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The nervous system in acrodynia
THE NERVOUS SYSTEM IN ACRODYNIA I~
OF T H E LITERATURE AND REPORT OF A CASE A L B E R T J . L U B I N AND HAROLD K .
FABER., M . D .
S A N ~RANCISCO, CALIF.
aerodynia has become a well-defined and fairly common A LTHOUGH clinical entity, reported examinations of the nervous system are not only somewhat meager but are conflicting. The confusion is evident not only in locating the site of the lesion, but also in the type of cellular response noted. This great variance in findings is demonstrated in the accompanying tabllla,tion, which includes all of the available pathologic descriptions. The original d e s c r i p t i o n of a e r o d y n i a was p u b l i s h e d b y O. Selter~ i~x 1908. I n 1914 Swifte r e p o r t e d a series of cases i n A u s t r a i i a . Since t h a t t i m e it h a s gone under a variety of names : ' ~S e l t e r - S w i f t - F e e r ' s Disease, ' ' c ~p i n k discus% ' ' ' ' e r y t h r o e d e m % ' ~ ~' dermatopolyneuritis~ ' ' ~' t r o p h o d e r m a t o n e u r o s i % ' ' a n d ~~vegetative n e u r o s i s . " I t a p p e a r s i n y o u n g children, chiefly ' % o , d d l e r s , " a n d h a s been said to h a v e occurred in epidemics. The onset is u s u a l l y insidious. C h a n g e s i a t h e disposition, s u c h as a p a t h y , m a y a p p e a r first. The e x t r e m i t i e s become swollen a n d podgy, a n d e r y t h e m a t o u s r a s h e s a p p e a r on t h e skin. t I y p e r e s t h e s i a s a n d p r u r l t l s a r e common. S i g n s o f d y s f u n c t i o n o f t h e a u t o n o m i c n e r v o u s s y s t e m include prof u s e s w e a t i n g , d i g e s t i v e disorders, t a c h y c a r d i a a n d h y p e r t e n s i o n , d i l a t a t i o n of t h e p u p i l s a n d p h o t o p h o b i a , increased metabolic rate, alopecia neurotica, ~'hinorrhe% sialorrhea, v a s o m o t o r d i s t u r b a n c e s in t h e extremities, a ~ d t r o p h i c ulcers. Occasionally m u s c u l a r w e a k n e s s is t h e first s y m p t o m , a n d t h e deep reflexes o f t e n disa p p e a r . I n severe cases t h i s weakness is followed b y p a r a l y s i s . P l e o c y t o s i s a n d increase of spinal fluid p r o t e i n h a v e been noted. The p r o g n o s i s is u s u a l l y good, a n d complete recovery occurs i n t h r e e to n i n e m o n t h s . E m a c i a t i o n or i n t e r c u r r e n t inf e c t i o n is t h e cause of d e a t h in a few cases. SUlYI]KARY
OF
NEUROPATHOLOGIC
CHANGES
REPORTED
Spinal Cord.--Of the total of thirty-seven cases reported, nothing abnormal was noted in eighteen. Four cases showed only a slight diffuse increase of small round cells. Edema without inflammatory infiltration was observed in two cases. One case contained inflammatory nodules, consisting mostly of ]ymphocytes, near the entrance of the dorsal roots. Involvement of nerve cells was described in twelve cases. One of these consisied of vacuolar degeneration of posterior horn cells, one of poorly stained anterior horn cells, and one of a few swollen anterior horn cells. Distinct chromatolysis of nerve cells was cited in nine egses; in seven of these it was confined to anterior horn cells, in one to cells of the anterior horns, lateral horns, and Clarke's column, and in another to cells of the lateral horns, with lesser changes in the anterior horns. From partment
the Division of :N-euro!osychiatry (Netlropathology of Pediatrics, Stanford. University School of ~r 515
Laboratory)
and
the De-
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I n eleven eases a diffnse i n c r e a s e of s m a l l r o u n d cells was n o t e d , W i l l i e a n d S t e r n r e p o r t i n g seven of these. M y e l i n s h e a t h a b n o r m a l i t i e s w e r e o b s e r v e d in o n l y t h r e e instances, a n d in two of these it was m i l d . No abnormalities noted Slight increase of small round cells Edema without inflammatory reaction Inflammatory nodules Nerve cell involvement posterior horn cells anterior horn cells alone anterior and lateral horn cells an"cerior and lateral horn cells and cells of Clarke's celmnn Total
18 4 2
1 12
37
Brain.--No p a t h o l o g i c m a n i f e s t a t i o n s were n o t e d in e i g h t e e n eases. I n a n o t h e r t e n the c h a n g e s were nonspecifie, c o n s i s t i n g of g e n e r a l i z e d congestion, edema, h y p e r e m i a , a n e m i a , o r s l i g h t i n c r e a s e o f s m a l l r o u n d Cells. I n seven cases t h e r e was i n v o l v e m e n t of t h e r e g i o n a d j a c e n t to t h e t h i r d v e n t r i c l e , p o s t u l a t e d as t h e site of t h e d i e n e e p h a l i e s y m p a t h e t i c center. I n two cases t h e lesions were w i d e l y s c a t t e r e d t h r o u g h o u t v a r i ous p o r t i o n s of t h e brMn. No abnormalities noted Nonspeei~c changes, as edema and congestion Involvement of sympathetic center in dieneephalon Scattered lesions Total
1.8 10 7 2 37
Peripheral Nerves.--lnvolvement of p e r i p h e r a l n e r v e s was d e s c r i b e d in t w e l v e instances. A c t u a l d e g e n e r a t i o n of m y e l i n s h e a t h s o r axis c y l i n d e r s was p r e s e n t in seven of these. C h r o m a t o l y s i s of cells in t h e g a s s e r i a n g a n g l i o n was n o t e d in two eases. I n n i n e eases t h e r e was specific m e n t i o n t h a t no a b n o r m a l i t i e s w e r e f o u n d in t h e p e r i p h e r a l nerves. Sympathetic Nervous System.--The p e r i p h e r a l s y m p a t h e t i c system was i n v o l v e d in e i g h t cases. I n one ease m a n y n e r v e cells w i t h two n u c l e i w e r e f o u n d ; l y m p h o c y t i c i n f i l t r a t i o n w a s d e s c r i b e d in t h r e e cases; in two cases t h e r e was n e u r o n o p h a g i a i n a d d i t i o n to t h e l y m p h o c y t i c i n f i l t r a t i o n ; in a n o t h e r two cases t h e r e was m a r k e d n e u r o n o p h a g i a a n d c e l l u l a r d e g e n e r a t i o n . T h e r e is specific m e n t i o n t h a t no a b n o r m a l i t i e s were f o u n d in e i g h t cases. T h e r e were f e w cases, however, in which a d e q u a t e e x a m i n a t i o n was m a d e of t h e p a r a v e r t e b r a l c h a i n g a n g l i a a n d t h e i r p e r i p h e r a l connections. Vagus Nerve.--Some d e g e n e r a t i o n was n o t e d in one instance. Peripheral nerve involvement Sympathetic nerve involvement Gasserian ganglion, chromatolysis Vagus degeneration, mild Dorsal root involvement
12 8 2 1 9
TABLE I NEUtCOPATI~OLOGIC CHANGES DESCRIBED IN ACROI)YNIA AUTtIO]g
Byfield (1920)
Paterson and Greenfield (1923) 2 cases
Helmholz (1925) IIoMand (1925)
S P I N A L CORD A N D ROOTS
BRAIN
P E R I P H E R A L AND SYMPATIIETIC NERVES
A few anterior horn Edema of m y e l i n cells stained poorly; sheaths and connecgliosis around central tive t i s s u e about canal; some variation nerve f b e r s in sciatic in fiber size in lumbar nerve. posterior roots with edema and swelling of myelin sheaths. Slight diffuse increase Cortex, thalamus, and Vagus and cervical of small cells, appar- pons negative. sympathetic nerves ently glial, in cervical negative ; nuclei apa~d ]umbosaeral enpeared to be more largements a n d in numerous in brachial roots (especially dorplexus but median sal roots). nerve was negative. Capillary congestion Negative. Myelin degeneration and diffuse increase in internM and exof small cells in cord t er n a1 popliteM and roots ; swelling, nerves; most marked eccentric nuclei, and distally ; some chromatolysis of anchanges in lmnbar terior horn cells, most nerve. marked in lmnbosaeral region. Definite nerve Negative. changes. Negative. Few changes but not Cord negative enough to warrant diagnosis of peripheral neuritis.
Cord and roots nega- Marked congestion and tive except for edema edema of meninges with proliferation of 2 cases of meninges. r e t i e u l o - endothelial cells. congestion and Perivascular edema; no 3s degenerative or in- edema of brain and meninges and marked flammatory changes. proliferation of retienlo-endothelial cells. F~er (Vetter) Cord negative Sympathetic nerves negative. (1925) Woringer Brain edematous; some Many cells in sympa(1926) macrophagie loci at thetic ganglion with some posterior commissure two n u c l e i , with chroma~t[n of ~hird ventricle. granules. Kernohan and Chromatolysis - of ante- Advanced chromatoly- Myelin sheath disin:Kennedy rior horn tells, espe- sis in floor of fourth tegration and swol(1928) cially in ventrolateral ventricle, locus caeru- len, nodular axis cylgroup in sacral re- ] e u s , meseneephalic inders, especially in gion; lateral horn cells root of fifth nerve, sciatic and femoral and cells of Clarke's lenticular nucleus, an- n e r v e s ; marked column involved in terior nucleus of fhal- chromatolysis in gas'serian ganglia. thoracic reglon; ap- a l n a s . parent i n c r e a s e in glia; no one cell group completely involved; chromatolysis in post e r i o r root ganglia, especially at lumbar level. Warthin (1926)
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I--CONT
'D
I AUTIIOR
Fruneioni and Vigi (199.8) (developed a f t e r epidemic encephalitis) Findlay and Stern (1929) 0 r t o n and Bender (1931) (review of Byfield's case)
Willie and Stern (1931) 7 cases
SPINAL CORD A N D ROOTS
BKAII~
Chromatolysis, eceentrio nuclei, and some shadow cells in infundibulum and tuber cinereum ; dissipation of lesions toward hypothalamus. Small round cell infilt r a t i o n in medulla; negative above medulla.
' PERIPHERAL AND SYhIPATIIETIC N E R V E S
Perivascular collars of small round cells in cervical sympathetic ganglia.
Small round cell infilCervical and abdomtration in cord a~d in a1 sympathetic along posterior roots; ganglia negative. early anterior horn cell changes. Chromatolysis, sclerosis, and destruction of many l a t e r a l horn ceils ; loss of myelin sheaths, glial increase, small hemorrhages in lateral horns ; chromato]ysis of a n t e r i o r horn c e l l s withou% glial reaction. Slight anterior horn Negative. Beading and fragcell chromutolysis with mentation in sciatic some satellitosls in nerve and brachial seventh cervical segplexus. ment; advanced changes in anterior horn cells in fourth and fifth l u m b a r ; slight round cell infilt r a t i o n ; some myelin degeneration. Few swollen anterior Increased vascularity Negative. horn cells; diffuse in- of cortex; slight small filtration of s m a 11 cell infiltration in corround cells; f a t drop- tex and medulla. lets in dorsal roots. Some anterior horn cell Small round cell infil- Negative. chromatolysis in lure- tration in cortex and bar region; small cell basal ganglia. infiltration, especially in dorsal horns. Slight excess of small Negative. Negative. cells. Few rounded anterior Negative. F a t globules along horn cells in cervical course of all periphenlargement ; slight eral n e r v e s , espechromatolysis in antecially median. romedial g r o u p in third and fourth lure-: b a r ; small round c e l l infiltration. Chromatolysis and few Negative. Early degeneration of eccentric nuclei in anperipheral nerves, esterior horn cells of pecially near Ranlumbar enlargement; vier's nodes. small cell infiltration. Slight i n c r e a s e of Negative. Some degeneration of vagus fibers. round cells.
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TABLE I - - C O N T ' D
AUTHOR
SPINAL CORD AND ROOTS
So6s (1931)
de Lange (1932)
Spinal cord negative; chromatolysis and eccentric nuclei in posterior root ganglia.
Bellocq and Meyer (1932)
Some degeneration and vacuolization of posterior horn Cells.
BRAIN
PERIPHERAL AND SYMPATHETIC NERVES
B r a i n substance soft Marked differences in doughy, and anemic. size, pyknotic and absent nuclei, poorly stained tigroid substance, and marked neuronophagia in cells of solar and paravertebral chain ganglia. Circumscribed f r o n t a l Chromatolysis and ecmeningitis, perivascu- centric nuclei in gaslar infiltration in pia- serian ganglion. arachnoid; increase of glia (especially mieroglia) without neuronophagia in infundibulotuberous region and c~gliaknStchen ' ' ; less marked glial increase in midbrain, locus caeruleus, putamen, globus pallidus, and right dentate nucleus; c h a n g e s not found in controls. Cellular 1 e s i o n s and Numerous l o c i of neuronophagia in the neuronophagia a n d inf undibulocellular degeneration tuberous region and in sympathetic chain along the walls of the ganglia; myelin dethird ventricle. generation in crura] andintraspinal nerves.
Blackfan and McKhann (1933) 5 cases Braithwaite (1933) 2 cases
Wolf and Davison (]934)
Examination of the central nervous system, peripheral nerves, and sympathetic nervous system failed to disclose changes which could not be related to the terminal infection. Cord negative.
B r a i n i n j e c t e d ; increase in cerebrospina] fluid; apparent increase in neuroglial cells of white matter. Cord negative. B r a i n congested and edematous ; glia slightly edematous. Chromatolysis and vae- Slight disarrangement Early disintegration uolization in nucleus of all layers of cortex, and swelling of myeventralis of eleventh" especially t h i r d ; some lin, early axis cylinnerve a n d anterior chromatolysis and fall- der changes in pehorn cells; mild disin- ing out of cells, slight ripheral nerves, more tegration of single increase in glia in cor- advanced in lower fibers in spino-olivary, tex; swelling of gan~ extremities. spinocerebellar, a n d glion cells in basal lateral pyramidal ganglia; severe cell tracts. changes in locus eaeruleus; a b s e n c e of fibrillary processes, $ lack of chromatin, and I swelling of P u r k i n j e I cells in cerebellum ; ] some s w e l l i n g of / ganglion cells about ] fourth ventricle aud 1 pens. {
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TABLE I---(]ONT ~D AUT]:IOI% l)eamer and
Biskind
(193~)
SPINALC0gD AND !~OOTS
Spinal cord negative; Negative. chromatolysis and neuronophagia in thoracic posterior roots.
Fessler (1935) i~[ouriquand, Dechaume, Bernheim, and Weill (1935)
Inflammatory nodules, consisting mostly of lymphocytes, in thoracic region near entry of dorsal roots; lymphocytic infiltration and satellitosis of ganglion cells in dorsal root ganglion.
Pehu,
Cord and roots negative.
Dechaum% and Boueomont (1936)
BRAIN
Mouriquand, Dechaume, and S4da]lian (1936)
Cord negative.
Harris (1935)
Small round cell infiltration a~d wellmarked chromatolysis of anterior horn cells in spilm.1 cord.
PERIPHEKAL
AN])
SY1VfPATttETIC NEgVES Chromatolysis an d neuronophagia in sympathetic c h a i n ganglia with phagocytic cell infiltration resembling tubercle of rabies; sympathetic g a n g l i a of thoracic aorta negative; slight spreading of bundles of vagus and sciatic nerves.
Hyperemia and edema of b r a i n ; internal hydrocephalus. B r a i n congested; slight Lymphocytic masses, inflaznmation, perivas- perivascular cuffing, eular cuKing of lym- lymphocytic invasion phocytes and plasma of stroma, satellitocells in meninges; sis and pseudoneunodules of lympho- ronophagia, an d cytes or glia in supra- some neuronophagia optic nuclei ; vascular in coeliac and cervicongestion and disten- cal s y m p a t h e t i c tion of perivascular ganglia ; peripheral sheaths around third nerves negative. ventricle. Perivascular cuffing Increase of ]ymphoand lymphocytic infil- eytes, perivascularly t r a t i o n in meninges; and in stroma, and m a r k e d congestion, of satellite cells in and engorgement of sympathetic ganglia. vessels, l e u e o e y t i c thrombi in region of third ventricle ; lymphoplasmocytie infiltration, as partial perivascular cuffs, near vegetative nuclei in walls of t h i r d yentricle. Congestion of s m a l l Perivascular lymphovessels w i t h hemor- eyrie infiltration in rhages in perivascular coeliac ganglion. spates in walls of third ventricle; similar changes in cerebral cortex.
demyelinizaCongestion of cortical Patchy vessels ; small round l tion in most periphespecell infiltration ; but eral n e r v e s , cially in left phrenie no degeneration. and left sciatic nerves and in right brachial p l e x u s ; both vagi negative..
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Dorsal Roots and Ganglia.--Abnormalities in the dorsal roots were present in nine cases. ~[n four this consisted of an increase or infiltration of small r o u n d cells, in three there was chromatolysis of ganglion cells, in one fat droplets were noted, and in one there was edema. CASE
REPORT
P. I~.~ a boy~ 2 years and i0 months old~ entered the Imspital ~[ay 25~ 1935j with bronchopneumonia. He had had a previous attack of pneumonia in December, 1934, accompanied by otorrhea and tonsillitis. In February~ 1935~ he became listles% his legs became weak~ and all of his extremities cold and pink, turning definitely red in a few days. Itis temperature was slightly elevated. There was profuse sweating. When he was placed on his feet, he showed evidence of discomfort. Later in the month his feet scaled, and the distal phalanges of the fingers became swollen and puffy. He slept i~ grotesque positions an~d was very irritable, t i t s appetite was poor, and he lost a slight amount of weight. During March he became somewhat worse, i n April an abscess developed in the right ear and was drained. Swelling of the hands increased and also appeared in the feet. The child was unable to walk. During the next month the paralysis increased and involved both arms and legs. The pink color disappeared. On May 23 a cough developed, he became prostra.ted~ breathing became difficult, and the temperature rose to 102.2 ~ F., dropping ~o 101.6 ~ 1~. the next day when he entered the hospital.
Physical Examdnation.--He was a well-developed but malnourished boy, breathing rapidly and coughing frequently. There was marked scaling and thickening of the epidermis of the extremities. The tonsils were reddened but not enlarged. The percussion note was dull over the entire right side of the chest; the breath sounds were diminished and were bronchial in character posteriorly. X-ray films revealed collapse of the right m~dd]e and upper lobes. The neurological examination showed a flaccid paralysis of both legs with absent knee and ankle jerks. No pathologic reflexes were elicited. Both biceps and triceps reflexes on the right were not obtained. There was marked weakness of both upper extremities. The elec'trieal reactions of the muscles were not impaired. The abdominal and eremasterie reflexes were absent. There was marked hyperalgesia. Bloa8 Count.--5,3007000 rod ceils; 95 per cent hemoglobin; 47,800 white ceils, with 85 per cellt polymorphonuelears, of which 29 per cent were banded. Course.-- During the next few days he improved ; the right lung expauded~ and the white count decreased to 26,000 on klay 29. But on June 1 the respiratory rate increased, the right lower lobe collapsed, and a mucous rattle was audible. Carbogen was given, but on the morning of June 2 the patient suddenly died. No cyanosis was present. A~ttopsy.--Sections of skeletal muscle from the back, pectoral muscles, and diaphragm were normal. There was a slight f a t t y infiltration of the heart~ but the muscle fibers were normal. Sections through the aorta were negative, ttassall corpuscles were quite numerous in the thymus; the cellular elements were normal. The lungs were moderately congested, and there were a f e w areas of collapse. In places the alveoli were filled with fluid and contained ]urge mononuelears, ]ymphoeytes, and polymorphonuelear leucocytes. The bronchi contained desquamated epithelial eellsj a few Iymphoeytes and polymorphonuclears, and red cells; the mucosa was moderately infiltrated. Smears from the right lniddle lobe contained gram-posltlve eocai in pairs and short chains; no acid-fast bacilli were seen. A peribronchial lymph node was moderately congested and contained many leucocytes; the germinal centers were large and several mitotic figures were present.
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Nothing abnormM trabeculae of the contained a small moderate amounts
was present in ti~e gastrointesthxal tract. The capsule and spleen were normal; some large phagocytic cells in the pulp amount of brown pigment. Adrenal cortical cells contained of lipoid material. ~'xa~ni~atio~ of the iVervous System.--Examination of the coeliac ganglion revealed nothing abnormal. Unfortunately no other part of the sympathetic nervous system and none of the peripheral nerves were available for examination. Macroscopically there were no abnormalities in either" the bruin or spinal cord. Celloidin sections were made from various portions of the brain and spinal cord. Nothing abnormal was found in the cortex, mesencephMon, ports, cerebellum, or medulla. Serial sections of the diencephMou from the level of the subthMamic nucleus through the tuber einereum were studied. Careful examination was made of the puraventricular nucleus, the supraoptic nucleus, the nucleus of the tuber cineream, the mammillary body, and tim subthalamic nucleus (corpus ]uysi). There was no perivascular infiltration or increase of glia. IvIany of the cells contained eccentric nuclei and only small amounts of Nissl substance; pseudoneuronophagia was present in places. Such findings, however, were interpreted as normal in this portion of the brain. There was no true neuronophagla. The nuclei were of regular contour, the nuclear membranes were intact, and the nucleoli were not pyknotic. The cells were neither swollen nor shrunken, and no shadow forms were present. I n the spinal cord, sections through the cervical region were normal. The intermediolateral cell column in the thoracic region contained many degenerating cells. Extrusion of the nucleus, folding of the nuclear membrane, absence of Niss] bodies, vacuole formation, and occasional shadow forms were observed (Fig. 1). The cells of Clarke's colunm were larger than the anterior horn cells at the same level, and degenerative changes were seen in a few of them. Anterior horn cells in the cervical, thoracic, and upper lumbar segments were normal. The most striking changes were present in the lower lmubar and upper sacral regions, involving the anterior horn cells of the posterolateral cell column (Fig. 2). There were many round and swollen cells, marked central chromatolysis, eccentric nuclei, and vacuole formation. The nuclear membranes were often hyperchromatic and folded and the nucleoli pyknotic. I n some cells the nuclei were missing or protruding. Shallow forms indicated advanced degeneration. Compared with the amount of cellular involvemerit, there was but little glial response. Sate]litosis and neuronophagia were seen only in a few places. Frozen sections stained with the Cajal gold-sublimate method revealed no increase in neuroglia. No myelin sheath abnormalities were present with ~he Weigert stain. DISCUSSION
The clinical picture of aerodynia clearly points in all cases to an involvement of the sympathetic nervous system. The symptomatology is so widespread that this involvement must necessarily be either localized in a center of sympathetic activity, as in the diencephalon, or diffuse throughout more peripheral portions of the sympathetic system. Pathologic changes have been located by various authors in the following places: (]) the diencephalic sympathetic centers, (2) the intermediolateral cell column in the spinal cord, (3) the paravertebral chain ganglia and the other peripheral sympathetic nervous pathways, and (4) the peripheral nerve trunks and posterior roots. Francioni and Vigi, ~~ de Lange, ~ and Belloeq and Meyer ~6 described lesions in the region of the tuber cinereum and infundibulum; Mouriquand, et al, 22 noted inflammatory lesions in the region adjacent to the
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t h i r d ventricle. 0 r t o n and Bender 12 found the most marked changes in the intermediolateral cell column, in which sympathetic motor cells
Fig. 1 . - - E x t r u d i n g n u c l e i ( A ) a n d d e g e n e r a t e d cells w i t h a b s e n t n u c l e i ( B ) in i n t e r m e d i o l a t e r a l ,cell c o l u m n . A cell w h i c h is n o t in f o c u s ( C ) c o n t a i n s a l a r g e vacuole. Cresyl violet stain.
F i g . 2 . - - A n t e r i o r h o r n cells o f t h e p o s t e r o l a t e r a l cell c o l u m n in t h e Ul~per s a c r a l r e g i o n , s h o w i n g m a r k e d s w e l l i n g , c h r o m a t o l y s i s , e c c e n t r i c nuclei, a n d s h a d o w f o r m s . Cresyl violet stain,
form synapses with descending sympathetic pathways in the spinal cord and ~ v e off sympathetic neurones to the peripheral sympathetic ganglia. Kernohan and Kennedy 9 also noted involvement of this re-
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gion, although merely as part of widespread damage. Sofs TM and others described neuronophagia in paravertebral and other sympathetic ganglia. Paterson and Greenfield4 believed that the disease was a polyneuritis. Varying degrees of posterior root involvement were mentioned in nine cases.
Those findings in the dieneephalon particularly warrant skepticism. Sehwarz, Goolker, and Globus24 have pointed out normM findings in infants' brains that are frequently misinterpreted as pathologic. This was in an attempt to disprove Goldzieher's theory that intestinal intoxication of infants (Goldzieher's "diencephalitis dehydrans") was due to cellular infiltration of the region adjacent to the walls of tile third vent,ride. They observed that discrete cellular aggregations, often perivascular, in this region were but normal manifestations of a ripening brain. In the case described here interest was particularly focused on the dieneephalic sympathetic nuclei. Serial sections through this region, including the subthalamie nneleus, the periventrieular nuelei, and the tuber einereum, failed to reveal anything which could be interpreted as pathologic. Eccentricity of nuclei and lack of centrally placed Nissl bodies were considered as normal in this area. Pathologic findings were all confined to the spinal cord. Involvement of anterior horn cells in the lumbosaeral region and of cells of the intermediolateral cell column in the thoracic region were noted, the changes being especially striking in the anterior horn cells. These changes consisted of swelling and central ehromatolysis, folding of the nuclear membrane, nuclear displacement, and shadow forms, but there was no marked gliM reaction. Changes in the anterior horn cells explain the flaccid paralysis found in this ease. The changes in the intermediolateral cell column, in which are located sympathetic motor cells, seem significant. In only two other eases (Kernehan and Kennedy s and Orton and Bender12), however, have similar changes been noted, so that it is difficult to evaluate whether they are of fundamental importance. A review of the literature shows that reported changes in the nervous system are inconstant. Degenerative changes i n anterior horn cells, as noted in.this ease, were lacking in many reports. FVr example, in Willie and Stern's series~a of seven cases ehromatolysis was not noted in two, was mild in four, and was advanced in only one case. In the same series varying degrees~,of peripheral nerve involvement were found in four eases, and there were no changes in three; in two of the eases small cell infiItration in the cerebrum was mentioned and was not found in five. Failure in finding constant and fundamental pathologic changes, however, is not without precedent in diseases of the nervous system. Honeyman 2~ has reported four fatal cases of acute febrile polyneuritis
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525
(or neuronitis) in which a detailed and systematic histopathologic examination failed to reveal any significant changes. The etiology of this condition, as is the case with acrodynia, is not known. There is evidence indicating that infections or toxins may ascend in the perineural lymph spaces and pass through large areas of the nervous System without leaving behind evidence that is demonstrable by modern methods. A glance at the summary of the pathologic studies will make it clear that many of them have not been systematic or thorough. The vascular changes, forming so constant and characteristic a feature of the clinical picture, suggest that alterations in the sympathetic fibers of the peripheral blood vessels might be found, but they apparently have not been sought. Detailed studies of all of the sympathetic ganglia have rarely been made. This is, of course, the more surprising since the constant and characteristic features of the disease are those of disturbed sympathetic function. The present study will best serve its purpose if it encourages more detailed examinations of the entire nervous system, with special emphasis on its autonomic components. While previous studies and the present one have failed to show any constant lesions, either in occurrence, character, or distribution, nevertheless nervous lesions have been noted frequently enough to indicate quite strongly t h a t a specific etiologic agent with special effects on the nervous tissues actually exists. Since clinically the disease appears to be of an infectious nature, f u r t h e r search is certainly desirable for a specific virus or perhaps a bacterial agent with toxic properties. SUMMARY
1. The findings in the nervous system in a case of acrodynia are reported. 2. No pathologic changes were found in serial sections through the diencephalic sympathetic nuclei. This fails to support the belief that this region is the p r i m a r y focus of involvement. 3. Degenerative changes were present in the anterior horn cells of the lumbosacrM region and in the intermediolateral eel1 column of the spinal cord. 4. A review of the literature and tile data supplied by tile present ease show that while alterations in the nervous system are not infrequently observed, they are not constant in oce~trrence, kind, or localization and hence do not offer a satisfactory explanation Of the clinical picture. 5. Since the latter, nevertheless, quite consistently points to a disturbance in the sympathetic nervous system, it is desirable that further and more systematic search for lesions in this system be made.
526
THE JOURNAL OlV PEDIATR%CS R~FE~ENCES
1. 2. 3. 4. 5.
Selter, P.: Arch. f. Kinderh. 80: 244, 1927. Wood, A. J . : M. J. Australia 1: ]45, 1921. Byfie]d, A. H.: Am. J. Dis. Child. 20: 347, 1920. Paterson, D., and Greenfield, J. G . : Quart. J. /~ed. 17: 6, 1923. Itelmholz and ttowland, in Discussion of I~odda, F. C.: Am. J. Dis. Child. 30: 597, 1925. 6. Warthin, A. S.: Arch. Path. & Lab. lV~ed. 1: 64, 1926. 7. )'eer, E.: Jahrb. f. ](inderh. 108: 267, 1925. 8. Woringer, P:: ]~ev. fran~, de p~diat. 2: 440, ]920. 9. I~ernohan, J. W., and Kennedy, 1~. L. J. : Am. J. Dis. Child. 36: 341, 1928. 10. Francioni, C., and Vigi, F. : Bull. d. se. meal. Bologna 6: 66, 1928; Riv. sper. di freniat. 52: 307, 1928. 11. Findlay, G. M., and Stern, R. O.: Arch. Dis. Childhood 4: 1, 1929. ]2. Orton, S. T., and Bender, L.: Bull. Neuro]. Inst. New York 1: 506, 1931. 13. Willie, W. G., and Stern, 1~. O.: Arch. Dis. Childhood 6: ]37, 193]. ]4. SoTs, J . : Centralb. f. allg. Path. u. path. Anat. 53: 211, 1931. ]5..de Lange, C.: Jahrb. f. Kinderh. 136: 193, 1932. ]6. Bellocq, G. Ph., and Meyer, 1~.: Rev. fran~, de p4diat. 8: 495, ]932. 17. Blackfan, 1~., and ]YIcKhann, C. ~ . : J. PEDIAT. 3: 45, ]933. ]8. Braithwaite, J. u Arch. Dis. Childhood 8: ], 1933. ]9. Wolf, I. J., and Davison, C.: J. PE])IAT. 4: 498, 1934. 20. Deamer, W. C., and Biskind, G. 1~. : Am. Y. Dis. Child. 48: 1326, ]93& 21. Fessler~ A.: Arch. f. Dermat. u. Syph. 173: 283, 1935. 22. Mouriquand, G., Dechaume~ J., Bernheim, and WelU, L. : Lyon mSd. 156: 203, ]935; Pehu, l~[., Dechaume, J., and Boucomont, J . : Lyon m6d. 157: 301, 1936; ~r G., Dechuume, J., and S4da]lian, P. : Lyon mSd. 158: 210, 1936; Pehu, M., Dechaume, J., a n d Boucomont, J. : Rev. fran~, de p~diat. 19.: 239, 1936. 23. Harris~ C. F.: St. Barth. Hosp. Rep. 68: 137, 1935. 24, Sehwarz~ H., Goolker, P., and G]obus, J. H.: Am. J. Dis. Child. 43: 889, 1932. 25. Honeyman, W. 1VL: Bull. Neurol. Inst. New York 6: 519, 1937.
OF T H E LITERATURE AND REPORT OF A CASE A L B E R T J . L U B I N AND HAROLD K .
FABER., M . D .
S A N ~RANCISCO, CALIF.
aerodynia has become a well-defined and fairly common A LTHOUGH clinical entity, reported examinations of the nervous system are not only somewhat meager but are conflicting. The confusion is evident not only in locating the site of the lesion, but also in the type of cellular response noted. This great variance in findings is demonstrated in the accompanying tabllla,tion, which includes all of the available pathologic descriptions. The original d e s c r i p t i o n of a e r o d y n i a was p u b l i s h e d b y O. Selter~ i~x 1908. I n 1914 Swifte r e p o r t e d a series of cases i n A u s t r a i i a . Since t h a t t i m e it h a s gone under a variety of names : ' ~S e l t e r - S w i f t - F e e r ' s Disease, ' ' c ~p i n k discus% ' ' ' ' e r y t h r o e d e m % ' ~ ~' dermatopolyneuritis~ ' ' ~' t r o p h o d e r m a t o n e u r o s i % ' ' a n d ~~vegetative n e u r o s i s . " I t a p p e a r s i n y o u n g children, chiefly ' % o , d d l e r s , " a n d h a s been said to h a v e occurred in epidemics. The onset is u s u a l l y insidious. C h a n g e s i a t h e disposition, s u c h as a p a t h y , m a y a p p e a r first. The e x t r e m i t i e s become swollen a n d podgy, a n d e r y t h e m a t o u s r a s h e s a p p e a r on t h e skin. t I y p e r e s t h e s i a s a n d p r u r l t l s a r e common. S i g n s o f d y s f u n c t i o n o f t h e a u t o n o m i c n e r v o u s s y s t e m include prof u s e s w e a t i n g , d i g e s t i v e disorders, t a c h y c a r d i a a n d h y p e r t e n s i o n , d i l a t a t i o n of t h e p u p i l s a n d p h o t o p h o b i a , increased metabolic rate, alopecia neurotica, ~'hinorrhe% sialorrhea, v a s o m o t o r d i s t u r b a n c e s in t h e extremities, a ~ d t r o p h i c ulcers. Occasionally m u s c u l a r w e a k n e s s is t h e first s y m p t o m , a n d t h e deep reflexes o f t e n disa p p e a r . I n severe cases t h i s weakness is followed b y p a r a l y s i s . P l e o c y t o s i s a n d increase of spinal fluid p r o t e i n h a v e been noted. The p r o g n o s i s is u s u a l l y good, a n d complete recovery occurs i n t h r e e to n i n e m o n t h s . E m a c i a t i o n or i n t e r c u r r e n t inf e c t i o n is t h e cause of d e a t h in a few cases. SUlYI]KARY
OF
NEUROPATHOLOGIC
CHANGES
REPORTED
Spinal Cord.--Of the total of thirty-seven cases reported, nothing abnormal was noted in eighteen. Four cases showed only a slight diffuse increase of small round cells. Edema without inflammatory infiltration was observed in two cases. One case contained inflammatory nodules, consisting mostly of ]ymphocytes, near the entrance of the dorsal roots. Involvement of nerve cells was described in twelve cases. One of these consisied of vacuolar degeneration of posterior horn cells, one of poorly stained anterior horn cells, and one of a few swollen anterior horn cells. Distinct chromatolysis of nerve cells was cited in nine egses; in seven of these it was confined to anterior horn cells, in one to cells of the anterior horns, lateral horns, and Clarke's column, and in another to cells of the lateral horns, with lesser changes in the anterior horns. From partment
the Division of :N-euro!osychiatry (Netlropathology of Pediatrics, Stanford. University School of ~r 515
Laboratory)
and
the De-
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T H E JOUR,NAL OF PEDIATRICS
I n eleven eases a diffnse i n c r e a s e of s m a l l r o u n d cells was n o t e d , W i l l i e a n d S t e r n r e p o r t i n g seven of these. M y e l i n s h e a t h a b n o r m a l i t i e s w e r e o b s e r v e d in o n l y t h r e e instances, a n d in two of these it was m i l d . No abnormalities noted Slight increase of small round cells Edema without inflammatory reaction Inflammatory nodules Nerve cell involvement posterior horn cells anterior horn cells alone anterior and lateral horn cells an"cerior and lateral horn cells and cells of Clarke's celmnn Total
18 4 2
1 12
37
Brain.--No p a t h o l o g i c m a n i f e s t a t i o n s were n o t e d in e i g h t e e n eases. I n a n o t h e r t e n the c h a n g e s were nonspecifie, c o n s i s t i n g of g e n e r a l i z e d congestion, edema, h y p e r e m i a , a n e m i a , o r s l i g h t i n c r e a s e o f s m a l l r o u n d Cells. I n seven cases t h e r e was i n v o l v e m e n t of t h e r e g i o n a d j a c e n t to t h e t h i r d v e n t r i c l e , p o s t u l a t e d as t h e site of t h e d i e n e e p h a l i e s y m p a t h e t i c center. I n two cases t h e lesions were w i d e l y s c a t t e r e d t h r o u g h o u t v a r i ous p o r t i o n s of t h e brMn. No abnormalities noted Nonspeei~c changes, as edema and congestion Involvement of sympathetic center in dieneephalon Scattered lesions Total
1.8 10 7 2 37
Peripheral Nerves.--lnvolvement of p e r i p h e r a l n e r v e s was d e s c r i b e d in t w e l v e instances. A c t u a l d e g e n e r a t i o n of m y e l i n s h e a t h s o r axis c y l i n d e r s was p r e s e n t in seven of these. C h r o m a t o l y s i s of cells in t h e g a s s e r i a n g a n g l i o n was n o t e d in two eases. I n n i n e eases t h e r e was specific m e n t i o n t h a t no a b n o r m a l i t i e s w e r e f o u n d in t h e p e r i p h e r a l nerves. Sympathetic Nervous System.--The p e r i p h e r a l s y m p a t h e t i c system was i n v o l v e d in e i g h t cases. I n one ease m a n y n e r v e cells w i t h two n u c l e i w e r e f o u n d ; l y m p h o c y t i c i n f i l t r a t i o n w a s d e s c r i b e d in t h r e e cases; in two cases t h e r e was n e u r o n o p h a g i a i n a d d i t i o n to t h e l y m p h o c y t i c i n f i l t r a t i o n ; in a n o t h e r two cases t h e r e was m a r k e d n e u r o n o p h a g i a a n d c e l l u l a r d e g e n e r a t i o n . T h e r e is specific m e n t i o n t h a t no a b n o r m a l i t i e s were f o u n d in e i g h t cases. T h e r e were f e w cases, however, in which a d e q u a t e e x a m i n a t i o n was m a d e of t h e p a r a v e r t e b r a l c h a i n g a n g l i a a n d t h e i r p e r i p h e r a l connections. Vagus Nerve.--Some d e g e n e r a t i o n was n o t e d in one instance. Peripheral nerve involvement Sympathetic nerve involvement Gasserian ganglion, chromatolysis Vagus degeneration, mild Dorsal root involvement
12 8 2 1 9
TABLE I NEUtCOPATI~OLOGIC CHANGES DESCRIBED IN ACROI)YNIA AUTtIO]g
Byfield (1920)
Paterson and Greenfield (1923) 2 cases
Helmholz (1925) IIoMand (1925)
S P I N A L CORD A N D ROOTS
BRAIN
P E R I P H E R A L AND SYMPATIIETIC NERVES
A few anterior horn Edema of m y e l i n cells stained poorly; sheaths and connecgliosis around central tive t i s s u e about canal; some variation nerve f b e r s in sciatic in fiber size in lumbar nerve. posterior roots with edema and swelling of myelin sheaths. Slight diffuse increase Cortex, thalamus, and Vagus and cervical of small cells, appar- pons negative. sympathetic nerves ently glial, in cervical negative ; nuclei apa~d ]umbosaeral enpeared to be more largements a n d in numerous in brachial roots (especially dorplexus but median sal roots). nerve was negative. Capillary congestion Negative. Myelin degeneration and diffuse increase in internM and exof small cells in cord t er n a1 popliteM and roots ; swelling, nerves; most marked eccentric nuclei, and distally ; some chromatolysis of anchanges in lmnbar terior horn cells, most nerve. marked in lmnbosaeral region. Definite nerve Negative. changes. Negative. Few changes but not Cord negative enough to warrant diagnosis of peripheral neuritis.
Cord and roots nega- Marked congestion and tive except for edema edema of meninges with proliferation of 2 cases of meninges. r e t i e u l o - endothelial cells. congestion and Perivascular edema; no 3s degenerative or in- edema of brain and meninges and marked flammatory changes. proliferation of retienlo-endothelial cells. F~er (Vetter) Cord negative Sympathetic nerves negative. (1925) Woringer Brain edematous; some Many cells in sympa(1926) macrophagie loci at thetic ganglion with some posterior commissure two n u c l e i , with chroma~t[n of ~hird ventricle. granules. Kernohan and Chromatolysis - of ante- Advanced chromatoly- Myelin sheath disin:Kennedy rior horn tells, espe- sis in floor of fourth tegration and swol(1928) cially in ventrolateral ventricle, locus caeru- len, nodular axis cylgroup in sacral re- ] e u s , meseneephalic inders, especially in gion; lateral horn cells root of fifth nerve, sciatic and femoral and cells of Clarke's lenticular nucleus, an- n e r v e s ; marked column involved in terior nucleus of fhal- chromatolysis in gas'serian ganglia. thoracic reglon; ap- a l n a s . parent i n c r e a s e in glia; no one cell group completely involved; chromatolysis in post e r i o r root ganglia, especially at lumbar level. Warthin (1926)
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I--CONT
'D
I AUTIIOR
Fruneioni and Vigi (199.8) (developed a f t e r epidemic encephalitis) Findlay and Stern (1929) 0 r t o n and Bender (1931) (review of Byfield's case)
Willie and Stern (1931) 7 cases
SPINAL CORD A N D ROOTS
BKAII~
Chromatolysis, eceentrio nuclei, and some shadow cells in infundibulum and tuber cinereum ; dissipation of lesions toward hypothalamus. Small round cell infilt r a t i o n in medulla; negative above medulla.
' PERIPHERAL AND SYhIPATIIETIC N E R V E S
Perivascular collars of small round cells in cervical sympathetic ganglia.
Small round cell infilCervical and abdomtration in cord a~d in a1 sympathetic along posterior roots; ganglia negative. early anterior horn cell changes. Chromatolysis, sclerosis, and destruction of many l a t e r a l horn ceils ; loss of myelin sheaths, glial increase, small hemorrhages in lateral horns ; chromato]ysis of a n t e r i o r horn c e l l s withou% glial reaction. Slight anterior horn Negative. Beading and fragcell chromutolysis with mentation in sciatic some satellitosls in nerve and brachial seventh cervical segplexus. ment; advanced changes in anterior horn cells in fourth and fifth l u m b a r ; slight round cell infilt r a t i o n ; some myelin degeneration. Few swollen anterior Increased vascularity Negative. horn cells; diffuse in- of cortex; slight small filtration of s m a 11 cell infiltration in corround cells; f a t drop- tex and medulla. lets in dorsal roots. Some anterior horn cell Small round cell infil- Negative. chromatolysis in lure- tration in cortex and bar region; small cell basal ganglia. infiltration, especially in dorsal horns. Slight excess of small Negative. Negative. cells. Few rounded anterior Negative. F a t globules along horn cells in cervical course of all periphenlargement ; slight eral n e r v e s , espechromatolysis in antecially median. romedial g r o u p in third and fourth lure-: b a r ; small round c e l l infiltration. Chromatolysis and few Negative. Early degeneration of eccentric nuclei in anperipheral nerves, esterior horn cells of pecially near Ranlumbar enlargement; vier's nodes. small cell infiltration. Slight i n c r e a s e of Negative. Some degeneration of vagus fibers. round cells.
LUBIN AND FABF.~, :
ACRODYNIA
519
TABLE I - - C O N T ' D
AUTHOR
SPINAL CORD AND ROOTS
So6s (1931)
de Lange (1932)
Spinal cord negative; chromatolysis and eccentric nuclei in posterior root ganglia.
Bellocq and Meyer (1932)
Some degeneration and vacuolization of posterior horn Cells.
BRAIN
PERIPHERAL AND SYMPATHETIC NERVES
B r a i n substance soft Marked differences in doughy, and anemic. size, pyknotic and absent nuclei, poorly stained tigroid substance, and marked neuronophagia in cells of solar and paravertebral chain ganglia. Circumscribed f r o n t a l Chromatolysis and ecmeningitis, perivascu- centric nuclei in gaslar infiltration in pia- serian ganglion. arachnoid; increase of glia (especially mieroglia) without neuronophagia in infundibulotuberous region and c~gliaknStchen ' ' ; less marked glial increase in midbrain, locus caeruleus, putamen, globus pallidus, and right dentate nucleus; c h a n g e s not found in controls. Cellular 1 e s i o n s and Numerous l o c i of neuronophagia in the neuronophagia a n d inf undibulocellular degeneration tuberous region and in sympathetic chain along the walls of the ganglia; myelin dethird ventricle. generation in crura] andintraspinal nerves.
Blackfan and McKhann (1933) 5 cases Braithwaite (1933) 2 cases
Wolf and Davison (]934)
Examination of the central nervous system, peripheral nerves, and sympathetic nervous system failed to disclose changes which could not be related to the terminal infection. Cord negative.
B r a i n i n j e c t e d ; increase in cerebrospina] fluid; apparent increase in neuroglial cells of white matter. Cord negative. B r a i n congested and edematous ; glia slightly edematous. Chromatolysis and vae- Slight disarrangement Early disintegration uolization in nucleus of all layers of cortex, and swelling of myeventralis of eleventh" especially t h i r d ; some lin, early axis cylinnerve a n d anterior chromatolysis and fall- der changes in pehorn cells; mild disin- ing out of cells, slight ripheral nerves, more tegration of single increase in glia in cor- advanced in lower fibers in spino-olivary, tex; swelling of gan~ extremities. spinocerebellar, a n d glion cells in basal lateral pyramidal ganglia; severe cell tracts. changes in locus eaeruleus; a b s e n c e of fibrillary processes, $ lack of chromatin, and I swelling of P u r k i n j e I cells in cerebellum ; ] some s w e l l i n g of / ganglion cells about ] fourth ventricle aud 1 pens. {
520
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TABLE I---(]ONT ~D AUT]:IOI% l)eamer and
Biskind
(193~)
SPINALC0gD AND !~OOTS
Spinal cord negative; Negative. chromatolysis and neuronophagia in thoracic posterior roots.
Fessler (1935) i~[ouriquand, Dechaume, Bernheim, and Weill (1935)
Inflammatory nodules, consisting mostly of lymphocytes, in thoracic region near entry of dorsal roots; lymphocytic infiltration and satellitosis of ganglion cells in dorsal root ganglion.
Pehu,
Cord and roots negative.
Dechaum% and Boueomont (1936)
BRAIN
Mouriquand, Dechaume, and S4da]lian (1936)
Cord negative.
Harris (1935)
Small round cell infiltration a~d wellmarked chromatolysis of anterior horn cells in spilm.1 cord.
PERIPHEKAL
AN])
SY1VfPATttETIC NEgVES Chromatolysis an d neuronophagia in sympathetic c h a i n ganglia with phagocytic cell infiltration resembling tubercle of rabies; sympathetic g a n g l i a of thoracic aorta negative; slight spreading of bundles of vagus and sciatic nerves.
Hyperemia and edema of b r a i n ; internal hydrocephalus. B r a i n congested; slight Lymphocytic masses, inflaznmation, perivas- perivascular cuffing, eular cuKing of lym- lymphocytic invasion phocytes and plasma of stroma, satellitocells in meninges; sis and pseudoneunodules of lympho- ronophagia, an d cytes or glia in supra- some neuronophagia optic nuclei ; vascular in coeliac and cervicongestion and disten- cal s y m p a t h e t i c tion of perivascular ganglia ; peripheral sheaths around third nerves negative. ventricle. Perivascular cuffing Increase of ]ymphoand lymphocytic infil- eytes, perivascularly t r a t i o n in meninges; and in stroma, and m a r k e d congestion, of satellite cells in and engorgement of sympathetic ganglia. vessels, l e u e o e y t i c thrombi in region of third ventricle ; lymphoplasmocytie infiltration, as partial perivascular cuffs, near vegetative nuclei in walls of t h i r d yentricle. Congestion of s m a l l Perivascular lymphovessels w i t h hemor- eyrie infiltration in rhages in perivascular coeliac ganglion. spates in walls of third ventricle; similar changes in cerebral cortex.
demyelinizaCongestion of cortical Patchy vessels ; small round l tion in most periphespecell infiltration ; but eral n e r v e s , cially in left phrenie no degeneration. and left sciatic nerves and in right brachial p l e x u s ; both vagi negative..
LUBIN AND FAI~ER:
ACRODYNIA
521
Dorsal Roots and Ganglia.--Abnormalities in the dorsal roots were present in nine cases. ~[n four this consisted of an increase or infiltration of small r o u n d cells, in three there was chromatolysis of ganglion cells, in one fat droplets were noted, and in one there was edema. CASE
REPORT
P. I~.~ a boy~ 2 years and i0 months old~ entered the Imspital ~[ay 25~ 1935j with bronchopneumonia. He had had a previous attack of pneumonia in December, 1934, accompanied by otorrhea and tonsillitis. In February~ 1935~ he became listles% his legs became weak~ and all of his extremities cold and pink, turning definitely red in a few days. Itis temperature was slightly elevated. There was profuse sweating. When he was placed on his feet, he showed evidence of discomfort. Later in the month his feet scaled, and the distal phalanges of the fingers became swollen and puffy. He slept i~ grotesque positions an~d was very irritable, t i t s appetite was poor, and he lost a slight amount of weight. During March he became somewhat worse, i n April an abscess developed in the right ear and was drained. Swelling of the hands increased and also appeared in the feet. The child was unable to walk. During the next month the paralysis increased and involved both arms and legs. The pink color disappeared. On May 23 a cough developed, he became prostra.ted~ breathing became difficult, and the temperature rose to 102.2 ~ F., dropping ~o 101.6 ~ 1~. the next day when he entered the hospital.
Physical Examdnation.--He was a well-developed but malnourished boy, breathing rapidly and coughing frequently. There was marked scaling and thickening of the epidermis of the extremities. The tonsils were reddened but not enlarged. The percussion note was dull over the entire right side of the chest; the breath sounds were diminished and were bronchial in character posteriorly. X-ray films revealed collapse of the right m~dd]e and upper lobes. The neurological examination showed a flaccid paralysis of both legs with absent knee and ankle jerks. No pathologic reflexes were elicited. Both biceps and triceps reflexes on the right were not obtained. There was marked weakness of both upper extremities. The elec'trieal reactions of the muscles were not impaired. The abdominal and eremasterie reflexes were absent. There was marked hyperalgesia. Bloa8 Count.--5,3007000 rod ceils; 95 per cent hemoglobin; 47,800 white ceils, with 85 per cellt polymorphonuelears, of which 29 per cent were banded. Course.-- During the next few days he improved ; the right lung expauded~ and the white count decreased to 26,000 on klay 29. But on June 1 the respiratory rate increased, the right lower lobe collapsed, and a mucous rattle was audible. Carbogen was given, but on the morning of June 2 the patient suddenly died. No cyanosis was present. A~ttopsy.--Sections of skeletal muscle from the back, pectoral muscles, and diaphragm were normal. There was a slight f a t t y infiltration of the heart~ but the muscle fibers were normal. Sections through the aorta were negative, ttassall corpuscles were quite numerous in the thymus; the cellular elements were normal. The lungs were moderately congested, and there were a f e w areas of collapse. In places the alveoli were filled with fluid and contained ]urge mononuelears, ]ymphoeytes, and polymorphonuelear leucocytes. The bronchi contained desquamated epithelial eellsj a few Iymphoeytes and polymorphonuclears, and red cells; the mucosa was moderately infiltrated. Smears from the right lniddle lobe contained gram-posltlve eocai in pairs and short chains; no acid-fast bacilli were seen. A peribronchial lymph node was moderately congested and contained many leucocytes; the germinal centers were large and several mitotic figures were present.
522
THE JOURNAL OF PEDIATRICS
Nothing abnormM trabeculae of the contained a small moderate amounts
was present in ti~e gastrointesthxal tract. The capsule and spleen were normal; some large phagocytic cells in the pulp amount of brown pigment. Adrenal cortical cells contained of lipoid material. ~'xa~ni~atio~ of the iVervous System.--Examination of the coeliac ganglion revealed nothing abnormal. Unfortunately no other part of the sympathetic nervous system and none of the peripheral nerves were available for examination. Macroscopically there were no abnormalities in either" the bruin or spinal cord. Celloidin sections were made from various portions of the brain and spinal cord. Nothing abnormal was found in the cortex, mesencephMon, ports, cerebellum, or medulla. Serial sections of the diencephMou from the level of the subthMamic nucleus through the tuber einereum were studied. Careful examination was made of the puraventricular nucleus, the supraoptic nucleus, the nucleus of the tuber cineream, the mammillary body, and tim subthalamic nucleus (corpus ]uysi). There was no perivascular infiltration or increase of glia. IvIany of the cells contained eccentric nuclei and only small amounts of Nissl substance; pseudoneuronophagia was present in places. Such findings, however, were interpreted as normal in this portion of the brain. There was no true neuronophagla. The nuclei were of regular contour, the nuclear membranes were intact, and the nucleoli were not pyknotic. The cells were neither swollen nor shrunken, and no shadow forms were present. I n the spinal cord, sections through the cervical region were normal. The intermediolateral cell column in the thoracic region contained many degenerating cells. Extrusion of the nucleus, folding of the nuclear membrane, absence of Niss] bodies, vacuole formation, and occasional shadow forms were observed (Fig. 1). The cells of Clarke's colunm were larger than the anterior horn cells at the same level, and degenerative changes were seen in a few of them. Anterior horn cells in the cervical, thoracic, and upper lumbar segments were normal. The most striking changes were present in the lower lmubar and upper sacral regions, involving the anterior horn cells of the posterolateral cell column (Fig. 2). There were many round and swollen cells, marked central chromatolysis, eccentric nuclei, and vacuole formation. The nuclear membranes were often hyperchromatic and folded and the nucleoli pyknotic. I n some cells the nuclei were missing or protruding. Shallow forms indicated advanced degeneration. Compared with the amount of cellular involvemerit, there was but little glial response. Sate]litosis and neuronophagia were seen only in a few places. Frozen sections stained with the Cajal gold-sublimate method revealed no increase in neuroglia. No myelin sheath abnormalities were present with ~he Weigert stain. DISCUSSION
The clinical picture of aerodynia clearly points in all cases to an involvement of the sympathetic nervous system. The symptomatology is so widespread that this involvement must necessarily be either localized in a center of sympathetic activity, as in the diencephalon, or diffuse throughout more peripheral portions of the sympathetic system. Pathologic changes have been located by various authors in the following places: (]) the diencephalic sympathetic centers, (2) the intermediolateral cell column in the spinal cord, (3) the paravertebral chain ganglia and the other peripheral sympathetic nervous pathways, and (4) the peripheral nerve trunks and posterior roots. Francioni and Vigi, ~~ de Lange, ~ and Belloeq and Meyer ~6 described lesions in the region of the tuber cinereum and infundibulum; Mouriquand, et al, 22 noted inflammatory lesions in the region adjacent to the
I , U B I N AND FABER :
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523
t h i r d ventricle. 0 r t o n and Bender 12 found the most marked changes in the intermediolateral cell column, in which sympathetic motor cells
Fig. 1 . - - E x t r u d i n g n u c l e i ( A ) a n d d e g e n e r a t e d cells w i t h a b s e n t n u c l e i ( B ) in i n t e r m e d i o l a t e r a l ,cell c o l u m n . A cell w h i c h is n o t in f o c u s ( C ) c o n t a i n s a l a r g e vacuole. Cresyl violet stain.
F i g . 2 . - - A n t e r i o r h o r n cells o f t h e p o s t e r o l a t e r a l cell c o l u m n in t h e Ul~per s a c r a l r e g i o n , s h o w i n g m a r k e d s w e l l i n g , c h r o m a t o l y s i s , e c c e n t r i c nuclei, a n d s h a d o w f o r m s . Cresyl violet stain,
form synapses with descending sympathetic pathways in the spinal cord and ~ v e off sympathetic neurones to the peripheral sympathetic ganglia. Kernohan and Kennedy 9 also noted involvement of this re-
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THE JOURNAL OF PEI)IATRICS
gion, although merely as part of widespread damage. Sofs TM and others described neuronophagia in paravertebral and other sympathetic ganglia. Paterson and Greenfield4 believed that the disease was a polyneuritis. Varying degrees of posterior root involvement were mentioned in nine cases.
Those findings in the dieneephalon particularly warrant skepticism. Sehwarz, Goolker, and Globus24 have pointed out normM findings in infants' brains that are frequently misinterpreted as pathologic. This was in an attempt to disprove Goldzieher's theory that intestinal intoxication of infants (Goldzieher's "diencephalitis dehydrans") was due to cellular infiltration of the region adjacent to the walls of tile third vent,ride. They observed that discrete cellular aggregations, often perivascular, in this region were but normal manifestations of a ripening brain. In the case described here interest was particularly focused on the dieneephalic sympathetic nuclei. Serial sections through this region, including the subthalamie nneleus, the periventrieular nuelei, and the tuber einereum, failed to reveal anything which could be interpreted as pathologic. Eccentricity of nuclei and lack of centrally placed Nissl bodies were considered as normal in this area. Pathologic findings were all confined to the spinal cord. Involvement of anterior horn cells in the lumbosaeral region and of cells of the intermediolateral cell column in the thoracic region were noted, the changes being especially striking in the anterior horn cells. These changes consisted of swelling and central ehromatolysis, folding of the nuclear membrane, nuclear displacement, and shadow forms, but there was no marked gliM reaction. Changes in the anterior horn cells explain the flaccid paralysis found in this ease. The changes in the intermediolateral cell column, in which are located sympathetic motor cells, seem significant. In only two other eases (Kernehan and Kennedy s and Orton and Bender12), however, have similar changes been noted, so that it is difficult to evaluate whether they are of fundamental importance. A review of the literature shows that reported changes in the nervous system are inconstant. Degenerative changes i n anterior horn cells, as noted in.this ease, were lacking in many reports. FVr example, in Willie and Stern's series~a of seven cases ehromatolysis was not noted in two, was mild in four, and was advanced in only one case. In the same series varying degrees~,of peripheral nerve involvement were found in four eases, and there were no changes in three; in two of the eases small cell infiItration in the cerebrum was mentioned and was not found in five. Failure in finding constant and fundamental pathologic changes, however, is not without precedent in diseases of the nervous system. Honeyman 2~ has reported four fatal cases of acute febrile polyneuritis
LUBIN
AND, FABEIR :
ACRODYNIA
525
(or neuronitis) in which a detailed and systematic histopathologic examination failed to reveal any significant changes. The etiology of this condition, as is the case with acrodynia, is not known. There is evidence indicating that infections or toxins may ascend in the perineural lymph spaces and pass through large areas of the nervous System without leaving behind evidence that is demonstrable by modern methods. A glance at the summary of the pathologic studies will make it clear that many of them have not been systematic or thorough. The vascular changes, forming so constant and characteristic a feature of the clinical picture, suggest that alterations in the sympathetic fibers of the peripheral blood vessels might be found, but they apparently have not been sought. Detailed studies of all of the sympathetic ganglia have rarely been made. This is, of course, the more surprising since the constant and characteristic features of the disease are those of disturbed sympathetic function. The present study will best serve its purpose if it encourages more detailed examinations of the entire nervous system, with special emphasis on its autonomic components. While previous studies and the present one have failed to show any constant lesions, either in occurrence, character, or distribution, nevertheless nervous lesions have been noted frequently enough to indicate quite strongly t h a t a specific etiologic agent with special effects on the nervous tissues actually exists. Since clinically the disease appears to be of an infectious nature, f u r t h e r search is certainly desirable for a specific virus or perhaps a bacterial agent with toxic properties. SUMMARY
1. The findings in the nervous system in a case of acrodynia are reported. 2. No pathologic changes were found in serial sections through the diencephalic sympathetic nuclei. This fails to support the belief that this region is the p r i m a r y focus of involvement. 3. Degenerative changes were present in the anterior horn cells of the lumbosacrM region and in the intermediolateral eel1 column of the spinal cord. 4. A review of the literature and tile data supplied by tile present ease show that while alterations in the nervous system are not infrequently observed, they are not constant in oce~trrence, kind, or localization and hence do not offer a satisfactory explanation Of the clinical picture. 5. Since the latter, nevertheless, quite consistently points to a disturbance in the sympathetic nervous system, it is desirable that further and more systematic search for lesions in this system be made.
526
THE JOURNAL OlV PEDIATR%CS R~FE~ENCES
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Selter, P.: Arch. f. Kinderh. 80: 244, 1927. Wood, A. J . : M. J. Australia 1: ]45, 1921. Byfie]d, A. H.: Am. J. Dis. Child. 20: 347, 1920. Paterson, D., and Greenfield, J. G . : Quart. J. /~ed. 17: 6, 1923. Itelmholz and ttowland, in Discussion of I~odda, F. C.: Am. J. Dis. Child. 30: 597, 1925. 6. Warthin, A. S.: Arch. Path. & Lab. lV~ed. 1: 64, 1926. 7. )'eer, E.: Jahrb. f. ](inderh. 108: 267, 1925. 8. Woringer, P:: ]~ev. fran~, de p~diat. 2: 440, ]920. 9. I~ernohan, J. W., and Kennedy, 1~. L. J. : Am. J. Dis. Child. 36: 341, 1928. 10. Francioni, C., and Vigi, F. : Bull. d. se. meal. Bologna 6: 66, 1928; Riv. sper. di freniat. 52: 307, 1928. 11. Findlay, G. M., and Stern, R. O.: Arch. Dis. Childhood 4: 1, 1929. ]2. Orton, S. T., and Bender, L.: Bull. Neuro]. Inst. New York 1: 506, 1931. 13. Willie, W. G., and Stern, 1~. O.: Arch. Dis. Childhood 6: ]37, 193]. ]4. SoTs, J . : Centralb. f. allg. Path. u. path. Anat. 53: 211, 1931. ]5..de Lange, C.: Jahrb. f. Kinderh. 136: 193, 1932. ]6. Bellocq, G. Ph., and Meyer, 1~.: Rev. fran~, de p4diat. 8: 495, ]932. 17. Blackfan, 1~., and ]YIcKhann, C. ~ . : J. PEDIAT. 3: 45, ]933. ]8. Braithwaite, J. u Arch. Dis. Childhood 8: ], 1933. ]9. Wolf, I. J., and Davison, C.: J. PE])IAT. 4: 498, 1934. 20. Deamer, W. C., and Biskind, G. 1~. : Am. Y. Dis. Child. 48: 1326, ]93& 21. Fessler~ A.: Arch. f. Dermat. u. Syph. 173: 283, 1935. 22. Mouriquand, G., Dechaume~ J., Bernheim, and WelU, L. : Lyon mSd. 156: 203, ]935; Pehu, l~[., Dechaume, J., and Boucomont, J . : Lyon m6d. 157: 301, 1936; ~r G., Dechuume, J., and S4da]lian, P. : Lyon mSd. 158: 210, 1936; Pehu, M., Dechaume, J., a n d Boucomont, J. : Rev. fran~, de p~diat. 19.: 239, 1936. 23. Harris~ C. F.: St. Barth. Hosp. Rep. 68: 137, 1935. 24, Sehwarz~ H., Goolker, P., and G]obus, J. H.: Am. J. Dis. Child. 43: 889, 1932. 25. Honeyman, W. 1VL: Bull. Neurol. Inst. New York 6: 519, 1937.