and promotes

ulcer healing in some patients with Buerger’s disease, but carries no long-

term benefit. Spinal cord stimulator and vascular endothelial growth factor

gene therapy have been used experimentally in patients with Buerger’s

disease with promising results.6 Ultimate surgical therapy for refractory

Buerger disease (in patients who continue smoking) is distal limb

amputation for non-healing ulcers, gangrene, or intractable pain. Avoid

amputation when possible, but, if it is necessary, perform the operation in

a way that preserves as much of the limb as possible.5

2.6 Complications

Buerger's disease typically affects the extremities leading to claudication,

ischemic ulcers, and digital infarction. If Buerger's disease worsens, blood flow to

your arms and legs decreases. This is due to blockages that make it hard for blood

to reach the tips of your fingers and toes. Tissues that don't receive blood don't get

the oxygen and nutrients they need to survive. This can cause the skin and tissue

on the ends of your fingers and toes to die (gangrene). Signs and symptoms of

gangrene include black or blue skin, a loss of feeling in the affected finger or toe,

and a foul smell from the affected area. Gangrene is serious condition that usually

requires amputation of the affected finger or toe. Buerger’s disease also can

develop any infection and ulceration due to necrosis of the tissue.12,13,14

2.7 Prognosis

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The disease is progressive in patients who do not stop smoking. Among patients

with who quit smoking, 94% avoid amputation; among patients who quit smoking

before gangrene develops, the amputation rate is near 0%. If the condition is

diagnosed early, a fair outcome including partial healing of the affected area and

some restoration of blood flow can sometimes be achieved if the individual quit

from smoking. This is contrast to patients who continue smoking, for whom there

is a 43% chance that an amputation will be required sometime during a 7- to 8-

year period. It is not uncommon for patients with Buerger disease who continue to

smoke to require multiple amputations, and reports have even been made of

patients who have required bilateral above-knee and above-elbow amputations.

While smoking cessation generally removes the need for limb amputation,

patients may continue to have claudication or Raynaud phenomenon even after

complete discontinuation of tobacco use.5,14

13

CHAPTER 3

CONCLUSION

Buerger's disease, is a nonatherosclerotic, segmental, inflammatory disease which

is characterized by highly cellular and inflammatory occlusive thrombus with

relative sparing of the blood vessel wall. Since oxygenated blood cannot get to the

tissues, this will eventually damages or destroys skin tissues and may lead to

infection, peripheral skin ulcers and gangrene along with intractable pain. The

etiology of thromboangiitis obliterans (Buerger’s disease) is not known although

there is a definite relationship to cigarette smoking / tobacco use in patients with

the disease. Clinical manifestations include hand or foot ischaemia due to distal

small arteries and veins involvement of the limbs, ischaemia of the lower and

upper limb, superficial thrombophlebitis, parasthesias lower and upper limb, and

systemic sign and symptom. The diagnosis of Buerger’s disease is can be done by

history taking and physical examination to see the clinical manifestation but it is

difficult caused by the lack of specific clinical, radiological and biological

features, the rarity of histopathological evidence of inflammatory vascular lesions

and the lack of diagnostic criteria validated or accepted internationally. The

diagnosis criteria that can be used such as Shionoya’s and Olin’s criteria.

Therefore, the diagnosis is made at the end of investigations aiming to eliminate

differential diagnoses and to search for other signs of the disease. The most

important treatment for Buerger’s disease is smoking cessation, but

pharmacological treatment such as prostaglandins analogue as vasodilator and

thrombolytic drugs can be used. Surgical therapy also can be done as a supporting

therapy. The complication of Buerger’s disease includes ulceration, gangrenes,

infections, and amputation. The risk of amputation is higher in patients who

continue smoking and significantly lower after the patients stop smoking.

14