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Cardiac Involvement and Prognosis in Acute Mucocutaneous Lymph Node Syndrome
Cardiac Involvement and Prognosis in Acute Mucocutaneous Lymph Node Syndrome* Zenshiro Onouchi, M.D.; Nunehiko Tomizawa, M.D.; Masakatsu Goto, M.D.; Kazuyasu Nakata, M.D.; Masaru Fukuda, M.D.; and Motoko Goto, M.D.
Cardiac involvement and prognosis were studied in the acute febrile mucocutaneous lymph node syndrome which recently has been found among Japanese infants and younger children. The reason for its particular predilec-
A cute
mucocutaneous lymph node syndrome ( MLNS) is a disease of unknown etiology and pathogenesis affecting most frequently infants and children under five years of age. Its onset produces an acute, febrile condition accompanied by swelling of cervical lymph nodes. Since MLNS was first established as a separate entity by Kawasaki 1 in 1967, much attention has been focused upon it by the Japanese Pediatric Society. According to a nationwide survey conducted by the MLNS Research Committee of the Ministry of Health and Welfare starting in 1970, more than 7,000 cases were reported by 1973. The syndrome has 1.4 percent mortality; 2 the death is caused either by rupture of an aneurysm of the main coronary artery, by thrombosis of same, 3 or mitral insufficiency4 due to papillary muscle dysfunction. We have recently determined, and report here, the relationship between the clinical findings in the active stage of the disease and the pathologic change in the main coronary artery. In addition, we discuss its pathogenesis and predisposing cause of invasion of the main coronary arteries. MATERIALS AND METHODS
We selected 21 from 60 patients who fulfilled the diagnostic criteria set forth by the MLNS Research Committee of Ministry of Heal~ and Welfare, whose coronary arteries to examine. After the diagnosis of MLNS was made, erythrocyte sedimentation rate, C-reactive protein levels, electrocardiogram, cardiothoratic ratio of chest x-ray films, complete blood count, urinalysis and blood chemistry were examined weekly, until acute reactants returned to normal. ECGs were analyzed with respect to P-Q intervals, corrected Q-T intervals<~ ( Bazett's index), ST changes,6.7 and T/R ratioll in left precordial leads. On the evaluation of CTR9 and P-Q inter-
°From Kyoto Prefectural University School of Medicine,
Kyoto City, Japan. Manuscript received December 5; revision accepted January 27. Reprint requests: Dr. Onouchi, Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto City, Japan
CHEST, 68: 3, SEPTEMBER, 1975
tion for the main coronary arteries and the pathologic process are discussed in relation to the pathogenesis and nutrient of the main coronary arteries.
vals, weiO registered a~ abnonnal (even if they were within normal limit~ in reference with patient's age and heart rate) those values which changed in the healing stage less than those in the active stage. Left ventricular and selective coronary angiography were perfom1ed in 20 patients after the active stage had passed; two patients had these repeated a half year later. Myocardial biopsies were performed in three cases for histologic examination. Of the 20 cases and an additional one upon whom autopsy was perfonned, findings of the three main hranches ol coronary artery were classified into three groups : (I) normal, ( 2) stenosis or diminished blood flow, and ( 3) aneurysm. Results of the various examinations and after steroid hormone treatment were carefully examined. It was also noted at what part of the main coronary arteries the aneurysms were seen. Light and electronmicroscopic studies were performed in four cases from whom samples of myocarditun had heen obtained at the time of angiography and from those with skin eruptions before administration of steroid hormone. RESULTS
There was no difference in values of transminase and LDH in the three groups. Myocardial LDH levels were not elevated, even in the cases with prominent cardiac enlargement. Acute reactants had low values and became normal rapidly in the "normal" group. The values were high in the "stenosis" and "aneurysm" groups, which persisted in the former group for a shorter period than in the latter. Moreover, in the "aneurysm" group, administration of steroid hormones tended to be too late, as well as too little (Table I) . Cardiothoracic ratios in the active stage were within normal range in the "normal" group and in some of the "stenosis" group. But in the latter group some were noted to have slightly increased cardiathoracic ratios less than the value of 0.55. In the "aneurysm" group the cardiothoracic range in most showed a marked increase, and remained abnormal even after the active stage had passed (cases 18 and 21 ). ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 297
Table !--Coronary Arterial Lesions and Clinical Data .-\('lit(' He:wtants
('a>'<' numl ... r St•x I 2 :l ·I .'i fi
F F :\I :\I
.\gp
0.-t 0 .7
12 l:l II
F :\I
.')
l.'i I fi •
:\I :\I :\I :\I F :\I
0 .7 I :l -t -1 5
:\I
(j
7
s
!I 10 II
17 IS
1!1 20 21
I
:--itpnosis
I
or dt•t•rt•a>'<'tl flow
2 3
a
--- - - ,
Duration .-\V!:'r:lji;P BPginning of ESR ESR and ovPr of CatPgory CHP IPvt·l 30mm / hour tn•atment
I Yr. :\ormal 2 2
l\1 :\I :\I F :\I :\I :\I F
Prednisolonp
-1 -1
Hmm i -t+ IH / 1+ 36 / 6+
da~·s
0 II
69 /5+ 6-l / 6+ 53 17+ 83 15+ 71 1-l + 77 !5+ lll / .'J+ li7 i 3+ 8-t /8+ 7-t/7+ 136 / 10+
18 12 22 13 1-l 18 17 22 20 15 2-t
81 15+ 8fi/ 5 + 88 / -1+ 71 16+ 80 / -1+ !l6/ 6+
3-1 26 2-1 61 50 35 31
.,.,
.-\rwurysm or dilatation
18
'?In:uiP'lll:tlt• rPeortling
9 days 6 7 8 7 3 8 9 7 15 9 7 18 7 6 15
30 1-l
PQ :\lax prolongalion CTH
2 mg / kg 0.50 0.8 0.51 2 0.50 2 2 2 2 2 2 0 2 2 2 2 0.5 0.8 2 0 0 2
ECG
0.52 0.50 ? 0 .5-t 0.55 0.52 0.-t!)
.,
0.52 0.5-l 0.-!8 •)
0.68 0.56 0.5-1 0.66 ? 0.60
QTC;;: O.H S!'t'
STin \".; ~ -0.1 m\"
T 'H in \" ,~ I / 6
? +
+ + ?
.,
+ + +
+ + + +
+ +
+ + + +
+ + + +
?
+
+ + + + +
+ + + +
+ + + +
??Xot dom• in al'liw• >'tagt•
There were no abnormal ECG findings in the "normal" group, hut flattening of T waves or QTc prolongation in the active stage was seen in the other groups. ~1orcover, PQ interval was elongated in some cases of the "stenosis" and "aneurysm" group. While only in the "aneurysm" group were significant ST depressions noted in leads 2, aVF, and all chest leads, especially the Vr. lead. Even if MLI\'S left a large aneurysm in the coronary artery as a sequela, the electrocardiographic changes returned to normal when the active stage had passed, except the QTc was prolonged ten months after the onset of the disease in one of the "aneurysm" group (Case 21). Stenosis or decreased blood flow involved the left circumflex or left anterior descending branch on the coronary arteriogram and the regional myocardium was perfused by the dilated branches of right coronary artery (Fig 1 ) . Aneurysms (Fig 2, 3, 4) tended to involve preferentially the main coronary arteries, but were never seen at a distance of 10 mm or more from the coronary ostium (Fig 5) . ~Ioreover, thrombosis was always noted in large aneurysms. Skin biopsies showed no remarkable change on light microscopic studies, but ultrastructural observations hy electronmicroscopy made this clear. The capillary lesion showed its basement membrane extremely thickened (Fig 6) . 298 ONOUCHI ET Al
Initial dosp
ChPst x-ray
Histologic examinations of myocardiums obtained by biopsy revealed a small focus of Anitschkow ''myocytes" (Fig 7) which was considered to represent a microinfarct 11 even in one patient a year and
FIGURE 1. Dilated acute marginal artery as collateral circulation in a patient with narrowing of the ldt anterior descending artery.
CHEST, 68: 3, SEPTEMBER, 1975
FIGUHE
2. Large aneurysm at left main coronary artery.
a half after the active stage had passed. Electron microscopic investigation of myocardiocytes showed increased lipid droplets anti other degenerative changes.
Autopsy Filulings 12
FIGURE
4. Small aneurysms at both main coronary arteries.
nutrient arteries. The overall process is panarteritis. These lesions characteristically were in the same stage of development. The wall of the aneurysm showed massive necrosis due to the nutrient arteritis.
The patient was a 22-month-old boy. At necropsy, the enlarged heart was surrounded by large bleeding into the pericardium from a fissure of the aneurysmal wall which measured 3 x 2 x 1.5 em and was located at the left coronary artery 1.5 em distal to the ostium. The coronary arteries on both sides were very dilated and tortuous. Pathologic findings characteristically consisted of small and medium-sized muscular arteries. Although almost all organ systems were affected, these lesions were seen particularly in the coronary arteries in both the extra- and intramyocardium including its
FIGURE
.3. Large aneurysm at right main coronary artery.
CHEST, 68: 3, SEPTEMBER, 1975
FIGURE 5. Left side shows the right coronary aneurysm which is not displayed by aortography.
ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 299
6. Capillary with thickened basement membrane at the eruption ( 22000 X ) . En == endothelial cell, Er == erythrocyte; B~l == basement membrane; NCl == nucleus. FtGUHE
Drsc.ussiON The etiology of this syndrome remains unknown. \lemhers of the study committee consider that many agents, such as microorganisms or drugs, may act as triggers for the attack. Hamashima, 13 a pathologist, insists that some form of rickettsia is the specific cause. Kawasaki'-"-'• described in detail the differentiation between this syndrome and other diseases with erythema and fever. The pathogenesis of MLNS has not been established yet, as mentioned. But, of known entities, infantile polyarteritis nodosa 14 seems to be similar to \1LNS as to clinical symptoms and pathologic findings, except the prognosis. In the former, the patients always have a downhill course to death, while, in the latter, most patients had been said to be completely recovered until the frequent involvement of the coronary arteries comes to light, leaving grave damage. 15 MLNS and infantile polyarteritis pathogenctically seem to be related to hypersensitivity or allergic angiitis 16 but differ pathologically from classic polyarteritis 17 in that ( 1) smaller caliber arteries and arterioles are primarily affected, ( 2) capillaries in addition to arteries are involved, and ( 3) vascular lesions are generally at the same stage of development. Infantile polyarteritis nodosa seems to represent the most severe form of MLl\S and displays the broad clinical spectrum. It has recently been established that almost all cases of MLNS 10 •18 reveal the ECG abnormalities and/ or cardiac enlargement in the active stage. Cardiac involvement may be divided into two groups: one resulting from myocardial ischemia and another resulting from myocarditis and pericarditis. 19 ·20 In reference to myocardial ischemia, cardiac involvement may be also divided into two groups: one resulting from arteritis of the main coronary arteries and another from focal necrosis of myocardium due to intramyocardial small arteritis. Especially in the "aneurysm" group, the ECG 300 ONOUCHI ET Al
showed horizontal or downward sloping of the STsegment combined with Q-T prolongation; these findings are generally regarded as ischemic type.~1."" Because ECG abnormalities disappeared in most cases when the active stage had passed, the inner caliber of the coronary arteries became narrow in the active stage, but myocardial ischemia may improve during the healing of the arteritis. On the other hand, with reference to myocarditis, the pathologic process is not due to direct invasion of causative agents but to cell infiltration into the myocardium from the periarteritis. When the arteritis of the main coronary artery is moderate, it becomes stenotic in the healing stage. If the inflammation is extensive, the arterial wall ruptures before it is replaced by fibrous tissue. Those that do not rupture still have the possibility of thrombosing. The extent of cardiac involvement is closely related to the degree and the extent of the acute reaction in the active phase of the disease. Steroid hormones given in sufficient doses started early in the course of the disease seem to be fairly effective as treatment and as preventive measures in cardiac involvement. If the aneurysm has already devel-
FIGURE 7 . Small focus of Anitchkow myocytes or myoc.:ardial histiocytes which may represent the mkroinfarct.
CHEST, 68: 3, SEPTEMBER, 1975
OtA .....
••
,.&l
OGtC
(01t0 •• , ... , ... , • ,,,. '
14ii ,.._
1o
....... ,
0
"
...
J Pediat 24:2546, I97I Tanaka ;'\ : Study for autopsied cases of ML:.'\S (in Japanese) . Acta Paediat Jap 76:696, I972 Hamada I, Takao A, et a! : Cardiova~cular <:om plication in MU'\S: special reference to mitral regurgitation and coronary arterial aneurysm ( in Japanese). Rinsho Shoni lgaku 2I: I63, I973 ~fcCammon RW: A longitudinal study of electrocardiographic intervals in healthy children. Acta Paediat (Uppsala), Suppl.I26, I96I Myers CB, Talmers FN: The electrocardiographic diagnosis of acute myocardial ischemia. Ann Intern ~led 43 :36I, 1955 Rohh CP, Marks HH : Postexercise electrocardiogram in arteriosclerotic heart disease. Its value in diagnosis and prognosis. JA~fA 200 : 110, I967 Lepeschkin E : Modem Electrocardiography. Baltimore, Williams and Wilkins, 195I Maresh ~1~1, Washburn AH : Size of the heart in healthy ehildren. Am J Dis Child 56:33, I938 Onouchi Z, Tanaka K, et al : The study of ~ILXS (I) Cardiac involvement (in Japanese) . Acta Paediat Jap 77 :3:20, I973 Karsner HT, Dwyer JE Jr : Studies in infarction. n· Experimental blood infarction of the myocardium, myocardial regeneration and cicatrization. J ~led Res 34 :2I, I9I6 Tanaka K, Onouchi Z, et al: l11e study in MLXS (II). An autopsy case and reference with infantile polyarteritis nodosa (in Japanese). Acta Paediat Jap 77 :397, 1H73 Hamashin1a Y, Kishi K, Tasaka K: Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph-node syndrome. Lancet 11:42,1973 Roberts FB, Fetterman CH : Polyarteritis nodosa in infancy. J Pediat 63:519, 1963 Panel discussion on the eardiac involvement in ~ILl'\S . Japanese Congress of Pediat, April, 1974 Zeek P1\l: Periarteritis nodosa and other fonns of necrotizing angitis. N Eng! J Med 248:763, I953 Kussmaul A, Maier R: Uher eine hisher nieht heschreibene eigenthiimliche Arterienerkrankung ( Periarteritis nodosa), die mit :O.Iorbus Brightii und rapid fortschreitender allgemeiner Muskelliihmung einhergeht. Deutsches Arch f Klin ~led I :-!84, I866 Asai T, Kiguehi H, Nagai Y, et al: Analysis of cardiac involvement in 29 cases with ~ILNS (in Japanese). Jap J Pediat 26:824, I973 Yamamoto T, Kimura T : A case of MLNS with carditis (in Japanese) . Jap J Pediat 2I :336, I9fi8 Asai T, Knsakawa S, et al: Three eases of ~ILXS with myocarditis (in Japanese) . Jap J Pediat 23:1588, 1970 Winsor T: Electrolyte abnonnalities and electrocardiogram. JAMA 203:109, 1968 ca~es in MLNS (in Japanese). Jap
3 4
.5
6
7
8 9 10
11
FIGURE 8. 1\ utrient arteries distributed at main coronary artery and predisposition of involvement of main coronary artery.
oped, it would seem better to treat with anticoagulants. In this way, sudden occlusion of the aneurysm may be prevented, and we may place our hope on the development of collateral circulation. As to its particular predilection for the main coronary arteries in both MLNS and infantile polyarteritis in comparison with classic polyarteritis, 23 we mantion, in speculation, the distribution of its nutrient arteries studied by Clark 24 in 1964 and its narrow caliber due to the younger age of the patients (Fig 8) . The first nutrient artery originates at the coronary ostium and perfuses only the coronary wall of its proximal portion, while at the distal portion, the nutrient arteries are peripheral coronary arteries. Therefore, necrosis and inflammatory reaction in the coronary wall in that portion due to the nutrient arteritis seems to cause narrowing, resulting in diminished blood flow into the involved nutrient artery, and a vicious cycle comes into existence. ACKi\OWLEDGMENT : We Kusunoki , Director, Pediatric Fujita, Director, Deparhnent ment and critical advice; Drs. Coto for their cooperation.
wish to thank Prof. Tomoichi Department, and Prof. Tetsu of Pathology, for encourageKazuhiko Tanaka and Motoko
REFERENCES
Kawasaki T: ~ICLS-Clinical observation of 50 cases (in Japanese) . Jap J Allerg 16:178, 1967 2 MLSN Research Committee: Discussion on the autopsied
CHEST, 68: 3, SEPTEMBER, 1975
I2
13
14 15 16 I7
18
19 20 2I
22 Surawicz B, Lasseter KC : Effects of dmgs on the electrocardiogram. Prog Cardiovas Res 13:26, 1970 23 Holsinger DR, Osmundson PJ, Edwards JE : The heart in periarteritis nodosa. Circulation 25:610-618, 1962 24 Clark JA : An x-ray microscopic sh1dy of the vasa va~omm of nonnal human coronary arteries. J Anat 98:939, 1964 25 Kawasaki T , Kosaki F, Okawa S, et al : A new infantile acute febrile mucocutaneous lymph node syndrome ( MLNS) prevailing in Japan. Pediatrics 54:27I, I974
ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 301
Cardiac involvement and prognosis were studied in the acute febrile mucocutaneous lymph node syndrome which recently has been found among Japanese infants and younger children. The reason for its particular predilec-
A cute
mucocutaneous lymph node syndrome ( MLNS) is a disease of unknown etiology and pathogenesis affecting most frequently infants and children under five years of age. Its onset produces an acute, febrile condition accompanied by swelling of cervical lymph nodes. Since MLNS was first established as a separate entity by Kawasaki 1 in 1967, much attention has been focused upon it by the Japanese Pediatric Society. According to a nationwide survey conducted by the MLNS Research Committee of the Ministry of Health and Welfare starting in 1970, more than 7,000 cases were reported by 1973. The syndrome has 1.4 percent mortality; 2 the death is caused either by rupture of an aneurysm of the main coronary artery, by thrombosis of same, 3 or mitral insufficiency4 due to papillary muscle dysfunction. We have recently determined, and report here, the relationship between the clinical findings in the active stage of the disease and the pathologic change in the main coronary artery. In addition, we discuss its pathogenesis and predisposing cause of invasion of the main coronary arteries. MATERIALS AND METHODS
We selected 21 from 60 patients who fulfilled the diagnostic criteria set forth by the MLNS Research Committee of Ministry of Heal~ and Welfare, whose coronary arteries to examine. After the diagnosis of MLNS was made, erythrocyte sedimentation rate, C-reactive protein levels, electrocardiogram, cardiothoratic ratio of chest x-ray films, complete blood count, urinalysis and blood chemistry were examined weekly, until acute reactants returned to normal. ECGs were analyzed with respect to P-Q intervals, corrected Q-T intervals<~ ( Bazett's index), ST changes,6.7 and T/R ratioll in left precordial leads. On the evaluation of CTR9 and P-Q inter-
°From Kyoto Prefectural University School of Medicine,
Kyoto City, Japan. Manuscript received December 5; revision accepted January 27. Reprint requests: Dr. Onouchi, Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto City, Japan
CHEST, 68: 3, SEPTEMBER, 1975
tion for the main coronary arteries and the pathologic process are discussed in relation to the pathogenesis and nutrient of the main coronary arteries.
vals, weiO registered a~ abnonnal (even if they were within normal limit~ in reference with patient's age and heart rate) those values which changed in the healing stage less than those in the active stage. Left ventricular and selective coronary angiography were perfom1ed in 20 patients after the active stage had passed; two patients had these repeated a half year later. Myocardial biopsies were performed in three cases for histologic examination. Of the 20 cases and an additional one upon whom autopsy was perfonned, findings of the three main hranches ol coronary artery were classified into three groups : (I) normal, ( 2) stenosis or diminished blood flow, and ( 3) aneurysm. Results of the various examinations and after steroid hormone treatment were carefully examined. It was also noted at what part of the main coronary arteries the aneurysms were seen. Light and electronmicroscopic studies were performed in four cases from whom samples of myocarditun had heen obtained at the time of angiography and from those with skin eruptions before administration of steroid hormone. RESULTS
There was no difference in values of transminase and LDH in the three groups. Myocardial LDH levels were not elevated, even in the cases with prominent cardiac enlargement. Acute reactants had low values and became normal rapidly in the "normal" group. The values were high in the "stenosis" and "aneurysm" groups, which persisted in the former group for a shorter period than in the latter. Moreover, in the "aneurysm" group, administration of steroid hormones tended to be too late, as well as too little (Table I) . Cardiothoracic ratios in the active stage were within normal range in the "normal" group and in some of the "stenosis" group. But in the latter group some were noted to have slightly increased cardiathoracic ratios less than the value of 0.55. In the "aneurysm" group the cardiothoracic range in most showed a marked increase, and remained abnormal even after the active stage had passed (cases 18 and 21 ). ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 297
Table !--Coronary Arterial Lesions and Clinical Data .-\('lit(' He:wtants
('a>'<' numl ... r St•x I 2 :l ·I .'i fi
F F :\I :\I
.\gp
0.-t 0 .7
12 l:l II
F :\I
.')
l.'i I fi •
:\I :\I :\I :\I F :\I
0 .7 I :l -t -1 5
:\I
(j
7
s
!I 10 II
17 IS
1!1 20 21
I
:--itpnosis
I
or dt•t•rt•a>'<'tl flow
2 3
a
--- - - ,
Duration .-\V!:'r:lji;P BPginning of ESR ESR and ovPr of CatPgory CHP IPvt·l 30mm / hour tn•atment
I Yr. :\ormal 2 2
l\1 :\I :\I F :\I :\I :\I F
Prednisolonp
-1 -1
Hmm i -t+ IH / 1+ 36 / 6+
da~·s
0 II
69 /5+ 6-l / 6+ 53 17+ 83 15+ 71 1-l + 77 !5+ lll / .'J+ li7 i 3+ 8-t /8+ 7-t/7+ 136 / 10+
18 12 22 13 1-l 18 17 22 20 15 2-t
81 15+ 8fi/ 5 + 88 / -1+ 71 16+ 80 / -1+ !l6/ 6+
3-1 26 2-1 61 50 35 31
.,.,
.-\rwurysm or dilatation
18
'?In:uiP'lll:tlt• rPeortling
9 days 6 7 8 7 3 8 9 7 15 9 7 18 7 6 15
30 1-l
PQ :\lax prolongalion CTH
2 mg / kg 0.50 0.8 0.51 2 0.50 2 2 2 2 2 2 0 2 2 2 2 0.5 0.8 2 0 0 2
ECG
0.52 0.50 ? 0 .5-t 0.55 0.52 0.-t!)
.,
0.52 0.5-l 0.-!8 •)
0.68 0.56 0.5-1 0.66 ? 0.60
QTC;;: O.H S!'t'
STin \".; ~ -0.1 m\"
T 'H in \" ,~ I / 6
? +
+ + ?
.,
+ + +
+ + + +
+ +
+ + + +
+ + + +
?
+
+ + + + +
+ + + +
+ + + +
??Xot dom• in al'liw• >'tagt•
There were no abnormal ECG findings in the "normal" group, hut flattening of T waves or QTc prolongation in the active stage was seen in the other groups. ~1orcover, PQ interval was elongated in some cases of the "stenosis" and "aneurysm" group. While only in the "aneurysm" group were significant ST depressions noted in leads 2, aVF, and all chest leads, especially the Vr. lead. Even if MLI\'S left a large aneurysm in the coronary artery as a sequela, the electrocardiographic changes returned to normal when the active stage had passed, except the QTc was prolonged ten months after the onset of the disease in one of the "aneurysm" group (Case 21). Stenosis or decreased blood flow involved the left circumflex or left anterior descending branch on the coronary arteriogram and the regional myocardium was perfused by the dilated branches of right coronary artery (Fig 1 ) . Aneurysms (Fig 2, 3, 4) tended to involve preferentially the main coronary arteries, but were never seen at a distance of 10 mm or more from the coronary ostium (Fig 5) . ~Ioreover, thrombosis was always noted in large aneurysms. Skin biopsies showed no remarkable change on light microscopic studies, but ultrastructural observations hy electronmicroscopy made this clear. The capillary lesion showed its basement membrane extremely thickened (Fig 6) . 298 ONOUCHI ET Al
Initial dosp
ChPst x-ray
Histologic examinations of myocardiums obtained by biopsy revealed a small focus of Anitschkow ''myocytes" (Fig 7) which was considered to represent a microinfarct 11 even in one patient a year and
FIGURE 1. Dilated acute marginal artery as collateral circulation in a patient with narrowing of the ldt anterior descending artery.
CHEST, 68: 3, SEPTEMBER, 1975
FIGUHE
2. Large aneurysm at left main coronary artery.
a half after the active stage had passed. Electron microscopic investigation of myocardiocytes showed increased lipid droplets anti other degenerative changes.
Autopsy Filulings 12
FIGURE
4. Small aneurysms at both main coronary arteries.
nutrient arteries. The overall process is panarteritis. These lesions characteristically were in the same stage of development. The wall of the aneurysm showed massive necrosis due to the nutrient arteritis.
The patient was a 22-month-old boy. At necropsy, the enlarged heart was surrounded by large bleeding into the pericardium from a fissure of the aneurysmal wall which measured 3 x 2 x 1.5 em and was located at the left coronary artery 1.5 em distal to the ostium. The coronary arteries on both sides were very dilated and tortuous. Pathologic findings characteristically consisted of small and medium-sized muscular arteries. Although almost all organ systems were affected, these lesions were seen particularly in the coronary arteries in both the extra- and intramyocardium including its
FIGURE
.3. Large aneurysm at right main coronary artery.
CHEST, 68: 3, SEPTEMBER, 1975
FIGURE 5. Left side shows the right coronary aneurysm which is not displayed by aortography.
ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 299
6. Capillary with thickened basement membrane at the eruption ( 22000 X ) . En == endothelial cell, Er == erythrocyte; B~l == basement membrane; NCl == nucleus. FtGUHE
Drsc.ussiON The etiology of this syndrome remains unknown. \lemhers of the study committee consider that many agents, such as microorganisms or drugs, may act as triggers for the attack. Hamashima, 13 a pathologist, insists that some form of rickettsia is the specific cause. Kawasaki'-"-'• described in detail the differentiation between this syndrome and other diseases with erythema and fever. The pathogenesis of MLNS has not been established yet, as mentioned. But, of known entities, infantile polyarteritis nodosa 14 seems to be similar to \1LNS as to clinical symptoms and pathologic findings, except the prognosis. In the former, the patients always have a downhill course to death, while, in the latter, most patients had been said to be completely recovered until the frequent involvement of the coronary arteries comes to light, leaving grave damage. 15 MLNS and infantile polyarteritis pathogenctically seem to be related to hypersensitivity or allergic angiitis 16 but differ pathologically from classic polyarteritis 17 in that ( 1) smaller caliber arteries and arterioles are primarily affected, ( 2) capillaries in addition to arteries are involved, and ( 3) vascular lesions are generally at the same stage of development. Infantile polyarteritis nodosa seems to represent the most severe form of MLl\S and displays the broad clinical spectrum. It has recently been established that almost all cases of MLNS 10 •18 reveal the ECG abnormalities and/ or cardiac enlargement in the active stage. Cardiac involvement may be divided into two groups: one resulting from myocardial ischemia and another resulting from myocarditis and pericarditis. 19 ·20 In reference to myocardial ischemia, cardiac involvement may be also divided into two groups: one resulting from arteritis of the main coronary arteries and another from focal necrosis of myocardium due to intramyocardial small arteritis. Especially in the "aneurysm" group, the ECG 300 ONOUCHI ET Al
showed horizontal or downward sloping of the STsegment combined with Q-T prolongation; these findings are generally regarded as ischemic type.~1."" Because ECG abnormalities disappeared in most cases when the active stage had passed, the inner caliber of the coronary arteries became narrow in the active stage, but myocardial ischemia may improve during the healing of the arteritis. On the other hand, with reference to myocarditis, the pathologic process is not due to direct invasion of causative agents but to cell infiltration into the myocardium from the periarteritis. When the arteritis of the main coronary artery is moderate, it becomes stenotic in the healing stage. If the inflammation is extensive, the arterial wall ruptures before it is replaced by fibrous tissue. Those that do not rupture still have the possibility of thrombosing. The extent of cardiac involvement is closely related to the degree and the extent of the acute reaction in the active phase of the disease. Steroid hormones given in sufficient doses started early in the course of the disease seem to be fairly effective as treatment and as preventive measures in cardiac involvement. If the aneurysm has already devel-
FIGURE 7 . Small focus of Anitchkow myocytes or myoc.:ardial histiocytes which may represent the mkroinfarct.
CHEST, 68: 3, SEPTEMBER, 1975
OtA .....
••
,.&l
OGtC
(01t0 •• , ... , ... , • ,,,. '
14ii ,.._
1o
....... ,
0
"
...
J Pediat 24:2546, I97I Tanaka ;'\ : Study for autopsied cases of ML:.'\S (in Japanese) . Acta Paediat Jap 76:696, I972 Hamada I, Takao A, et a! : Cardiova~cular <:om plication in MU'\S: special reference to mitral regurgitation and coronary arterial aneurysm ( in Japanese). Rinsho Shoni lgaku 2I: I63, I973 ~fcCammon RW: A longitudinal study of electrocardiographic intervals in healthy children. Acta Paediat (Uppsala), Suppl.I26, I96I Myers CB, Talmers FN: The electrocardiographic diagnosis of acute myocardial ischemia. Ann Intern ~led 43 :36I, 1955 Rohh CP, Marks HH : Postexercise electrocardiogram in arteriosclerotic heart disease. Its value in diagnosis and prognosis. JA~fA 200 : 110, I967 Lepeschkin E : Modem Electrocardiography. Baltimore, Williams and Wilkins, 195I Maresh ~1~1, Washburn AH : Size of the heart in healthy ehildren. Am J Dis Child 56:33, I938 Onouchi Z, Tanaka K, et al : The study of ~ILXS (I) Cardiac involvement (in Japanese) . Acta Paediat Jap 77 :3:20, I973 Karsner HT, Dwyer JE Jr : Studies in infarction. n· Experimental blood infarction of the myocardium, myocardial regeneration and cicatrization. J ~led Res 34 :2I, I9I6 Tanaka K, Onouchi Z, et al: l11e study in MLXS (II). An autopsy case and reference with infantile polyarteritis nodosa (in Japanese). Acta Paediat Jap 77 :397, 1H73 Hamashin1a Y, Kishi K, Tasaka K: Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph-node syndrome. Lancet 11:42,1973 Roberts FB, Fetterman CH : Polyarteritis nodosa in infancy. J Pediat 63:519, 1963 Panel discussion on the eardiac involvement in ~ILl'\S . Japanese Congress of Pediat, April, 1974 Zeek P1\l: Periarteritis nodosa and other fonns of necrotizing angitis. N Eng! J Med 248:763, I953 Kussmaul A, Maier R: Uher eine hisher nieht heschreibene eigenthiimliche Arterienerkrankung ( Periarteritis nodosa), die mit :O.Iorbus Brightii und rapid fortschreitender allgemeiner Muskelliihmung einhergeht. Deutsches Arch f Klin ~led I :-!84, I866 Asai T, Kiguehi H, Nagai Y, et al: Analysis of cardiac involvement in 29 cases with ~ILNS (in Japanese). Jap J Pediat 26:824, I973 Yamamoto T, Kimura T : A case of MLNS with carditis (in Japanese) . Jap J Pediat 2I :336, I9fi8 Asai T, Knsakawa S, et al: Three eases of ~ILXS with myocarditis (in Japanese) . Jap J Pediat 23:1588, 1970 Winsor T: Electrolyte abnonnalities and electrocardiogram. JAMA 203:109, 1968 ca~es in MLNS (in Japanese). Jap
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FIGURE 8. 1\ utrient arteries distributed at main coronary artery and predisposition of involvement of main coronary artery.
oped, it would seem better to treat with anticoagulants. In this way, sudden occlusion of the aneurysm may be prevented, and we may place our hope on the development of collateral circulation. As to its particular predilection for the main coronary arteries in both MLNS and infantile polyarteritis in comparison with classic polyarteritis, 23 we mantion, in speculation, the distribution of its nutrient arteries studied by Clark 24 in 1964 and its narrow caliber due to the younger age of the patients (Fig 8) . The first nutrient artery originates at the coronary ostium and perfuses only the coronary wall of its proximal portion, while at the distal portion, the nutrient arteries are peripheral coronary arteries. Therefore, necrosis and inflammatory reaction in the coronary wall in that portion due to the nutrient arteritis seems to cause narrowing, resulting in diminished blood flow into the involved nutrient artery, and a vicious cycle comes into existence. ACKi\OWLEDGMENT : We Kusunoki , Director, Pediatric Fujita, Director, Deparhnent ment and critical advice; Drs. Coto for their cooperation.
wish to thank Prof. Tomoichi Department, and Prof. Tetsu of Pathology, for encourageKazuhiko Tanaka and Motoko
REFERENCES
Kawasaki T: ~ICLS-Clinical observation of 50 cases (in Japanese) . Jap J Allerg 16:178, 1967 2 MLSN Research Committee: Discussion on the autopsied
CHEST, 68: 3, SEPTEMBER, 1975
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22 Surawicz B, Lasseter KC : Effects of dmgs on the electrocardiogram. Prog Cardiovas Res 13:26, 1970 23 Holsinger DR, Osmundson PJ, Edwards JE : The heart in periarteritis nodosa. Circulation 25:610-618, 1962 24 Clark JA : An x-ray microscopic sh1dy of the vasa va~omm of nonnal human coronary arteries. J Anat 98:939, 1964 25 Kawasaki T , Kosaki F, Okawa S, et al : A new infantile acute febrile mucocutaneous lymph node syndrome ( MLNS) prevailing in Japan. Pediatrics 54:27I, I974
ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 301