GCA (,,dark halo" sign). However, findings of temporal artery US did not correlate with eye complications. For this reason, Color Doppler Imaging of the retrobulbar vessels may be helpful to detect the blood flow in the orbital vessels, especially in cases of opacity of the medium, or when the clinical appearance of ophthalmologic complications in temporal arteritis is athypical. The Spectral Doppler Analysis of the orbital vessels in GCA reveales low blood velocities, especially end-diastolic velocities, and high resistance index in all retrobulbar vessels, in both orbits, for all patients (especially on the affected side).

Corticosteroids are the cornerstone of treatment in GCA. Alternative corticosteroid- sparing drugs, in particular MTX, should be considered in GCA patients with severe corticosteroidrelated side effects and/or in patients who require prolonged corticosteroid therapy due to relapses of the disease.

**Key words**: Giant cell arteritis, temporal headache, superficial temporal artery biopsy, "dark halo" sign, central retinal artery obstruction, arteritic anterior ischaemic optic neuropathy.

#### **8. References**

GCA (,,dark halo" sign). However, findings of temporal artery US did not correlate with eye complications. For this reason, Color Doppler Imaging of the retrobulbar vessels may be helpful to detect the blood flow in the orbital vessels, especially in cases of opacity of the medium, or when the clinical appearance of ophthalmologic complications in temporal arteritis is athypical. The Spectral Doppler Analysis of the orbital vessels in GCA reveales low blood velocities, especially end-diastolic velocities, and high resistance index in all

Corticosteroids are the cornerstone of treatment in GCA. Alternative corticosteroid- sparing drugs, in particular MTX, should be considered in GCA patients with severe corticosteroidrelated side effects and/or in patients who require prolonged corticosteroid therapy due to

**Key words**: Giant cell arteritis, temporal headache, superficial temporal artery biopsy, "dark halo" sign, central retinal artery obstruction, arteritic anterior ischaemic optic neuropathy.

Agard C, Barrier JH, Dupas B, et al. (2008): Aortic involvement in recent-onset giant cell

Ahuja R.M., Chaturvedi S., Elliot A., et al. (1999) – Mechanism of retinal arterial occlusive

Arida A, Kyprianou M, Kanakis M, Sfikakis PP (2010): The diagnostic value of

Arnold A.C. (2004) - Chapter 191 - Ischemic optic neuropathy, in *Ianoff M., Duker J.S.*, ed.,

Berger CT, Wolbers M, Meyer P, et al.(2009): High incidence of severe ischaemic

Breuer GS, Nesher R, Nesher G (2009): Effect of biopsy length on the rate of positive temporal artery biopsies. *Clin Exp Rheumatol* 2009, 27(Suppl 52):S10–S13. Collignon-Robe N.J., Feke G.T., Rizzo J.F. (2004) - Optic nerve head circulation in

Connolly B.P., Krishnan A., Shah G.K., Whelan J., Brown G.C., Eagle R.C. Jr., Shakin E.P.

Duhaut P, Pinède L, Bornet H, et al.(1999): Biopsy proven and biopsy negative temporal

size, and platelet inhibition. *Rheumatology* (Oxford) 2009, 48:258–261. Bley TA, Reinhard M, Hauenstein C, et al.(2008): Comparison of duplex sonography and

tomodensitometric scan. *Arthritis Rheum* 2008, 59:670–676.

second meta-analysis. *BMC Musculoskelet Disord* 2010, 11:44.

Ophtalmology, second edition, Mosby, 2004:1268-1272.

(temporal) arteritis. *Arthritis Rheum* 2008, 58:2574–2578.

control study. *J Rheumatol* 1999;26:361–9.

(temporal) arteritis: a case-control prospective study using helical aortic computed

disease in African, American and Caucasian patients, *Stroke* 1999 Aug; 30(8): 479-84.

ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a

complications in patients with giant cell arteritis irrespective of platelet count and

high-resolution magnetic resonance imaging in the diagnosis of giant cell

nonarteritic anterior ischemic optic neuropathy and optic neuritis, *Ophthalmol*. 2004;

(2000) – Characteristics of patients presenting with central retinal artery occlusion with and without giant cell arteritis, *Can. J. Ophthalmol*. 2000 Dec; 35(7):379-84. Duhaut P, Bosshard S, Calvet A, Pinede L, Demolombe-Rague S, Dumontet C, et al (1999),

for the Groupe de Recherche sur l'Arterite a` Cellules Geantes. Giant cell arteritis, polymyalgia rheumatica, and viral hypotheses: a multicenter, prospective case-

arteritis: differences in clinical spectrum at the onset of the disease. Groupe de Recherche sur l'Artérite à Cellules Géantes. *Ann Rheum Dis* 1999, 58:335–341.

retrobulbar vessels, in both orbits, for all patients (especially on the affected side).

relapses of the disease.

111: 1663-72.

**8. References**

**17**

**Kawasaki Disease in a Tertiary Pediatric**

Chrysanthi L. Skevaki1,2, Elpida Charalampaki1, Georgia Pinna1, Michail Pararas2, Athanassios Tsakris2 and Dimitrios A. Kafetzis1 *1P & A Kyriakou" Children's Hospital, Second Department of Pediatrics,*

*2Department of Microbiology, School of Medicine, University of Athens, Athens,*

Kawasaki disease (KD), an acute febrile mucotaneous lymph node syndrome, was initially described as a distinct clinical entity in 1967 by the Japanese physician, Dr Tomisaku Kawasaki (Kawasaki et al., 1974). Today the disease is recognized as an acute self - limited vasculitis of unknown etiology that predominantly affects young children of all racial and ethnic groups (Shulman et al., 1987). It is characterised by prolonged fever unresponsive to antibiotics, a polymorphous skin rash, erythema of the oral mucosa, lips and tongue, erythema of the palms and soles, bilateral conjunctival injection and cervical lymphadenopathy. This disease has become the leading cause of acquired heart disease among children in the developed world, with coronary artery aneurysms occurring in up to

Approximately 85% of children with KD are aged less than five years, with a relatively higher incidence reported for boys (Chang, 2002). Patients either younger than three months or older than five years are scarcely encountered and are regarded to be at a higher cardiovascular risk (Burns et al.,1986; Stockheim et al., 2000). Occurrence beyond late childhood is extremely rare. Less than 100 cases of adult KD have actually been reported in the world literature since the recognition of this illness, according to a 2010 case series and review of the disease in adults (Gomard – Mennesson et al., 2010; Wolff et al., 2007). In fact, many of the reported cases in adults have been misdiagnosed as KD, while the correct

diagnosis was toxic shock syndrome ( Meissner & Leung 1995; Shulman et al., 1995).

The epidemiology of KD is best documented in Japan, where regular nationwide epidemiological surveys are being conducted every two years since 1970. Based on the recent 20th survey, the number of patients with KD are continuously increasing, with an average annual incidence rate in 2007 and 2008 that reached 217/ 100.000 children younger

**1. Introduction**

**2. Epidemiology**

25% of untreated cases (Newburger & Fulton, 2004).

**Referral Center in Athens, Greece and**

**Review of the Literature**

*University of Athens,*

*Greece*

## **Kawasaki Disease in a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature**

Chrysanthi L. Skevaki1,2, Elpida Charalampaki1, Georgia Pinna1, Michail Pararas2, Athanassios Tsakris2 and Dimitrios A. Kafetzis1 *1P & A Kyriakou" Children's Hospital, Second Department of Pediatrics, University of Athens, 2Department of Microbiology, School of Medicine, University of Athens, Athens, Greece*

## **1. Introduction**

330 Advances in the Diagnosis and Treatment of Vasculitis

Lee MS, Smith SD, Galor A, Hoffman GS (2006): Antiplatelet and anticoagulant therapy in

Mahr AD, Jover JA, Spiera RF, et al.(2007): Adjunctive methotrexate for treatment of giant

Mahr A, Saba M, Kambouchner M, et al.(2006): Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better? *Ann Rheum Dis* 2006, 65:826–828. Martínez-Valle F, Solans-Laqué R, Bosch-Gil J, et al.(2010): Aortic involvement in giant cell

Mazlumzadeh M, Hunder GG, Easley KA, et al.(2006): Treatment of giant cell arteritis using

Nesher G, Berkun Y, Mates M, et al.(2004): Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. *Arthritis Rheum* 2004, 50:1332–1337. Pipitone N, Versari A, Salvarani C (2008): Role of imaging studies in the diagnosis and

Rodriguez-Pla A, Bosch-Gil JA, Echevarria-Mayo JE, Rossello-Urgell J, Solans-Laque R,

Salvarani C, Cantini F, Hunder GG (2008): Polymyalgia rheumatica and giant-cell arteritis.

Salvarani C, Gabriel SE, O'Fallon WM, Hunder GG. (1995) The incidence of giant cell

Salvarani C, Macchioni P, Zizzi F, Mantovani W, Rossi F, Castri C, et al. (1991)

Schmidt W.A. (2006) Takayasu and temporal arteritis, in Baumgartner R.W. (ed.): Handbook on Neurovascular Ultrasound. *Front.Neurol.Neurosci*.Basel, Karger, 2006, 21:96-104. Schmidt WA, Kraft HE, Vorpahl K, et al.(1997): Color duplex ultrasonography in the

Taylor-Gjevre R, Vo M, Shukla D, Resch L (2005): Temporal artery biopsy for giant cell

Tranquart F., Aubert-Urena A.S., Arsene S., Audrierie C., Rossazza C., Pourcelot L. (1997) -

Weyand CM, Goronzy JJ. (2003) Giant-cell arteritis and polymyalgia rheumatica. *Ann Intern*

Weyand CM, Tetzlaff N, Bjornsson J, Brack A, Younge B, Goronzy JJ. (1997) Disease patterns and tissue cytokine profiles in giant cell arteritis. *Arthritis Rheum* 1997;40:19–26.

cell arteritis in northern Italy. *Arthritis Rheum* 1991;34:351–6.

ischemique anterieure aigue, *J.E.MU.* 1997; 18(1):6871.

diagnosis of temporal arteritis. *N Engl J Med* 1997, 337:1336–1342.

rate is associated with the development of visual complications in biopsy-proven

cell arteritis: an individual patient data metaanalysis. *Arthritis Rheum* 2007, 56:2789–

induction therapy with high-dose glucocorticoids: a double-blind, placebocontrolled, randomized prospective clinical trial. *Arthritis Rheum* 2006, 54:3310–

follow-up of large-vessel vasculitis: an update. *Rheumatology* (Oxford) 2008, 47:403–

Huguet-Redecilla P, et al. (2004) No detection of parvovirus B19 or herpesvirus

arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern.

Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant

Echo-Doppler couleur des arteres ciliaires posterieures dans la neuropathie optique

patients with giant cell arteritis. *Arthritis Rheum* 2006, 54:3306–3309. Levine SM, Hellmann DB. (2002) Giant cell arteritis. *Curr Opin Rheumatol* 2002;14:3–10. Lopez-Diaz MJ, Llorca J, Gonzalez-Juanatey C, et al.(2008): The erythrocyte sedimentation

giant cell arteritis. *Semin Arthritis Rheum* 2008, 38:116–123.

arteritis. *Autoimmun Rev* 2010, 9:521–524.

DNA in giant cell arteritis. *J Clin Virol* 2004;31:11–5.

2797.

3318.

408.

*Lancet* 2008, 372:234–245.

*Med* 2003;139:505–15.

*Ann Intern Med* 1995;123:192–4.

arteritis. *J Rheumatol* 2005, 32:1279–1282.

Kawasaki disease (KD), an acute febrile mucotaneous lymph node syndrome, was initially described as a distinct clinical entity in 1967 by the Japanese physician, Dr Tomisaku Kawasaki (Kawasaki et al., 1974). Today the disease is recognized as an acute self - limited vasculitis of unknown etiology that predominantly affects young children of all racial and ethnic groups (Shulman et al., 1987). It is characterised by prolonged fever unresponsive to antibiotics, a polymorphous skin rash, erythema of the oral mucosa, lips and tongue, erythema of the palms and soles, bilateral conjunctival injection and cervical lymphadenopathy. This disease has become the leading cause of acquired heart disease among children in the developed world, with coronary artery aneurysms occurring in up to 25% of untreated cases (Newburger & Fulton, 2004).

## **2. Epidemiology**

Approximately 85% of children with KD are aged less than five years, with a relatively higher incidence reported for boys (Chang, 2002). Patients either younger than three months or older than five years are scarcely encountered and are regarded to be at a higher cardiovascular risk (Burns et al.,1986; Stockheim et al., 2000). Occurrence beyond late childhood is extremely rare. Less than 100 cases of adult KD have actually been reported in the world literature since the recognition of this illness, according to a 2010 case series and review of the disease in adults (Gomard – Mennesson et al., 2010; Wolff et al., 2007). In fact, many of the reported cases in adults have been misdiagnosed as KD, while the correct diagnosis was toxic shock syndrome ( Meissner & Leung 1995; Shulman et al., 1995).

The epidemiology of KD is best documented in Japan, where regular nationwide epidemiological surveys are being conducted every two years since 1970. Based on the recent 20th survey, the number of patients with KD are continuously increasing, with an average annual incidence rate in 2007 and 2008 that reached 217/ 100.000 children younger

Kawasaki Disease in

**3. Aetiology**

months

et al, 2005).

al., 1999).

(Burns & Glode, 2004).

January

March

May

July

September

November

shock syndrome (TSS).

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 333

Fig. 1. Monthly distribution of the 34 cases hospitalized for Kawasaki disease in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005

disease. Evidence supporting this hypothesis includes the following:

infectious agents responsible for the disease (Hirata et al., 2001).

The cause of KD remains unknown. Most investigators suspect the existence of an infectious agent or the response to one or more pathogens to be responsible for the development of the

number of patients

01234567

a. Seasonal clustering of KD during the winter months in most geographical areas (Burns

b. Geographical distribution of recorded periodic epidemics (Kao et al., 2008; Yanagawa et

c. The fact that the disease occurs most often among toddlers, with only rare cases of infants younger than three years of age, which suggests the involvement of transplacental antibodies. Maternal immunoglobulin G may offer some protection to young infants and this protection diminishes as levels of maternal antibodies decrease

d. The 3–5 % of recurrency among cases in Japan, that may suggest either an aberrant immune response in this particular group of patients or the existence of more than one

e. The clinical presentation of the disease with fever, cervical lymphadenitis, exanthema and conjunctivitis that resembles other infectious diseases such as scarlet fever and toxic

While the infectious agent hypothesis remains plausible, research on associating KD with a specific pathogen has been yet fruitless. A wide variety of microbiological and molecular methods have been employed in order to isolate pathogens from body fluidsand/or detect

than five years of age, while the same value was 184.6/100.000 for the years 2005 and 2006 (Nakamura et al., 2010, 2008).Over the past years, incidence figures have also been reported based on surveys upon hospital admission from Korea, Taiwan, the United States of America and the United Kingdom, enabling comparisons to be made. The highest incidence rate of KD per 100.000 children less than five years of age is recorded in Japan. Korea and Taiwan hold the second and third place respectively (Huang et al., 2009; Park et al., 2011 ). The United Kingdom and the United States are credited with a significantly lower annual incidence, which however, shows an increasing tendency over the past years (Harnden et al., 2002; Holman et al., 2010).

A study performed from 1996 through 2001, showed that the annual incidence rate for KD among children younger than five years of age was 45.2 in Hawaii, the highest figure in the United States (Holman et al., 2005). Interestingly, the study showed that Japanese children in Hawaii were more likely to develop Kawasaki disease than children of other races in the same state or even children living in Japan. It is thus suggested that the incidence rate is higher in children either living in East Asia or being of Asian ancestry and living in other parts of the world. The overall prevalence in the United States is the highest among Asian and Pacific Islanders, intermediate in non-Hispanic African-Americans and the lowest for Caucasians (Holman et al., 2010a, 2010b).

Other than the racial variations in the different geographical areas, a seasonal parameter in the distribution of KD cases also seems to exist. In most countries that hold records of KD occurrence, the greatest frequency is noted during winter months. In Japan, the disease shows a bimodal seasonality, that peaks once in January and secondly in June and July (Burns et al., 2005). Moreover, a bimodal pattern of occurrence is reported in Korea (Park et al., 2011). In Taiwan, recent studies have shown that KD is noted most frequently in the summer and least frequently in the winter (Huang et al., 2009). It is therefore noticed that although the period may not always be the same, seasonal clustering of the disease does take place. Such seasonality and temporal occurrence suggest that infectious agents or other environmental factors that are yet unknown, might trigger the onset of the disease.

The standardized mortality ratio associated with KD is 1,14 (Nakamura et al., 2008). There is a slightly increased mortality ratio in boys with the disease, which is mainly recorded during the acute phase and returns to baseline thereafter. This likely reflects the fact that cardiac and coronary artery abnormalities occur more frequently in boys than in girls and that most deaths related to KD are due to acute phase coronary disease or cardiac complications. In a study conducted in Japan, researchers have concluded that the mortality rate among males with cardiac lesions due to KD appeared to be higher than in the general population. Meanwhile, the mortality for girls with cardiac sequelae and for both male and female patients without sequelae, was not elevated (Nakamura et al., 2008).

In a retrospective study we conducted in "P & A Kyriakou" Children's Hospital, a tertiary pediatric referral center in Athens, Greece, we retrieved thirty-four cases of KD within a period of 16 years (1989-2005). The age upon diagnosis was between 2 months to 11 years (average: 2.9 years) and there was no significant gender preference (18 girls versus 16 boys). The duration of hospitalization varied from 5 to 29 days depending on the severity of associated symptoms. Thirty two children were Greek and 2 were of Albanian origin. In regards to seasonality, 58.8% of the cases occurred between November and March of any given year as depicted in figure 1.

Fig. 1. Monthly distribution of the 34 cases hospitalized for Kawasaki disease in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005

## **3. Aetiology**

332 Advances in the Diagnosis and Treatment of Vasculitis

than five years of age, while the same value was 184.6/100.000 for the years 2005 and 2006 (Nakamura et al., 2010, 2008).Over the past years, incidence figures have also been reported based on surveys upon hospital admission from Korea, Taiwan, the United States of America and the United Kingdom, enabling comparisons to be made. The highest incidence rate of KD per 100.000 children less than five years of age is recorded in Japan. Korea and Taiwan hold the second and third place respectively (Huang et al., 2009; Park et al., 2011 ). The United Kingdom and the United States are credited with a significantly lower annual incidence, which however, shows an increasing tendency over the past years (Harnden et

A study performed from 1996 through 2001, showed that the annual incidence rate for KD among children younger than five years of age was 45.2 in Hawaii, the highest figure in the United States (Holman et al., 2005). Interestingly, the study showed that Japanese children in Hawaii were more likely to develop Kawasaki disease than children of other races in the same state or even children living in Japan. It is thus suggested that the incidence rate is higher in children either living in East Asia or being of Asian ancestry and living in other parts of the world. The overall prevalence in the United States is the highest among Asian and Pacific Islanders, intermediate in non-Hispanic African-Americans and the lowest for

Other than the racial variations in the different geographical areas, a seasonal parameter in the distribution of KD cases also seems to exist. In most countries that hold records of KD occurrence, the greatest frequency is noted during winter months. In Japan, the disease shows a bimodal seasonality, that peaks once in January and secondly in June and July (Burns et al., 2005). Moreover, a bimodal pattern of occurrence is reported in Korea (Park et al., 2011). In Taiwan, recent studies have shown that KD is noted most frequently in the summer and least frequently in the winter (Huang et al., 2009). It is therefore noticed that although the period may not always be the same, seasonal clustering of the disease does take place. Such seasonality and temporal occurrence suggest that infectious agents or other

environmental factors that are yet unknown, might trigger the onset of the disease.

female patients without sequelae, was not elevated (Nakamura et al., 2008).

The standardized mortality ratio associated with KD is 1,14 (Nakamura et al., 2008). There is a slightly increased mortality ratio in boys with the disease, which is mainly recorded during the acute phase and returns to baseline thereafter. This likely reflects the fact that cardiac and coronary artery abnormalities occur more frequently in boys than in girls and that most deaths related to KD are due to acute phase coronary disease or cardiac complications. In a study conducted in Japan, researchers have concluded that the mortality rate among males with cardiac lesions due to KD appeared to be higher than in the general population. Meanwhile, the mortality for girls with cardiac sequelae and for both male and

In a retrospective study we conducted in "P & A Kyriakou" Children's Hospital, a tertiary pediatric referral center in Athens, Greece, we retrieved thirty-four cases of KD within a period of 16 years (1989-2005). The age upon diagnosis was between 2 months to 11 years (average: 2.9 years) and there was no significant gender preference (18 girls versus 16 boys). The duration of hospitalization varied from 5 to 29 days depending on the severity of associated symptoms. Thirty two children were Greek and 2 were of Albanian origin. In regards to seasonality, 58.8% of the cases occurred between November and March of any

al., 2002; Holman et al., 2010).

Caucasians (Holman et al., 2010a, 2010b).

given year as depicted in figure 1.

The cause of KD remains unknown. Most investigators suspect the existence of an infectious agent or the response to one or more pathogens to be responsible for the development of the disease. Evidence supporting this hypothesis includes the following:

While the infectious agent hypothesis remains plausible, research on associating KD with a specific pathogen has been yet fruitless. A wide variety of microbiological and molecular methods have been employed in order to isolate pathogens from body fluidsand/or detect

Kawasaki Disease in

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 335

Age at onset <5 years of age >4 years of age 90% girls reaching the

A streptococcal pyrogenic exotoxin (SPE- A, B,C)

Epidemic + + -

Conjunctival injection + \_ +

lymphadenopathy + + -

Strawberry tongue + + +

Palmar desquamation + + +

Shock or hypotension \_ \_ + Coronary arteriitis + \_ \_

and soles + + +

Recurrence 3 – 4 % rare 30,00%

Table 2. Comparison of clinical features of Kawasaki disease, Scarlet fever, and Toxic shock

Other researchers have found evidence of an oligoclonal antibody response, suggesting that the disease is elicited by a conventional antigen rather than a superantigen (Rowley

The predilection of the disease for children either living in Asia or being of Asian ancestry as well as the relatively higher recurrence within families point towards a genetic predisposition for developing KD (Caquard et al., 2006; Uehara et al., 2003). In Japan, the relative risk of developing the disease among siblings is 10, and it reaches to 13 when referring to twins (Harada et al., 1986). Several studies have been conducted, trying to link susceptibility to KD or disease outcome to genetic polymorphisms (Ahn et al., 2003; Burns et al., 2005; Furuno et al., 2004; Sato et al., 2009). However, most of these studies have been carried out on single small cohorts of KD patients and findings were reported without validation in additional case–control studies. Other limitations include the small scale number of alleles examined, control and sample populations heterogeneity that complicates comparison and the existence of silent undiagnosed cases within the control group. As opposed to candidate gene studies, genome–wide studies, which search for disease causing

hyperemia Whole area Localized to

disease Scarlet fever Toxic shock syndrome

rash Diffuse erythema Diffuse erythema

pharynx, soft palate Whole area

menstrual age

Staphylococcus enterotoxin (TSST-1)

Kawasaki

Cause unknown

Features of rash Polymorphous

Labial and oral

Cervical

Erythema of the palms

syndrome

et al., 2001).

agent – specific nucleic acids retrospectively, however with,limited results (Kawasaki et al., 1974; Melish et al., 1976; Rowley et al., 1994). Although there have been numerous reports suggesting the involvement of infectious agents such as Parvovirus B19, Bocavirus, Cytomegalovirus or other viruses, *Propionibacterium acnes*, Rickettciae, and Yersiniae, none of these agents have been seen consistently isolated in children with KD (Catalano-Pons et al., 2007; Esper et al., 2005; Wang et al., 2004). Among the 34 cases of children hospitalized with KD in our study, some were examined for a variety of infectious agents as presented in table 1. Most of the children were tested negative for recent exposure to the tested infectious agents. Nevertheless, the small number of subjects tested and the lack of a control population precludes any definitive conclusions.

Table 1. Microbiological findings among the 34 cases of Kawasaki disease identified in "P & A Kyriakou" Children's Hospital, Second Department of Pediatrics, University of Athens, Greece during the period 1989-2005

Due to the aforementioned clinical resemblance of KD with scarlet fever and TSS, it was suggested that superantigens, especially toxic shock syndrome toxin – 1 (TSST–1) and group A streptococcal exotoxins A, B and C (SPEA, SPEB, SPEC) may be involved in the pathogenesis of the disease (Table 2). This was strongly supported by a study that reported associated increase of IgM antibodies against TSST–1, streptococcal pyogenic exotoxin A and staphylococcal enterotoxin A (Matsubara & Fukaya, 2007). However, an earlier multicentre, prospective study detected no difference in the isolation of superantigenproducing bacteria between patients with the disease and febrile controls, thus complicating the matter further (Leung et al., 2002). On the other hand, bacterial toxins'-induced clonal expansion of T–cell receptors Vβ2 and Vβ8 is found among a subset of patients at the early stages of disease. This expansion seems to withdraw during the convalescent phase and may be responsible for the non specific T–cell activation that can lead to massive cytokine release and the development of KD (Abe et al.,1992; Brogan et al., 2008).

Another hypothesis for the etiology of KD involves the implication of an environmental cause, such as pesticides, chemicals, heavy metals, toxins and pollutants. However, poisoning with environmental agents does not usually manifest acutely and is the result of chronic exposure. Nonetheless, some studies correlate KD to recent exposure to freshly shampooed carpets, habitation near a body of stagnant water and the use of a humidifier (Rauch et al., 1991; Treadwell et al., 2002).

agent – specific nucleic acids retrospectively, however with,limited results (Kawasaki et al., 1974; Melish et al., 1976; Rowley et al., 1994). Although there have been numerous reports suggesting the involvement of infectious agents such as Parvovirus B19, Bocavirus, Cytomegalovirus or other viruses, *Propionibacterium acnes*, Rickettciae, and Yersiniae, none of these agents have been seen consistently isolated in children with KD (Catalano-Pons et al., 2007; Esper et al., 2005; Wang et al., 2004). Among the 34 cases of children hospitalized with KD in our study, some were examined for a variety of infectious agents as presented in table 1. Most of the children were tested negative for recent exposure to the tested infectious agents. Nevertheless, the small number of subjects tested and the lack of a control

EBV 16 - 100 12,5 87,5 Parvo B19 10 - 100 30 70 CMV 14 - 100 21,4 78,6

 1 - 100 10 90 1 10 90 - 100

Coxsackie - Virus 10 10 90 10 90

ECHO - Virus 13 23 77 - -

Table 1. Microbiological findings among the 34 cases of Kawasaki disease identified in "P & A Kyriakou" Children's Hospital, Second Department of Pediatrics, University of Athens,

Due to the aforementioned clinical resemblance of KD with scarlet fever and TSS, it was suggested that superantigens, especially toxic shock syndrome toxin – 1 (TSST–1) and group A streptococcal exotoxins A, B and C (SPEA, SPEB, SPEC) may be involved in the pathogenesis of the disease (Table 2). This was strongly supported by a study that reported associated increase of IgM antibodies against TSST–1, streptococcal pyogenic exotoxin A and staphylococcal enterotoxin A (Matsubara & Fukaya, 2007). However, an earlier multicentre, prospective study detected no difference in the isolation of superantigenproducing bacteria between patients with the disease and febrile controls, thus complicating the matter further (Leung et al., 2002). On the other hand, bacterial toxins'-induced clonal expansion of T–cell receptors Vβ2 and Vβ8 is found among a subset of patients at the early stages of disease. This expansion seems to withdraw during the convalescent phase and may be responsible for the non specific T–cell activation that can lead to massive cytokine

Another hypothesis for the etiology of KD involves the implication of an environmental cause, such as pesticides, chemicals, heavy metals, toxins and pollutants. However, poisoning with environmental agents does not usually manifest acutely and is the result of chronic exposure. Nonetheless, some studies correlate KD to recent exposure to freshly shampooed carpets, habitation near a body of stagnant water and the use of a humidifier

release and the development of KD (Abe et al.,1992; Brogan et al., 2008).

tested % IgM (+) % IgM (-) % IgG (+) % IgG (-)

population precludes any definitive conclusions.

Greece during the period 1989-2005

(Rauch et al., 1991; Treadwell et al., 2002).

Children

Other researchers have found evidence of an oligoclonal antibody response, suggesting that the disease is elicited by a conventional antigen rather than a superantigen (Rowley et al., 2001).

The predilection of the disease for children either living in Asia or being of Asian ancestry as well as the relatively higher recurrence within families point towards a genetic predisposition for developing KD (Caquard et al., 2006; Uehara et al., 2003). In Japan, the relative risk of developing the disease among siblings is 10, and it reaches to 13 when referring to twins (Harada et al., 1986). Several studies have been conducted, trying to link susceptibility to KD or disease outcome to genetic polymorphisms (Ahn et al., 2003; Burns et al., 2005; Furuno et al., 2004; Sato et al., 2009). However, most of these studies have been carried out on single small cohorts of KD patients and findings were reported without validation in additional case–control studies. Other limitations include the small scale number of alleles examined, control and sample populations heterogeneity that complicates comparison and the existence of silent undiagnosed cases within the control group. As opposed to candidate gene studies, genome–wide studies, which search for disease causing

Kawasaki Disease in

in patients with polyarteritis nodosa (Jennette, 2002).

**5. Diagnosis & clinical features**

Table 3 and Table 4 respectively.

a. Fever lasting for at least 5 days

b. Presence of 4 of the following 5 conditions: 1. Bilateral conjunctival injection

periungual desquamation. 5. Cervical lymphadenopathy.

a. Fever lasting for at least 5 days.

3. Polymorphous rash, primarily truncal.

c. Absence of any other reasonable explanation for the illness.

b. At least 2 of the 5 clinical criteria for Kawasaki disease (Table 3: B 1-5 ).

d. Laboratory findings, consistent with severe systemic inflammation.

Table 4. Diagnostic criteria for incomplete/ atypical Kawasaki disease

Table 3. Diagnostic criteria for complete Kawasaki disease

c. Absence of any other sensible explanation for the illness.

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 337

The histological findings in KD strongly resemble polyarteriitis nodosa, and even though fine differences between the two illnesses do exist, differential diagnosis can only be made clinically. Most importantly, KD manifests with lymphadenopathy, which is usually absent

Signs and symptoms of KD develop over the first ten days of the illness and then gradually disappear spontaneously in most patients. In 20–25 % of the cases the disease is complicated by coronary artery lesions that may remain silent and diagnosed only years later, after the occurrence of a myocardial infarction episode or sudden death (Burns et al., 1996; Kato et al., 1992). The disease may be separated in three phases according to its clinical presentation. The acute phase, which may last 7-14 days, the sub-acute phase from the 10th to the 24th day of the disease, and finally the convalescent phase, typically lasting 6-8 weeks. Diagnosis of the disease during the acute phase is of utmost significance, as treatment with high dose of intravenous immunoglobulin within the first 10 days of onset reduces the risk of coronary artery lesions (Newburger et al.,1986, 1991). However, diagnosis of the disease is quite challenging, first because it remains clinically silent for some time, and secondly because there is no specific diagnostic test available. Aside from key elements of the history and physical examination, as well as indications based on laboratory markers of inflammation, the disease is presently diagnosed by the use of a case definition created for epidemiological surveys in Japan. The diagnostic criteria for complete and incomplete KD are presented in

2. Changes of the mucous membranes of the upper respiratory tract: injected

4. Changes of the extremities such as peripheral edema, peripheral erythema, and

Although according to the criteria diagnosis requires a minimum of 5 days of fever, many experts prefer to treat classic KD earlier than the 5th day. The reason is that the case definition of KD is of questionable value as a clinical tool (Stapp & Marshall, 2002; Witt et

pharynx, injected or/and dry fissured lips, strawberry tongue

mutations within the whole genome, seem very promising. One such recent study, has identified inositol 1,4,5-trisphosphate 3-kinase C (ITPK-C) gene as a susceptibility gene for KD (Onouchi et al., 2008). A functional single nucleotide polymorphism was recognized and associated with disease development but also with increased risk for the formation of coronary artery lesions. This polymorphism is shown to reduce splicing efficiency of ITPK-C mRNA. While ITPK-C is shown to act as a negative regulator of T-cell activation through the Ca2+/nuclear factor of activated T-cells signal pathway, the reduced splicing efficiency may contribute to immune hyperreactivity and thus the pathogenesis of KD (Onouchi, 2010). Further research on the biological significance of ITPK-C in other immune or non-immune cells may lead to better understanding of the disease pathogenesis.

## **4. Pathology**

The histological findings of KD are consistent with those of a systemic vasculitis affecting medium sized arteries and veins to a lesser extent, with inflammatory lesions in virtually every organ. With the exception of arterial lesions, inflammatory lesions heal without residual changes (Amano et al., 1980; Masuda et al., 1986). Our understanding of the histopathological findings in KD is restricted due to the scarcity of study material for reasons such as the low mortality rate and the difficulties encountered upon sampling medium sized arteries, especially coronary arteries.

After the encounter of a genetically predisposed individual with the unknown trigger, an activation of mononuclear cells and platelets occurs (Jennette, 2002). The two latter cell populations interact with the endothelium that expresses surface adhesion molecules leading to margination of circulating cells, especially large mononuclear cells, lymphocytes and IgA plasma cells (Brown et al., 2001;Rowley et al., 2001). Activated endothelial cells also secrete monocyte chemoattractant protein 1 (MCP-1), which further attracts monocytes and vascular endothelial cell growth factor (VEGF), which increases vessel permeability (Asano & Ogawa, 2000; Maeno et al., 1998; Yasukawa et al., 2002) . Afterwards, platelets adhere to the vascular wall, while inflammatory cells cross the endothelium, gather in the intima, and liberate proinflammatory molecules such as interleukins, tumor necrosis factor α (TNFα), and matrix metalloproteinases (MMP) (Eberhard et al., 1995; Gavin et al., 2003; Lin et al., 1992). Neutrophils release neutrophil elastase which destroys the internal elastic lamina and contributes to disruption of the extracellular matrix. Active inflammation is succeeded by progressive fibrosis and finally scar formation.

In the heart, perivasculitis and endarteritis of the three major coronary arteries are seen during the acute phase, followed by panvasculitis in the consequent two weeks period. Aneurysms, phlebitis, formation of intraluminal thrombi and potential pancarditis with lesions of the conduction system are also present during this phase of the disease. As the disease progresses, inflammation is replaced by granulation in the form of scarring, stenosis of major coronary arteries, fibrosis of the myocardium, coagulation necrosis, and endocardial fibroelastosis (Fujiwara & Hamashima, 1978).

Inflammatory changes of the lungs, spleen, lymph nodes and salivary glands remain for more than 61 days from the onset of the disease, while in other organs these changes resolve much earlier. A predilection of KD for duct systems such as the prostate, pancreas, bile ducts and salivary glands has also been documented. However, in contrast to the irreversible changes that may occur in the cardiovascular system, histological changes on other parts of the body seem to fully recover after the convalescent phase of the disease (Amano et al., 1980).

The histological findings in KD strongly resemble polyarteriitis nodosa, and even though fine differences between the two illnesses do exist, differential diagnosis can only be made clinically. Most importantly, KD manifests with lymphadenopathy, which is usually absent in patients with polyarteritis nodosa (Jennette, 2002).

## **5. Diagnosis & clinical features**

336 Advances in the Diagnosis and Treatment of Vasculitis

mutations within the whole genome, seem very promising. One such recent study, has identified inositol 1,4,5-trisphosphate 3-kinase C (ITPK-C) gene as a susceptibility gene for KD (Onouchi et al., 2008). A functional single nucleotide polymorphism was recognized and associated with disease development but also with increased risk for the formation of coronary artery lesions. This polymorphism is shown to reduce splicing efficiency of ITPK-C mRNA. While ITPK-C is shown to act as a negative regulator of T-cell activation through the Ca2+/nuclear factor of activated T-cells signal pathway, the reduced splicing efficiency may contribute to immune hyperreactivity and thus the pathogenesis of KD (Onouchi, 2010). Further research on the biological significance of ITPK-C in other immune or non-immune

The histological findings of KD are consistent with those of a systemic vasculitis affecting medium sized arteries and veins to a lesser extent, with inflammatory lesions in virtually every organ. With the exception of arterial lesions, inflammatory lesions heal without residual changes (Amano et al., 1980; Masuda et al., 1986). Our understanding of the histopathological findings in KD is restricted due to the scarcity of study material for reasons such as the low mortality rate and the difficulties encountered upon sampling

After the encounter of a genetically predisposed individual with the unknown trigger, an activation of mononuclear cells and platelets occurs (Jennette, 2002). The two latter cell populations interact with the endothelium that expresses surface adhesion molecules leading to margination of circulating cells, especially large mononuclear cells, lymphocytes and IgA plasma cells (Brown et al., 2001;Rowley et al., 2001). Activated endothelial cells also secrete monocyte chemoattractant protein 1 (MCP-1), which further attracts monocytes and vascular endothelial cell growth factor (VEGF), which increases vessel permeability (Asano & Ogawa, 2000; Maeno et al., 1998; Yasukawa et al., 2002) . Afterwards, platelets adhere to the vascular wall, while inflammatory cells cross the endothelium, gather in the intima, and liberate proinflammatory molecules such as interleukins, tumor necrosis factor α (TNFα), and matrix metalloproteinases (MMP) (Eberhard et al., 1995; Gavin et al., 2003; Lin et al., 1992). Neutrophils release neutrophil elastase which destroys the internal elastic lamina and contributes to disruption of the extracellular matrix. Active inflammation is succeeded by

In the heart, perivasculitis and endarteritis of the three major coronary arteries are seen during the acute phase, followed by panvasculitis in the consequent two weeks period. Aneurysms, phlebitis, formation of intraluminal thrombi and potential pancarditis with lesions of the conduction system are also present during this phase of the disease. As the disease progresses, inflammation is replaced by granulation in the form of scarring, stenosis of major coronary arteries, fibrosis of the myocardium, coagulation necrosis, and

Inflammatory changes of the lungs, spleen, lymph nodes and salivary glands remain for more than 61 days from the onset of the disease, while in other organs these changes resolve much earlier. A predilection of KD for duct systems such as the prostate, pancreas, bile ducts and salivary glands has also been documented. However, in contrast to the irreversible changes that may occur in the cardiovascular system, histological changes on other parts of the body seem to fully recover after the convalescent phase of the disease

cells may lead to better understanding of the disease pathogenesis.

medium sized arteries, especially coronary arteries.

progressive fibrosis and finally scar formation.

(Amano et al., 1980).

endocardial fibroelastosis (Fujiwara & Hamashima, 1978).

**4. Pathology**

Signs and symptoms of KD develop over the first ten days of the illness and then gradually disappear spontaneously in most patients. In 20–25 % of the cases the disease is complicated by coronary artery lesions that may remain silent and diagnosed only years later, after the occurrence of a myocardial infarction episode or sudden death (Burns et al., 1996; Kato et al., 1992). The disease may be separated in three phases according to its clinical presentation. The acute phase, which may last 7-14 days, the sub-acute phase from the 10th to the 24th day of the disease, and finally the convalescent phase, typically lasting 6-8 weeks. Diagnosis of the disease during the acute phase is of utmost significance, as treatment with high dose of intravenous immunoglobulin within the first 10 days of onset reduces the risk of coronary artery lesions (Newburger et al.,1986, 1991). However, diagnosis of the disease is quite challenging, first because it remains clinically silent for some time, and secondly because there is no specific diagnostic test available. Aside from key elements of the history and physical examination, as well as indications based on laboratory markers of inflammation, the disease is presently diagnosed by the use of a case definition created for epidemiological surveys in Japan. The diagnostic criteria for complete and incomplete KD are presented in Table 3 and Table 4 respectively.

	- 1. Bilateral conjunctival injection
	- 2. Changes of the mucous membranes of the upper respiratory tract: injected pharynx, injected or/and dry fissured lips, strawberry tongue
	- 3. Polymorphous rash, primarily truncal.
	- 4. Changes of the extremities such as peripheral edema, peripheral erythema, and periungual desquamation.
	- 5. Cervical lymphadenopathy.

Table 3. Diagnostic criteria for complete Kawasaki disease

Table 4. Diagnostic criteria for incomplete/ atypical Kawasaki disease

Although according to the criteria diagnosis requires a minimum of 5 days of fever, many experts prefer to treat classic KD earlier than the 5th day. The reason is that the case definition of KD is of questionable value as a clinical tool (Stapp & Marshall, 2002; Witt et

Kawasaki Disease in

years 1989 and 2005

increased clinical awareness.

**6. Cardiovascular complications**

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 339

Clinical symptoms Number of patients % of patients

Table 6. Clinical presentation upon admission of the 34 cases of patients hospitalized for Kawasaki disease in "P & A Kyriakou" Children's Hospital in Athens, Greece between the

> IgG 3 3 4 IgM 3 7 - IgA 6 4 -

Table 7. Immune workup of the ten patients that underwent the examination in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005.

Even if the underlying cause remains unknown, there is an ever increasing need for the development of a unique diagnostic test that can help in identification of the disease. Although non specific markers of inflammation such as serum procalcitonin, interleukin–18 (IL-18), WBC count, ESR, and CRP are all found elevated in KD, no association to the severity of the illness has yet been established (Mitani et al., 2005; Nomura et al., 2004; Okada et al., 2004). Unfortunately, the diagnosis of the disease currently depends largely on

Kawasaki disease has become the leading cause of acquired heart disease among children in the developed world, even surpassing the impact of rheumatic fever in this respect. Twenty to 25% of untreated patients with KD develop coronary artery aneurysms and myocardial

Number of patients with e**levated titer**

Number of patients with **decreased titer**

Number of patients with **normal titer**

1. fever 34 100 2. rash 33 97,1 3. desquamation 27 79,4 4. conjunctivitis 26 76,5 5. lymphadenitis 26 76,5 6. fissured lips 26 76,5 7. glossitis 14 41,2 8. edema of the extremities 11 32,4 9. aneurysms 5 14,7 10. gastrointestinal abnormalities 5 14,7 11. arrhythmia 1 2,9 12. arthritis 1 2,9

al.,1999). A broader definition of the disease would ensure identification of all patients who could benefit from intravenous immunoglobulin treatment. It is very common that the criteria for diagnosis of KD are not all present at the same time during the course of the illness (Newburger & Fulton, 2004). Patients with an inflammatory disorder that did not meet all the clinical criteria but with echocardiographic abnormalities of the coronary arteries have been identified. It should also been noted that 5 of the patients in Kawasaki' s original report of 50 patients did not fulfill the current criteria for the diagnosis of the disease (Burns, 2002).

The lack of a specific and sensitive diagnostic test remains a great obstacle in the identification of all patients with KD. Besides the possibility that the illness may be underdiagnosed, there is an almost equally high chance that the disease is overdiagnosed since clinicians use non specific laboratory markers of inflammation to support their diagnosis. Thus, differential diagnosis among diseases that require different treatment remains a challenge (Table 5).

#### Table 5. Selected differential diagnosis of Kawasaki disease

Acknowledgement of the protective role that early administration of intravenous immunoglobulin may play in the disease has placed a significant burden on clinicians to consider diagnosis in patients with unexplained fever with rash. Certain features of KD that may potentially deceive physicians include sterile pyuria misdiagnosed as urinary tract infection, cerebrospinal fluid (CSF) pleiocytosis misdiagnosed as aseptic meningitis, rash that may resemble a viral or drug side-effect sign, and cervical lymphadenopathy that is often confused with bacterial adenitis ( Dengler et al., 1998; Wu et al, 2005).

The clinical symptoms upon presentation of the disease for the 34 hospitalized cases identified in our hospital between the years 1989 and 2005, are shown in Table 6. The predominant symptom was –as expected - fever with an average duration of 7,8 days. Other symptoms in decreasing order of frequency were rash, desquamation, conjunctivitis, lymphadenitis, fissured lips, glossitis, edema of the extremities, gastrointestinal abnormalities and arthritis. Aneurysms were identified in only 5 cases, and while tachycardia was absent in all cases, a 1st degree AV block was noted in 1 child.

Laboratory indices at the time of entrance were suggestive of a generalized activation of the inflammatory system. Average white blood cell (WBC) count was 16.193 cells/μl, average erythrocyte sedimentation rate (ESR) was 74.7 mm, average level of C–reactive protein (CRP) was 120,2 mg/l and average platelet count was 45.700/μl. Liver transaminases (aspartate aminotransferase, AST and alanine aminotransferase, ALT) were elevated in only 3 of the children. Urine analysis revealed the existence of aseptic pyuria in a 76,5% of the patients. An immune workup was performed for 10 of the children and is shown in Table 7. Finally, level of a1 – antithrypsin was tested in 3 cases and was found to be elevated in all three of them.

al.,1999). A broader definition of the disease would ensure identification of all patients who could benefit from intravenous immunoglobulin treatment. It is very common that the criteria for diagnosis of KD are not all present at the same time during the course of the illness (Newburger & Fulton, 2004). Patients with an inflammatory disorder that did not meet all the clinical criteria but with echocardiographic abnormalities of the coronary arteries have been identified. It should also been noted that 5 of the patients in Kawasaki' s original report of 50 patients did not fulfill the current criteria for the diagnosis of the

The lack of a specific and sensitive diagnostic test remains a great obstacle in the identification of all patients with KD. Besides the possibility that the illness may be underdiagnosed, there is an almost equally high chance that the disease is overdiagnosed since clinicians use non specific laboratory markers of inflammation to support their diagnosis. Thus, differential diagnosis among diseases that require different treatment

Acknowledgement of the protective role that early administration of intravenous immunoglobulin may play in the disease has placed a significant burden on clinicians to consider diagnosis in patients with unexplained fever with rash. Certain features of KD that may potentially deceive physicians include sterile pyuria misdiagnosed as urinary tract infection, cerebrospinal fluid (CSF) pleiocytosis misdiagnosed as aseptic meningitis, rash that may resemble a viral or drug side-effect sign, and cervical lymphadenopathy that is

The clinical symptoms upon presentation of the disease for the 34 hospitalized cases identified in our hospital between the years 1989 and 2005, are shown in Table 6. The predominant symptom was –as expected - fever with an average duration of 7,8 days. Other symptoms in decreasing order of frequency were rash, desquamation, conjunctivitis, lymphadenitis, fissured lips, glossitis, edema of the extremities, gastrointestinal abnormalities and arthritis. Aneurysms were identified in only 5 cases, and while

Laboratory indices at the time of entrance were suggestive of a generalized activation of the inflammatory system. Average white blood cell (WBC) count was 16.193 cells/μl, average erythrocyte sedimentation rate (ESR) was 74.7 mm, average level of C–reactive protein (CRP) was 120,2 mg/l and average platelet count was 45.700/μl. Liver transaminases (aspartate aminotransferase, AST and alanine aminotransferase, ALT) were elevated in only 3 of the children. Urine analysis revealed the existence of aseptic pyuria in a 76,5% of the patients. An immune workup was performed for 10 of the children and is shown in Table 7. Finally, level of a1 – antithrypsin was tested in 3 cases and was found to be elevated in all

disease (Burns, 2002).

Scarlet fever

Drug reactions

three of them.

remains a challenge (Table 5).

Toxic shock syndrome (TSS)

 Steven – Johnson' s syndrome Juvenile rheumatoid arthritis

 Staphylococcal scalded skin syndrome (SSSS) Measles and other febrile viral exanthems

Table 5. Selected differential diagnosis of Kawasaki disease

often confused with bacterial adenitis ( Dengler et al., 1998; Wu et al, 2005).

tachycardia was absent in all cases, a 1st degree AV block was noted in 1 child.

Table 6. Clinical presentation upon admission of the 34 cases of patients hospitalized for Kawasaki disease in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005

Table 7. Immune workup of the ten patients that underwent the examination in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005.

Even if the underlying cause remains unknown, there is an ever increasing need for the development of a unique diagnostic test that can help in identification of the disease. Although non specific markers of inflammation such as serum procalcitonin, interleukin–18 (IL-18), WBC count, ESR, and CRP are all found elevated in KD, no association to the severity of the illness has yet been established (Mitani et al., 2005; Nomura et al., 2004; Okada et al., 2004). Unfortunately, the diagnosis of the disease currently depends largely on increased clinical awareness.

## **6. Cardiovascular complications**

Kawasaki disease has become the leading cause of acquired heart disease among children in the developed world, even surpassing the impact of rheumatic fever in this respect. Twenty to 25% of untreated patients with KD develop coronary artery aneurysms and myocardial

Kawasaki Disease in

1 (no coronary artery changes at any stage of illness)

2 (transient coronary artery ectasia disappears within first 6–8 weeks)

3 (1 small-to-medium coronary artery aneurysm/ major coronary artery)

4 (1 large or giant coronary artery aneurysm, or multiple or complex aneurysms in the same coronary artery, without obstruction)

5 (coronary artery obstruction)

**Risk level Pharmacological**

**therapy**

None beyond first 6– 8 weeks

None beyond first 6– 8 weeks

Low-dose aspirin (3– 5 mg/kg aspirin/day), at least until aneurysm regression is documented

Long-term antiplatelet therapy and warfarin (target INR 2.0–2.5) or lowmolecular-weight heparin (target: antifactor Xa level 0.5–1.0 U/ml) should be combined in giant aneurysms.

Long-term low-dose aspirin. Warfarin or low-molecularweight heparin if giant aneurysm persists. Use of beta blockers to reduce myocardial O2 consumption should also be considered

Table 9. Risk stratification for Kawasaki disease (ECHO: echocardiography, EKG

electrocardiogram, INR: International normalized ratio)

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 341

**Follow – up &**

Cardiovascular risk assessment, counseling every 5 years

Cardiovascular risk assessment, counseling every 3-5 years

ECHO+ECG, cardiovascular risk assesment, counseling annually. Stress test/ evaluation of myocardial perfusion scan every 2 years

ECHO+ECG twice annually. Stress test /evaluation of myocardial perfusion annually.

ECHO+ECG twice annually. Stress test /evaluation of myocardial perfusion annually.

**diagnostic tests Invasive tests**

Angiography, if noninvasive test suggests ischemia

First angiography at 6–12 months or sooner if clinically indicated; repeated angiography if noninvasive test, clinical, or laboratory findings suggest ischemia; elective repeat angiography under some circumstances

Angiography recommended to address therapeutic options

infarction with an associated considerable morbidity and mortality (Taubert et al., 1994) . Other cardiovascular complications related with the disease include coronary artery stenosis, myocarditis, pericarditis with effusion and mitral valvulitis (Akagi et al.,1990; Dajani et al., 1993). Cardiac imaging is hence very important in the evaluation of patients with suspected KD. Echocardiography is both a sensitive and specific method to recognize coronary artery aneurysms in the acute and subacute phase of the disease (Yoshikawa et al., 1979). Serial ultrasound studies can provide evidence of aneurysm formation, they may help evaluate left ventricular function as well as detect possible existence of pericardial effusion (McMorrow Tuohy et al.,2001; Scott et al., 1999). Doppler echocardiography can assist in the identification of mitral valve regurgitation and is also advisable in the presence of a pansystolic murmur upon auscultation. Morphological assessment of coronary arteries is of high significance, as the prognosis of aneurysms in patients with KD depends on the size and shape of the aneurysm. These features are best evaluated with three– dimensional echocardiography (Miyashita et al., 2007). Coronary artery aneurysms are characterized as small if less than 5 mm in internal diameter, medium if 5–8 mm, or giant if larger than 8 mm (Dayani et al., 1993, 1994). Fusiform aneurysms with a diameter of less than 8 mm have the best outcome, while giant aneurysms more than 8 mm have the worst. The latter is attributed to the fact that giant coronary aneurysms are highly probable to cause ischemic heart disease (Kamiya et al., 1995; Tatara & Kusakawa, 1987). On the contrary, small and medium diameter aneurysms have been reported to regress in approximately 50% of the cases and progress to stenosis in another 20% of patients (Kato et al., 1996). However, the value of echocardiographic detection of thrombi and coronary artery stenosis is questionable. In a selection of patients with KD, a series of other tests are recommended, aiming at better visualization of the coronary arteries. These include angiography, intravascular ultrasound, transesophageal echocardiography, magnetic resonance imaging, magnetic resonance angiography and ultrafast computed tomography (Greil et al., 2002; Naiser et al., 2008; Newburger et al., 2004; Suzuki et al., 1996). Interestingly, coronary artery lesions following KD may remain silent until the patient becomes 30 or even 40 years old. Especially patients without pathological findings in their echocardiogram during the acute and subacute phases of the disease usually remain clinically asymptomatic for at least a decade. To this end, a pediatric history of illness resembling KD should be sought in young adults presenting with myocardial infarction or sudden death ( Burns et al., 1996; Kato et al., 1992).

Suggested risk factors for coronary artery formation include fever that endures even after intravenous immunogobulin administration, elevated CRP, low hemoglobin, thrombocytopenia, hypoalbuminemia, hyponatremia, male sex and age under one year ( Honkanen et al., 2003; Koren et al., 1986; Mori et al., 2002). A proposed stratification of patients according to the relative risk for developing myocardial ischemia is presented, in table 9 (Newburger et al.2004).

## **7. Treatment**

#### **7.1 Initial treatment**

Coronary artery aneurysms develop in 20 – 25% of patients left untreated. During the acute phase, the primary objective is to ascertain the diagnosis of the disease, provide supportive

infarction with an associated considerable morbidity and mortality (Taubert et al., 1994) . Other cardiovascular complications related with the disease include coronary artery stenosis, myocarditis, pericarditis with effusion and mitral valvulitis (Akagi et al.,1990; Dajani et al., 1993). Cardiac imaging is hence very important in the evaluation of patients with suspected KD. Echocardiography is both a sensitive and specific method to recognize coronary artery aneurysms in the acute and subacute phase of the disease (Yoshikawa et al., 1979). Serial ultrasound studies can provide evidence of aneurysm formation, they may help evaluate left ventricular function as well as detect possible existence of pericardial effusion (McMorrow Tuohy et al.,2001; Scott et al., 1999). Doppler echocardiography can assist in the identification of mitral valve regurgitation and is also advisable in the presence of a pansystolic murmur upon auscultation. Morphological assessment of coronary arteries is of high significance, as the prognosis of aneurysms in patients with KD depends on the size and shape of the aneurysm. These features are best evaluated with three– dimensional echocardiography (Miyashita et al., 2007). Coronary artery aneurysms are characterized as small if less than 5 mm in internal diameter, medium if 5–8 mm, or giant if larger than 8 mm (Dayani et al., 1993, 1994). Fusiform aneurysms with a diameter of less than 8 mm have the best outcome, while giant aneurysms more than 8 mm have the worst. The latter is attributed to the fact that giant coronary aneurysms are highly probable to cause ischemic heart disease (Kamiya et al., 1995; Tatara & Kusakawa, 1987). On the contrary, small and medium diameter aneurysms have been reported to regress in approximately 50% of the cases and progress to stenosis in another 20% of patients (Kato et al., 1996). However, the value of echocardiographic detection of thrombi and coronary artery stenosis is questionable. In a selection of patients with KD, a series of other tests are recommended, aiming at better visualization of the coronary arteries. These include angiography, intravascular ultrasound, transesophageal echocardiography, magnetic resonance imaging, magnetic resonance angiography and ultrafast computed tomography (Greil et al., 2002; Naiser et al., 2008; Newburger et al., 2004; Suzuki et al., 1996). Interestingly, coronary artery lesions following KD may remain silent until the patient becomes 30 or even 40 years old. Especially patients without pathological findings in their echocardiogram during the acute and subacute phases of the disease usually remain clinically asymptomatic for at least a decade. To this end, a pediatric history of illness resembling KD should be sought in young adults presenting with myocardial infarction or

Suggested risk factors for coronary artery formation include fever that endures even after intravenous immunogobulin administration, elevated CRP, low hemoglobin, thrombocytopenia, hypoalbuminemia, hyponatremia, male sex and age under one year ( Honkanen et al., 2003; Koren et al., 1986; Mori et al., 2002). A proposed stratification of patients according to the relative risk for developing myocardial ischemia is presented, in table

Coronary artery aneurysms develop in 20 – 25% of patients left untreated. During the acute phase, the primary objective is to ascertain the diagnosis of the disease, provide supportive

sudden death ( Burns et al., 1996; Kato et al., 1992).

9 (Newburger et al.2004).

**7.1 Initial treatment**

**7. Treatment**

Table 9. Risk stratification for Kawasaki disease (ECHO: echocardiography, EKG electrocardiogram, INR: International normalized ratio)

Kawasaki Disease in

failure.

patient (Newburger et al., 2004).

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 343

If initial therapy during the acute stage is successful, the primary objective at the subacute phase is to diminish platelet adhesion (usually by means of low dose aspirin administration), provision of supportive care when needed and monitoring patients in case of cardiovascular involvement. In both the subacute and convalescent phase, management plans are adjusted to coronary artery involvement and risk level, individualized for each

For the 34 cases included in our study, treatment comprised primarily of intravenous immunoglobulin G and aspirin as shown on Table 10. Aspirin was administered to 31 patients (91,2 %) during an average treatment duration of 5,7 days. Among children treated with aspirin, 23 continued with an antiplatelet dose (74,2%) after fever regression and only 1 patient had to discontinue aspirin treatment due to related hepatotoxicity. Twenty eight patients were treated with γ–globulin (82,4%) with an average treatment duration of 1,9 days. Additional therapy consisted of penicillin in 2 children, carbamazepine that was later replaced by sorvitole in 1 child, clindamycin in 1 and finally a combination of ampicillin and netilmycin in another 1 of the children. In terms of patients' management, there was also a case admitted to the intensive care unit of the hospital due to sepsis and multiple organ

**Treatment with various doses of aspirin**

% of patients treated with aspirin

% of patients treated with IVIG

with aspirin

with IVIG

1 g/ kg 2 3,6 2 g/ kg 19 67,9

Table 10. Treatment of the patients hospitalized for Kawasaki disease in "P & A Kyriakou"

About 10–15% of children with KD that are treated with high dose aspirin and 2 g/kg intravenous immunoglobulin G will not become afebrile (Burns et al., 1998). Fever that is not reduced 36 hours after the completion of the initial intravenous immunoglobulin G infusion is defined as persistent or recrudescent fever. This subgroup, consisting of unresponsive to

400 mg/ kg/ 24 h 7 25

5 mg/ kg 3 9,6 60 mg/ kg 3 9,6 80 mg/ kg 13 41,9 85 mg/ kg 1 3,2 100 mg/kg 11 35,5 **Treatment with intravenous immunoglobulin G**

dosage Number of patients treated

dosage Number of patients treated

Children's Hospital in Athens, Greece between the years 1989 and 2005

**7.2 Treatment of persistent or recrudescent fever**

care whenever needed (fluid and electrolytes), aim to attenuate the inflammatory process and prevent the formation of coronary artery aneurysms. Echocardiographic identification of coronary artery aneurysms not only redirects primary treatment plan, but also contributes to establishing the diagnosis of KD when there is absence of symptoms other than fever. It is thus suggested to consider echocardiography in a child with high fever of unknown etiology lasting more than 5 days and concurrent signs of generalized inflammation.

Intravenous immunoglobulin G is the cornerstone of treatment for KD during the acute phase. Several studies have shown that intravenous immunoglobulin G administration early in the course of the disease (before the 10th day from fever onset) reduces total duration of clinical symptoms as well as the incidence of coronary artery aneurysms (Durongpisitkul et al., 1995; Furusho et al., 1984). It has been demonstrated that a single dose of 2 g/kg intravenous immunoglobulin G infused over 10–12 hours is more effective than multiple doses, and together with aspirin (Kato et al., 1996) now comprise the standard therapy in the USA, UK, Europe, Australia and many parts of Asia (Brogan et al., 2002). Although treatment should be instituted within the first ten days of illness, intravenous immunoglobulin G administration to children beyond the tenth day of illness is also recommended if they have either persistent fever without other explanation or aneurysms and ongoing systemic inflammation (Marasini et al., 1991; Newburger et al., 2004) . The molecular basis for the anti-inflammatory action of intravenous immunoglobulin G is a field of extended research. Several mechanisms have been proposed including induction of immune inhibitory receptors such as FcγIII on macrophages (Samuelsson et al., 2001), blocked interaction between endothelial and natural killer (NK) cells, necrosis-like changes in morphologic features of neutrophils (Sugita et al., 2005), accelerated apoptosis of circulating neutrophils (Tsujimoto et al, 2002) and down-regulation of genes expressed mainly by monocytes (Abe et al., 2005; Popper et al., 2007). Gamma globulin is a biological product manufactured from pooled donor plasma and adverse effects vary according to the product infused. Generally, adverse effects are considered mild, comprising of headache, myalgia, fever, chills, backache, chest pain, nausea, vomiting, as well as increased plasma viscosity. These effects are usually self-limited, rarely demanding cessation of therapy, although slowing down of the infusion may be required (Rosenfeld et al., 1995) Live virus vaccines should not be administered to patients for at least eleven months following treatment, due to reduced immunogenicity related to passive antibodies in the infused product.

Aspirin may also be administered in the acute phase of the disease in order to enhance the efficacy of intravenous immunoglobulin G. Currently, 80–100 mg/kg (divided in four doses) are administered in the acute inflammatory stage of the disease, while a single dose of 3–5 mg/kg is given when patients have been afebrile for 3-7 days. Aspirin may be continued indefinitely in children that have already developed coronary artery abnormalities,. Despite the fact that aspirin has an important anti-inflammatory effect at high doses and an antiplatelet action at low doses, it does not shorten the frequency of coronary artery aneurysm complications (Terai & Shulman, 1997). The latter, along with aspirin's adverse effects and the risk for developing Reye's syndrome raise an important question regarding the value of exposing children with KD to high doses of aspirin.

Corticosteroids are the golden standard in the treatment of other forms of vasculitis. Nevertheless, their use in children with KD is limited (Shulman, 2003) even though they are found to suppress markers of inflammation and decrease total fever duration (Nonaka et al., 1995; Okada et al., 2003).

care whenever needed (fluid and electrolytes), aim to attenuate the inflammatory process and prevent the formation of coronary artery aneurysms. Echocardiographic identification of coronary artery aneurysms not only redirects primary treatment plan, but also contributes to establishing the diagnosis of KD when there is absence of symptoms other than fever. It is thus suggested to consider echocardiography in a child with high fever of unknown etiology lasting more than 5 days and concurrent signs of generalized

Intravenous immunoglobulin G is the cornerstone of treatment for KD during the acute phase. Several studies have shown that intravenous immunoglobulin G administration early in the course of the disease (before the 10th day from fever onset) reduces total duration of clinical symptoms as well as the incidence of coronary artery aneurysms (Durongpisitkul et al., 1995; Furusho et al., 1984). It has been demonstrated that a single dose of 2 g/kg intravenous immunoglobulin G infused over 10–12 hours is more effective than multiple doses, and together with aspirin (Kato et al., 1996) now comprise the standard therapy in the USA, UK, Europe, Australia and many parts of Asia (Brogan et al., 2002). Although treatment should be instituted within the first ten days of illness, intravenous immunoglobulin G administration to children beyond the tenth day of illness is also recommended if they have either persistent fever without other explanation or aneurysms and ongoing systemic inflammation (Marasini et al., 1991; Newburger et al., 2004) . The molecular basis for the anti-inflammatory action of intravenous immunoglobulin G is a field of extended research. Several mechanisms have been proposed including induction of immune inhibitory receptors such as FcγIII on macrophages (Samuelsson et al., 2001), blocked interaction between endothelial and natural killer (NK) cells, necrosis-like changes in morphologic features of neutrophils (Sugita et al., 2005), accelerated apoptosis of circulating neutrophils (Tsujimoto et al, 2002) and down-regulation of genes expressed mainly by monocytes (Abe et al., 2005; Popper et al., 2007). Gamma globulin is a biological product manufactured from pooled donor plasma and adverse effects vary according to the product infused. Generally, adverse effects are considered mild, comprising of headache, myalgia, fever, chills, backache, chest pain, nausea, vomiting, as well as increased plasma viscosity. These effects are usually self-limited, rarely demanding cessation of therapy, although slowing down of the infusion may be required (Rosenfeld et al., 1995) Live virus vaccines should not be administered to patients for at least eleven months following treatment, due to reduced immunogenicity related to passive antibodies in the

Aspirin may also be administered in the acute phase of the disease in order to enhance the efficacy of intravenous immunoglobulin G. Currently, 80–100 mg/kg (divided in four doses) are administered in the acute inflammatory stage of the disease, while a single dose of 3–5 mg/kg is given when patients have been afebrile for 3-7 days. Aspirin may be continued indefinitely in children that have already developed coronary artery abnormalities,. Despite the fact that aspirin has an important anti-inflammatory effect at high doses and an antiplatelet action at low doses, it does not shorten the frequency of coronary artery aneurysm complications (Terai & Shulman, 1997). The latter, along with aspirin's adverse effects and the risk for developing Reye's syndrome raise an important question regarding the value of

Corticosteroids are the golden standard in the treatment of other forms of vasculitis. Nevertheless, their use in children with KD is limited (Shulman, 2003) even though they are found to suppress markers of inflammation and decrease total fever duration (Nonaka et

inflammation.

infused product.

al., 1995; Okada et al., 2003).

exposing children with KD to high doses of aspirin.

If initial therapy during the acute stage is successful, the primary objective at the subacute phase is to diminish platelet adhesion (usually by means of low dose aspirin administration), provision of supportive care when needed and monitoring patients in case of cardiovascular involvement. In both the subacute and convalescent phase, management plans are adjusted to coronary artery involvement and risk level, individualized for each patient (Newburger et al., 2004).

For the 34 cases included in our study, treatment comprised primarily of intravenous immunoglobulin G and aspirin as shown on Table 10. Aspirin was administered to 31 patients (91,2 %) during an average treatment duration of 5,7 days. Among children treated with aspirin, 23 continued with an antiplatelet dose (74,2%) after fever regression and only 1 patient had to discontinue aspirin treatment due to related hepatotoxicity. Twenty eight patients were treated with γ–globulin (82,4%) with an average treatment duration of 1,9 days. Additional therapy consisted of penicillin in 2 children, carbamazepine that was later replaced by sorvitole in 1 child, clindamycin in 1 and finally a combination of ampicillin and netilmycin in another 1 of the children. In terms of patients' management, there was also a case admitted to the intensive care unit of the hospital due to sepsis and multiple organ failure.

Table 10. Treatment of the patients hospitalized for Kawasaki disease in "P & A Kyriakou" Children's Hospital in Athens, Greece between the years 1989 and 2005

#### **7.2 Treatment of persistent or recrudescent fever**

About 10–15% of children with KD that are treated with high dose aspirin and 2 g/kg intravenous immunoglobulin G will not become afebrile (Burns et al., 1998). Fever that is not reduced 36 hours after the completion of the initial intravenous immunoglobulin G infusion is defined as persistent or recrudescent fever. This subgroup, consisting of unresponsive to

Kawasaki Disease in

**8. Conclusion**

specificity diagnostic tests.

4066–4070.

2003 Dec 30;44(6):1021-6.

**9. References**

long-segment lesions ( Akagi, 2011; Ishii et al., 2001).

a Tertiary Pediatric Referral Center in Athens, Greece and Review of the Literature 345

symptoms, reversible ischemia on stress testing and at least 75% stenosis of the left anterior descending coronary artery. Although the use of percutaneous coronary rotational ablation is still limited, this procedure may be the most appropriate catheter intervention for patients with KD. The advantage is the high success rate even among patients with calcified coronary artery stenoses (Ishii et al., 2002; Sugimura et al., 1997), which renders this method a potential therapeutic option also for postponing coronary artery bypass surgery (Lee et al., 2005). Contraindications to catheter intervention include vessels with multiple, ostial, or

Kawasaki disease is a systemic vasculitis of early childhood and comprises one of the leading causes of acquired heart disease in the western world. Although great efforts have been made in order to improve our understanding of the cause, pathogenesis and natural history of the disease, many of these aspects remain vague. Physical examination, laboratory markers of inflammation, and a case definition created for epidemiological surveys in Japan are the main tools currently available for the diagnosis of KD. Treatment with intravenous immunoglobulin in association with aspirin early in the course of the disease shortens the

duration of symptoms and decreases the frequency of coronary artery abnormalities.

care unit, all other children did not develop any severe complications.

During the period 1989–2005, 34 children with KD were admitted in our hospital. Analysis of different clinical manifestations and laboratory indices showed similar results to other studies. All children presented with fever, while the other most common symptoms were conjunctivitis, lymphadenitis, fissured lips and desquamation. Laboratory analyses were suggestive of non-specific inflammation. Patients responded well to treatment with aspirin and γ – globulin, and with the exception of one patient that was admitted to the intensive

Therapy of intravenous immunoglobulin-resistant KD remains obscure. What is the main concern, is the extent to which it is going to influence adult cardiovascular disease. Long term management of patients with KD is therefore very important and evidence–based approaches are required in order to define the best medical practice. Further research is also essential in elucidating the cause of the disease and developing high sensitivity and

Abe J, Jibiki T, Noma S, et al. Gene expression profiling of the effect of highdose intravenous Ig in patients with Kawasaki disease. *J Immunol* 2005; 174:5837–5845 Abe, J., Kotzin, B.L., Jujo, K. *et al.*: Selective expansion of T cells expressing T-cell receptor

Ahn SY, Jang GC, Shin JS, Shin KM, Kim DS. Tumor necrosis factor-alpha levels and

Ahn SY, Kim DS. Treatment of intravenous immunoglobulin-resistant Kawasaki disease

Akagi T. Catheter interventions for kawasaki disease: current concepts and future

with methotrexate. *Scand J Rheumatol* 2005; 34:136–139.

directions. *Korean Circ J*. 2011 Feb;41(2):53-7. Epub 2011 Feb 28.

variable region V 2 and V 8 in Kawasaki disease. Proc Natl Acad Sci USA 1992; 89:

promoter polymorphism in patients with Kawasaki disease in Korea. *Yonsei Med J*.

intravenous immunoglobulin G patients, is proved to be at a higher risk for developing coronary artery aneurysms (Newburger, 2000). Unfortunately, no studies have yet proven the efficacy of a specific secondary treatment. Clinicians should first re-evaluate initial diagnosis and then move to selection of an appropriate secondary treatment. Most experts recommend re-treatment with intravenous immunoglobulin G, while plasmapheresis and treatment with corticosteroids, cyclophosphamide, methotrexate and monoclonal antibodies against TNF- α have also been suggested (Ahn &Kim, 2005; Al Mayouf, 2004; Mori et al., 1995; Weiss et al., 2004).

#### **7.3 Treatment of cardiovascular complications**

Treatment of coronary disease in patients with KD depends on the severity and extent of coronary involvement. Prevention of thrombosis and myointimal proliferation that leads to stenosis are the main objectives when managing patients with coronary aneurysms. Early coronary thrombosis occurs almost exclusively among patients with giant aneurysms (Takahashi, 1996). Unfortunately, no prospective data exist to guide clinicians towards the ideal plan; therefore, treatment of this subgroup of patients is still based on experts' recommendations. Prevention of thrombosis is accomplished by the administration of an antiplatelet or an anticoagulant agent, or most frequently by a combination of both.

Antiplatelet agents play a significant role in managing patients at every stage of the disease, since platelet activation is a fundamental component of thrombosis development in KD (Burns et al., 1984, Kuramochi et al., 2000). Therefore, low dose aspirin (3–5 mg/kg daily) is the backbone of therapy for asymptomatic patients with mild and stable disease. Use of other antiplatelet agents (such as clopidogrel or dipyridamole) alone or combined with aspirin, may be more effective in suppressing platelet activation with more advanced coronary abnormalities (O'Brien et al., 2000). Randomized trials are needed to establish the role of low molecular heparin, monoclonal antibodies against IIB/IIIA receptor and warfarin in the long term management of patients with giant aneurysms (Brogan et al., 2002; Williams et al., 2002).

In contrast to adult patients with aneurysms, the thrombus burden in children with KD is not related to the form of plaque instability and rupture (Kuramochi et al., 2000). Hence, randomized controlled trials involving children with coronary thrombosis are needed to set up the role of thrombolytic medication (traditionally used in adults) such as streptokinase, urokinase and tisue plasminogen activator.

Mechanical restoration of coronary blood flow is the other option in this group of patients that develop thrombosis. Coronary bypass grafting is the recommended surgical therapy upon evidence of reversible ischemia in stress imaging, if viable myocardium is present in the area of distribution of the affected vessel and when there is absence of coronary disease distal to the planned graft site (Kitamura et al., 1994). (Yoshikawa et al., 2000). Initially, the saphenous vein was used as the graft for this procedure; however, early failures in younger children led to the introduction of internal mammary arterial grafts (Kitamura et al., 1994). It was later found that patency rates of arterial grafts were higher as opposed to venal grafts. However, despite the encouraging results during the first decade after coronary artery bypass surgery, the arterial graft patency in later adult life is still unknown (Tsuda & Kitamura, 2004).

Catheter intervention (such as balloon angioplasty, stent implantation, rotational ablation and transluminal coronary revascularization) is indicated in the presence of ischemic symptoms, reversible ischemia on stress testing and at least 75% stenosis of the left anterior descending coronary artery. Although the use of percutaneous coronary rotational ablation is still limited, this procedure may be the most appropriate catheter intervention for patients with KD. The advantage is the high success rate even among patients with calcified coronary artery stenoses (Ishii et al., 2002; Sugimura et al., 1997), which renders this method a potential therapeutic option also for postponing coronary artery bypass surgery (Lee et al., 2005). Contraindications to catheter intervention include vessels with multiple, ostial, or long-segment lesions ( Akagi, 2011; Ishii et al., 2001).

## **8. Conclusion**

344 Advances in the Diagnosis and Treatment of Vasculitis

intravenous immunoglobulin G patients, is proved to be at a higher risk for developing coronary artery aneurysms (Newburger, 2000). Unfortunately, no studies have yet proven the efficacy of a specific secondary treatment. Clinicians should first re-evaluate initial diagnosis and then move to selection of an appropriate secondary treatment. Most experts recommend re-treatment with intravenous immunoglobulin G, while plasmapheresis and treatment with corticosteroids, cyclophosphamide, methotrexate and monoclonal antibodies against TNF- α have also been suggested (Ahn &Kim, 2005; Al Mayouf, 2004; Mori et al.,

Treatment of coronary disease in patients with KD depends on the severity and extent of coronary involvement. Prevention of thrombosis and myointimal proliferation that leads to stenosis are the main objectives when managing patients with coronary aneurysms. Early coronary thrombosis occurs almost exclusively among patients with giant aneurysms (Takahashi, 1996). Unfortunately, no prospective data exist to guide clinicians towards the ideal plan; therefore, treatment of this subgroup of patients is still based on experts' recommendations. Prevention of thrombosis is accomplished by the administration of an

Antiplatelet agents play a significant role in managing patients at every stage of the disease, since platelet activation is a fundamental component of thrombosis development in KD (Burns et al., 1984, Kuramochi et al., 2000). Therefore, low dose aspirin (3–5 mg/kg daily) is the backbone of therapy for asymptomatic patients with mild and stable disease. Use of other antiplatelet agents (such as clopidogrel or dipyridamole) alone or combined with aspirin, may be more effective in suppressing platelet activation with more advanced coronary abnormalities (O'Brien et al., 2000). Randomized trials are needed to establish the role of low molecular heparin, monoclonal antibodies against IIB/IIIA receptor and warfarin in the long term management of patients with giant aneurysms (Brogan et al., 2002;

In contrast to adult patients with aneurysms, the thrombus burden in children with KD is not related to the form of plaque instability and rupture (Kuramochi et al., 2000). Hence, randomized controlled trials involving children with coronary thrombosis are needed to set up the role of thrombolytic medication (traditionally used in adults) such as streptokinase,

Mechanical restoration of coronary blood flow is the other option in this group of patients that develop thrombosis. Coronary bypass grafting is the recommended surgical therapy upon evidence of reversible ischemia in stress imaging, if viable myocardium is present in the area of distribution of the affected vessel and when there is absence of coronary disease distal to the planned graft site (Kitamura et al., 1994). (Yoshikawa et al., 2000). Initially, the saphenous vein was used as the graft for this procedure; however, early failures in younger children led to the introduction of internal mammary arterial grafts (Kitamura et al., 1994). It was later found that patency rates of arterial grafts were higher as opposed to venal grafts. However, despite the encouraging results during the first decade after coronary artery bypass surgery, the arterial graft patency in later adult life is still unknown (Tsuda &

Catheter intervention (such as balloon angioplasty, stent implantation, rotational ablation and transluminal coronary revascularization) is indicated in the presence of ischemic

antiplatelet or an anticoagulant agent, or most frequently by a combination of both.

1995; Weiss et al., 2004).

Williams et al., 2002).

Kitamura, 2004).

urokinase and tisue plasminogen activator.

**7.3 Treatment of cardiovascular complications**

Kawasaki disease is a systemic vasculitis of early childhood and comprises one of the leading causes of acquired heart disease in the western world. Although great efforts have been made in order to improve our understanding of the cause, pathogenesis and natural history of the disease, many of these aspects remain vague. Physical examination, laboratory markers of inflammation, and a case definition created for epidemiological surveys in Japan are the main tools currently available for the diagnosis of KD. Treatment with intravenous immunoglobulin in association with aspirin early in the course of the disease shortens the duration of symptoms and decreases the frequency of coronary artery abnormalities.

During the period 1989–2005, 34 children with KD were admitted in our hospital. Analysis of different clinical manifestations and laboratory indices showed similar results to other studies. All children presented with fever, while the other most common symptoms were conjunctivitis, lymphadenitis, fissured lips and desquamation. Laboratory analyses were suggestive of non-specific inflammation. Patients responded well to treatment with aspirin and γ – globulin, and with the exception of one patient that was admitted to the intensive care unit, all other children did not develop any severe complications.

Therapy of intravenous immunoglobulin-resistant KD remains obscure. What is the main concern, is the extent to which it is going to influence adult cardiovascular disease. Long term management of patients with KD is therefore very important and evidence–based approaches are required in order to define the best medical practice. Further research is also essential in elucidating the cause of the disease and developing high sensitivity and specificity diagnostic tests.

## **9. References**

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**18**

 *Morocoo*

**Neurological Manifestations in Behcet Disease**

Behçet disease is a multisystem disease of unknown cause in which an inflammatory perivasculitis can arise in almost any tissue (Sakane et *al.,* 1999). Neurologic involvement in Behçet disease was first reported by Knapp in 1941. It represented between 4-49% of manifestations of BD (Haghighi et *al.,* 2005). There is one of the most serious causes of long term morbidity and mortality in Behçet's Disease. As well as, involvement of the central nervous system occurs late in the course of the disease (10–25%) (Ildan et *al.,* 1996; Nakasu et *al.,* 2001). It is caused by primary neural parenchymal lesions or is secondary to major

Treatment of the most cases of NB should be given as infusion of intravenous methyl prednisolone followed by a slowly tapering course of oral steroids. (Adnan et *al.,* 2000,). Immunopressives agents should be used in its severity forms of NB such as meningoencephalitis, deep veins thrombosis and myelopathy. In this Review, we

Epidemiological, Clinical characterization and pattern of neurological involvement of Behcet's disease have been reported in different series (Hentati et al., 1993; bohlega et al., 1993; nakamura et al., 1994; Farah et al,1998; Kidd et al.,1999; Akman et al.,1999; Al fahad et

Retrospective and prospective studies found that the prevalence of Neurobehcet disease (NBD) is very variable. Neurologic involovement were occured in 2-49% of cases, other authors estimated their prevalence of 3-50% of cases (Borhani et al., 2009). The age of onset of NBD is usually 20–40 years with an average age of 39 years. In two the last decade, Neurological complications have also been described in children. (Adnan et al., 2005 ; Araji

The highest incidence is in the Middle East, the Mediterranean basin, and the Far East regions, but it is rare in Europe and North America. The frequency was 13% in men and 5・6% in women. Neurological manifestations commonly develop a few years after the onset of the other systemic features of BD; The mean duration between onset of BD and development of NBD ranged from 3 to 6 years. (Siva et al., 2001). However, neurological syndrome might coincide or come in advance (~6% of patients) with other systemic

summarise and describe the clinicals manifestations of neurobehcet disease.

**1. Introduction**

**2. Epidemiology**

al.,1999).

et al., 2009).

vascular involvement (Adnan et al, 2009).

E. Ait Ben Haddou, A. Benomar, W. Regragui and M. Yahyaoui *Departement of Neurology B and Neurogenetic, Hopital des Spécialités, Rabat,*

*Mohammed V Souissi University, Faculty of Medicine of Rabat,*

## **Neurological Manifestations in Behcet Disease**

E. Ait Ben Haddou, A. Benomar, W. Regragui and M. Yahyaoui

*Departement of Neurology B and Neurogenetic, Hopital des Spécialités, Rabat, Mohammed V Souissi University, Faculty of Medicine of Rabat, Morocoo*

## **1. Introduction**

352 Advances in the Diagnosis and Treatment of Vasculitis

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coronary artery aneurysms in patients with mucocutaneous lymph node syndrome.

Behçet disease is a multisystem disease of unknown cause in which an inflammatory perivasculitis can arise in almost any tissue (Sakane et *al.,* 1999). Neurologic involvement in Behçet disease was first reported by Knapp in 1941. It represented between 4-49% of manifestations of BD (Haghighi et *al.,* 2005). There is one of the most serious causes of long term morbidity and mortality in Behçet's Disease. As well as, involvement of the central nervous system occurs late in the course of the disease (10–25%) (Ildan et *al.,* 1996; Nakasu et *al.,* 2001). It is caused by primary neural parenchymal lesions or is secondary to major vascular involvement (Adnan et al, 2009).

Treatment of the most cases of NB should be given as infusion of intravenous methyl prednisolone followed by a slowly tapering course of oral steroids. (Adnan et *al.,* 2000,). Immunopressives agents should be used in its severity forms of NB such as meningoencephalitis, deep veins thrombosis and myelopathy. In this Review, we summarise and describe the clinicals manifestations of neurobehcet disease.

## **2. Epidemiology**

Epidemiological, Clinical characterization and pattern of neurological involvement of Behcet's disease have been reported in different series (Hentati et al., 1993; bohlega et al., 1993; nakamura et al., 1994; Farah et al,1998; Kidd et al.,1999; Akman et al.,1999; Al fahad et al.,1999).

Retrospective and prospective studies found that the prevalence of Neurobehcet disease (NBD) is very variable. Neurologic involovement were occured in 2-49% of cases, other authors estimated their prevalence of 3-50% of cases (Borhani et al., 2009). The age of onset of NBD is usually 20–40 years with an average age of 39 years. In two the last decade, Neurological complications have also been described in children. (Adnan et al., 2005 ; Araji et al., 2009).

The highest incidence is in the Middle East, the Mediterranean basin, and the Far East regions, but it is rare in Europe and North America. The frequency was 13% in men and 5・6% in women. Neurological manifestations commonly develop a few years after the onset of the other systemic features of BD; The mean duration between onset of BD and development of NBD ranged from 3 to 6 years. (Siva et al., 2001). However, neurological syndrome might coincide or come in advance (~6% of patients) with other systemic

Neurological Manifestations in Behcet Disease 355

Second a progressive form of the disease which represents 10% of cases of NBD, including, a

Third, symptoms and signs suggestive of cerebral hemispheric involvement include encephalopathy, hemiparesis, Hemisensory loss, seizures, dysphasia, and mental changes

Fourth, symptoms and signs of spinal cord involvement include pyramidal signs in the

Finally, asymptomatic (silent) parenchymal NBD is diagnosed if there are no neurological symptoms, but neurological signs on examination (usually pyramidal signs ). Recognition of these clinical syndromes might help clinicians dealing with BD to predict the pattern of involvement. They might also help neurologists to remember BD in the differential diagnosis of a patient who presents with one of these neurological syndromes. In addition, other clinical syndromes might arise in BD, and although uncommon, it is important that

Neuro-BD-related epileptic disorder has been previously reported in a large series of Behçet disease. Generalized seizures are the predominant type (Aykutlu et *al.*, 2002). Convulsions were observed in 2 - 5% of large series (Al-Fahad et al., 2001).Behcet's syndrome may present with partial seizure and epilepsia partialis continua (Aktekin et *al*., 2006. Partial

Since the first described case in 1987; Focal necrotic lesions in the cerebral cortex; only a few cases have been published. (Litvan et *al.,* 2005; Matsuo et *al.,* 2005; Appenzeller et *al.,* 2005;

The regions usually affected are, brainstem, diencephalon, basal ganglia, and internal capsule. The clinical presentation depends on the localizations of brain tumors; usually include intracranial hypertension syndrome and/or impaired of consciousness.

Extrapyramidal manifestations whitch are indicating basal ganglion excessive dysfunction,

Aseptic meningitis commonly exists with many parenchymal CNS manifestations of BD. The signs and symptoms are relatively common in parenchymal NBD. However, isolated meningitis might only rarely be the presenting feature of NBD (Kidd et al., 1999; Akman et

Optic neuropathy is rare in BD, it has been described only in0.4% of the main series of behçet disease. It can be bilateral and can be recurrent over many years. The severity of the

worsening subcortical dementia, were usually accompanied by ataxia.

limbs, sensory level dysfunction, and, commonly, sphincter dysfunction.

seizures were a presenting feature of NBD in one report (Chroni et *al.*, 2008).

Kosters et *al.,* 2006; Bennett et *al.,* 2004; Park et *al.*, 2002).

with cognitive dysfunction and psychosis.

these syndromes are recognized.

**5.1.1 Epilepsy**

**5.1.2 Brain tumour**

**5.1.3 Movement disorders**

are rare in most series of patients with NBD.

**5.1.4 Acute meningeal syndrome**

*al.,* 1999; Al-Fahad et *al.,* 1999).

**5.1.5 Optic neuropathy**

symptoms features of BD, in that case diagnosis can be difficult and causes ambiguity with other systemic diseases (Akman et *al.,* 1999).

## **3. Classification**

There are two categories of neurological involvement in BD that have been generally accepted: parenchymal involvement and non-parenchymal involvement, also called cerebral angio-Behcet's syndrome. The most syndromes often involved in NBD were meningoencephalitis, myelopathy and deep veins thrombosis which presented 80% in retrospective series (Tohme et al., 2008)

## **4. Neuropathology**

NBD is considered as an inflamatory perivasculitis disease, in an acute meningoencephalitis the most common neuropathologic findings are Severe and acute inflammation consisting mainly of lymphocytic, eosinophils, macrophages, and neutrophilic infiltrations of the perivascular spaces and parenchyma. These lesions can lead to necrotizing and disseminated encephalitis involving the basal ganglia, brainstem, cerebellum and diencephalon.

In the progressive phase, authors found the inflammatory infiltration of lymphocytes and cytokines remains and cuts down.

## **5. Clinical characteristics**

In order to the accumulated data, it's now obvious that it is necessary to handle parenchymal CNS involvement and non parenchymal CNS involvement in Behçet'sdisease separately.

## **5.1 Parenchymal CNS involvement**

#### About 70 à 80% CNS involvement

First of all, Subacute meningoencephalitis accounts for 75% of cases in parenchymal NBD, which performs adverse symptoms, depending on the topography of lesions.

It's and often associated with exacerbation of the systemic features of BD, including fever, malaise, orogenital ulcers, skin lesions, or uveitis (Akman et *al.,* 2003; Joseph et *al.,* 2007).

The onset of signs is in the most cases acute or subacute. More rarely, the onset is chronic (Akman *et al.,* 1999). Onset is usually with an attack of headache, hemiparesis and / or gradual behavioural changes. The symptoms and signs are taking a few days to attempt Summit and during several weeks, rely on depending on the extent of the lesion and on how rapidly treatment is initiated. However, spontaneous remissions of symptoms could be taken before initiation of therapy as it has been reported (Hirohata et *al.,* 2007).

Different syndromes might be encountered during the course of parenchymal NBD.

The patient may frequently show brainstem signs, including pyramidal bilateral and cebellar syndromes, ophthalmoparesis and cranial neuropathy. Moreover, there is evidence for additional cerebral or spinal cord involvement like a day time sleeping with or without hyperphagia and which might be indicative of hypothalamic dysfunction (Wechsler et al., 2002; Houmana et *al.,* 2009)

Second a progressive form of the disease which represents 10% of cases of NBD, including, a worsening subcortical dementia, were usually accompanied by ataxia.

Third, symptoms and signs suggestive of cerebral hemispheric involvement include encephalopathy, hemiparesis, Hemisensory loss, seizures, dysphasia, and mental changes with cognitive dysfunction and psychosis.

Fourth, symptoms and signs of spinal cord involvement include pyramidal signs in the limbs, sensory level dysfunction, and, commonly, sphincter dysfunction.

Finally, asymptomatic (silent) parenchymal NBD is diagnosed if there are no neurological symptoms, but neurological signs on examination (usually pyramidal signs ). Recognition of these clinical syndromes might help clinicians dealing with BD to predict the pattern of involvement. They might also help neurologists to remember BD in the differential diagnosis of a patient who presents with one of these neurological syndromes. In addition, other clinical syndromes might arise in BD, and although uncommon, it is important that these syndromes are recognized.

#### **5.1.1 Epilepsy**

354 Advances in the Diagnosis and Treatment of Vasculitis

symptoms features of BD, in that case diagnosis can be difficult and causes ambiguity with

There are two categories of neurological involvement in BD that have been generally accepted: parenchymal involvement and non-parenchymal involvement, also called cerebral angio-Behcet's syndrome. The most syndromes often involved in NBD were meningoencephalitis, myelopathy and deep veins thrombosis which presented 80% in

NBD is considered as an inflamatory perivasculitis disease, in an acute meningoencephalitis the most common neuropathologic findings are Severe and acute inflammation consisting mainly of lymphocytic, eosinophils, macrophages, and neutrophilic infiltrations of the perivascular spaces and parenchyma. These lesions can lead to necrotizing and disseminated encephalitis involving the basal ganglia, brainstem, cerebellum and

In the progressive phase, authors found the inflammatory infiltration of lymphocytes and cytokines remains and cuts down. (Hirohata et al., 2008; Heo et al., 2008; Hadfi et al., 1996;

In order to the accumulated data, it's now obvious that it is necessary to handle parenchymal CNS involvement and non parenchymal CNS involvement in Behçet'sdisease

First of all, Subacute meningoencephalitis accounts for 75% of cases in parenchymal NBD,

It's and often associated with exacerbation of the systemic features of BD, including fever, malaise, orogenital ulcers, skin lesions, or uveitis (Akman et *al.,* 2003; Joseph et *al.,* 2007). The onset of signs is in the most cases acute or subacute. More rarely, the onset is chronic (Akman *et al.,* 1999). Onset is usually with an attack of headache, hemiparesis and / or gradual behavioural changes. The symptoms and signs are taking a few days to attempt Summit and during several weeks, rely on depending on the extent of the lesion and on how rapidly treatment is initiated. However, spontaneous remissions of symptoms could be

The patient may frequently show brainstem signs, including pyramidal bilateral and cebellar syndromes, ophthalmoparesis and cranial neuropathy. Moreover, there is evidence for additional cerebral or spinal cord involvement like a day time sleeping with or without hyperphagia and which might be indicative of hypothalamic dysfunction (Wechsler et al.,

which performs adverse symptoms, depending on the topography of lesions.

taken before initiation of therapy as it has been reported (Hirohata et *al.,* 2007). Different syndromes might be encountered during the course of parenchymal NBD.

other systemic diseases (Akman et *al.,* 1999).

retrospective series (Tohme et al., 2008)

Arai et al., 2006; Scardamaglia et al., 2001).

**5. Clinical characteristics**

2002; Houmana et *al.,* 2009)

**5.1 Parenchymal CNS involvement**  About 70 à 80% CNS involvement

**3. Classification**