ERYTHREMIA, OR POLYCYTHEMIA WITH CHRONIC CYANOSIS AND SPLENOMEGALY
REPORT OF TWO CASES WITH A SUMMARY OF 179 CASES REPORTED TO DATE * WALTER S. LUCAS, M.D. Jefferson Medical College Hospital, Out-Patient Department PHILADELPHIA Renewed interest has recently been shown in that primary form of polycythemia with chronic cyanosis and splenomegaly which was first brought to the attention of the profession in 1892 by H. Vaquez,1 and which has been well termed ``erythremia'' in contra-distinction to ``erythrocytosis'' or secondary polycythemia. Erythremia was long considered a rare condition and as late as 1907 Mackey,2 in a most excellent thesis, was able to cite but about forty cases. During the past few years, however, the increasing number of patients reported from various sources indicates that the malady is not by any means as uncommon as was at first supposed. Indeed, Staehelin,3 in 1911, reported eleven cases of polycythemia which came under his obser- vation in a single year, of which at least six appear to have been of the Vaquez type. As the result of a recent careful search through medical literature, I have succeeded in collecting reports on 179 cases of so-called polycy- themia, of which 149 cases appear to be unquestionable instances of erythremia, the other thirty cases being open to doubt as to their true classification. The two cases which have come under my observation and which aroused my interest in the condition are as follows :
CASE REPORTS Case 1.—B. W., male, married, white, aged 52, a native of Russia, grocer, was admitted to the service of Dr. H. A. Hare in the Jefferson Medical College Hos¬ pital, May 19, 1911. Family history is unimportant; no history of malignant or tuberculous disease.
*Manuscript submitted for publication July 15, 1912. *Ten additional cases have been collected since this paper was prepared for publication and too late to permit of their inclusion under the proper classification in the summary at the end of this article. These ten cases have been shown separately at the end of the summary, thus making a total of 189 cases in all. 1. Vaquez, H.: Compt. rend. Soc. de biol., 1892, series 9, p. 384; also Bull. m\l=e'\d.,Paris, 1892, vi, 849. 2. Mackey: Birmingham Med. Rev., 1907, N. S., lxii, 113 and 177. 3 Stachelin: Berl. klin. Wchnschr., 1911, xlviii, 101.
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Patient had measles in childhood. At the age of 20 he had an attack of pleurisy, was seriously ill and had a cough for some time subsequent but afterward became perfectly well. On Feb. 5, 1906, he was operated on at the German Hospital by Dr. John B. Deaver for a prostatic abscess, which was opened through the perineum and drained with an uneventful recovery. Subsequent to this operation he noticed that his color was changing and he became blue. Is said (by himself) to have had a punc¬ ture in the right kidney region and that pus was found, this operation being within a comparatively short time after the other. The physician who did this puncture has since died. At about this time he went to the Pennsylvania Hospital on account of failing vision, dizziness, etc. His symptoms then were the same as at present; namely, headache, vertigo, hazy vision and a feeling as though his head was stuffed with blood. From that time his general health was good with the exception of attacks of "asthma," cough and shortness of breath, up to May, 1910, when he began to have attacks of headache, confined to the right side of his head, and accompanied by dizziness and shortness of breath. Following theäe attacks his hands, face, lips and nose became dusky, the duskiness lasting from two to twenty-four hours. Beginning in the Autumn of 1910 he had frequent attacks of indigestion which seemed to precede the attacks of cyanosis and headache. Since January, 1911, he has had considerable difficulty with his eyes, stating that he has scarcely been able to read a newspaper and that he has had a con¬ tinual haze over his eyes and that stooping or suddenly turning his head brought on dizziness and cyanosis. He also complained of a lump in the throat on swallowing. Examination.—Patient is a well nourished and well developed adult. Skin is dry and warm. His face, and especially his nose, lips, cheeks and ears are of a bluish-red color. The hands, wrists and arms to elbows are bluish-red. Dorsum of feet present nothing abnormal but the soles both are bluish-red and somewhat edematous. The tongue is red and coated with grayish fur. The pharynx is purplish red. Fingers are clubbed with slightly curved nails. The examination of the abdomen proved negative, the liver not being enlarged and the spleen showing no enlargement except on one occasion, during an exacerba¬ tion, when it was very slightly enlarged. The chest is symmetrical; expansion equal and full; hyperresonant through¬ out; a few moist râles heard over both bases. Respiration 22. Heart sounds rhythmical, distant at apex, maximum intensity in epigastrium where the sounds are clear. Pulse 92. Blood-pressure, systolic 120, diastolic 86. None of the superficial lymph-nodes palpable. Genitals negative. A scar observed two inches below last rib on right side. Wassermann test proved negative. A'-ray examination reveals many enlarged mediastinal glands. Eyes: Pupils dilated, equal and react normally- Double optic neuritis with four diopters of swelling in each eye and hemorrhages into the retina. Vision about one-half normal with glasses. Fields concentrically contracted about one- half. (See subsequent reports.) Temperature 98.6. Urine: Slightly turbid, amber, 1.019, acid; faint trace of albumin; no sugar, crystals, blood or casts; a few urates, epithelial cells and leukocytes. Urea 2 per cent. Practically the same on a number of subsequent examinations. Quantity during first week in hospital averaged 500 c.c. for twenty-four hours; next two of weeks averaged 1,200 c.c, dropping to an average of 700 c.c. during rest stay. During second short stay in hospital the average was 500 c.c.
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Course.—Patient's temperature on admission was normal and during his stay ranged between 97 and 99 F. with one rise of short duration to 100.6 and one drop to 96.4. From May 20, 1911, the day after admission, to June 14, 1911, date of dis¬ charge, his weight dropped from 129.5 to 120 pounds. Pulse rather irregular, ranging between 80 and 100 with one rise to 110 and one drop to 74. His respiration was usually about 22 although occasionally as high as 30. Bowels moved once or twice daily with, occasionally, laxatives. His cyanosis continued throughout his entire stay in the hospital. Until May 20 he was free from headaches and dizziness but on that date had several attacks of dizziness, lasting a few minutes each, and also a slight right-sided headache. On May 21 he had two brief attacks of dizziness due to suddenly turning the head to the side and stooping. Also complained at this time of drawing sensation in calf of left leg.
J3 .. Date Erythro- Hgb. C. I. Leuko¬ Remarks cytes cytes
1911 5-12 7,810,000 135 8,200 From finger 5-13 8,060,000 138 8,800 54 20 15 From toe; also 9 per cent .eosinophils and 2 per cent, degener¬ ated eosinophils. 5-22 8,660,000 140 .81 1,000 57 27 Eosinophils 2 per cent, and neutrophilic mye- locytes 6 per cent. 6- 9 7,900,000 129 .81 ,400 Before bleeding. 6- 9 6,530,000 127 .97 ,880 After bleeding. 6- 9 6,800,000 112 .82 ,200 80 15 No parasites. Morpho¬ logic characteristics correspond to normal red cells. 11- 9 6,470,000 125 .97 10,200 74 15 Eosinophils 2 per cent. ; degenerated 2 per ct. 11-25 6,130,000 138 1.13 9,200 Before bleeding. 11-25 5,200,000 96 .92 7,500 After bleeding.
On May 23 again complained of being dizzy at irregular intervals. On June 9, 16 ounces of blood removed from right median basilic vein. Was slightly improved on June 12 and was discharged on June 14. Patient then felt very well until about the last of September, 1911, when old symptoms returned, and on November 8 he was readmitted, his condition in gen¬ eral being about the same as in June. The extremities at this time showed a slight pretibial edema. Eye examination revealed a swelling of two diopters in each eye. Vision 20/30 with glasses. Fields contracted about one-half as before. No hemorrhages. Every evidence of a subsiding inflammation with probably a secondary atrophy obscured by the inflammatory changes. The patient received no medication at this time except laxatives and was up and around the ward the second day, apparently very comfortable and was dis¬ charged on November 13. November 25, 1911, patient returned to ward for venesection to relieve symp¬ toms of dizziness, his condition being about the same as before, 16 ounces of
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blood being withdrawn from superficial vein of right elbow. No change was noted in his condition immediately following venesection but he felt better on the fol¬ lowing day, his color being less dusky, and he was discharged with instructions to report to the out-patient department. For some time thereafter he reported regularly at the out-patient department and was bled four times with temporary relief. An œ-ray examination of the chest at this time showed the heart to be apparently of normal size, rather horizontally placed. There seemed to be multiple adhesions between the pericardium and the diaphragm; also marked thickening of the peribronchial glands. No parasites or organisms of any kind were found in the blood at any time. In January, 1912, the patient spent several weeks in the German Hospital, where, in addition to other treatment, he was subjected to treatment by the ¿c-ray over the long bones. His condition at this time was about the same as before and he was not permanently benefited by treatment. Recently he has been a patient at the Pennsylvania Hospital complaining of an exacerbation of symptoms. Dr. William T. Shoemaker, who examined the patient or. both of the occasions when lie was in the Pennsylvania Hospital, and who has kindly given permission to include the results of his observation of the eye-grounds, states : "Although, of course, interesting in many ways, special interest from an ophthalmic standpoint lies in the violent changes which are shown in the optic nerve, retina and blood vessels. These changes are those of typical inflammatory choked disk, identical, it would seem, with those frequently seen with intracranial disturbance." The patient recently advised me that for some time he has been subject to periodic hemorrhages from the bowel, occurring on an average of once in six weeks and followed by some temporary relief. Despite all treatment his general condition at present is about the same as when first seen. Case 2.—Male, aged 43. Russian Jew, vest-maker, was admitted to the service of Dr. H. A. Hare in the Jefferson Medical College Hospital April 22, 1912, com¬ plaining of severe headache, dyspnea, dizziness and nervousness. His bowels were constipated, appetite poor. Family history unimportant; so far as he knows, no member of his family has suffered in a similar way. He came to the United States from Russia twenty years ago and since his arrival in this country has worked continuously as a vest-maker. For four years prior to leaving Russia he was a soldier. For fifteen years he has been troubled with "asthma" and cough. Suffered from hemorrhoids for fifteen years, undergoing an operation ten months ago for relief from same. Has had more or less headache for six years. Three months ago had a slight attack of hemoptysis. Two weeks prior to admission he began to suffer from severe headache, dyspnea, dizziness and nervousness. Two days prior to admission his wife called his attention to the change in his color. He is somewhat myopic. Examination.—The patient is a well-nourished adult male. His face is somewhat cyanotic, being markedly so when he lies down. The lips and ears are markedly dusky and the hands slightly so. The tongue is very red and the buccal mucosa and pharynx are bluish-red. Spleen was not palpable. Liver dulness was slightly increased. Lungs: Prolongation of expiration and many râles throughout the chest. Resonance impaired anteriorly at the right apex and slightly impaired posteriorly at both bases. Respiration 32. Heart: Faint systolic murmur at the mitral area. Muscle tone fairly good. Pulse somewhat rapid on admission (118), falling to 96 the following day.
Downloaded From: http://archinte.jamanetwork.com/ by a Monash University Library User on 06/20/2015 WALTER S. LUCAS 601 Systolic blood-pressure 132. Legs and feet swollen and edematous ; pit on pressure. Temperature 99.4 F. on admission; 98.4 the following day. Eyes: React normally to light and accommodation. Pupils equal. There was a marked congestion of the conjunctiva and retina. Urine: This showed a very faint trace of albumin; no casts. Sputum: Negative as to tubercle bacillus. Blood: The red cells Avere 8,430,000; hemoglobin 95 to 120; white cells 8,800 to 13,400. Polymorphonuclears 70 per cent.; small lymphocytes 16 per cent.; large lymphocytes 12 per cent.; eosinophils 2 per cent.; blood platelets four in one field. X-Ray.—-T-ray examination of the thorax revealed marked peribronchial thickening, particularly on the left side, and bronchiectasis. Treatment.—Under treatment with morphin sulphate, atropin, epinephrin, oil of cloves, purgatives and, finally, elixir iron, quinin and strychnin, patient left hospital with general condition apparently considerably improved. Six months later : Condition unchanged. Had several exacerbations and twice symptoms were sufficiently severe to require venesection, which gave prompt but only temporary relief. SYNONYMS Erythremia, or primary absolute polycythemia, is also known as Vaquez's disease, Osier's disease, polycythemia with chronic cyanosis, myelopathic polycythemia, splenomegalic polycythemia (Weber4), cryp- togenic polycythemia (Cabot), and erythrocytosis megalosplenica (Senator5). The term erythremia, suggested by previous authors,6 seems especially appropriate, distinguishing the condition as it does from ery- throcytosis,7 or polycythemia rubra of known origin, just as the terms leukemia and leukocytosis distinguish analagous condition in which the white cells are particularly affected. It is probable that cases of erythremia were formerly reported under such headings as "plethora," "venous congestion with cyanosis," etc., and, as Herringham8 points out, Cuffer and Sollier's two cases9 of "con¬ gestive venous diathesis," reported in 1889, may have been examples of this disease. HISTORY In 1892, Prof. H. Vaquez,1 of the Faculte Médicin, Paris, reported a case of peculiar cyanosis with persistent polycythemia, which he regarded as due to congenital heart disease. The liver and spleen were enlarged and the red cells and hemoglobin greatly increased. On the death of his patient in 1895, .Vaquez discovered the absence of organic heart involve¬ ment.
4. Weber: Med. Chir. Tr., London, 1905, lxxxviii, 191. 5. Senator: Ztschr. f. klin. Med., 1906, lx, 357. 6. W. Turk, Hirschfeld and W. Osler. 7. This term was suggested by Hirschfeld. 8. Herringham: Brit. Med. Jour., May 9, 1908, i, 1096. 9. Cuffer and Sollier: Rev. de Med., Paris, 1889, xxii, 825.
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In 1899, Rendu and Widal10 reported the case of a policeman with enlarged spleen, marked cyanosis and polycythemia. At autopsy the heart was found to be normal, but the spleen was tuberculous and con¬ tained large caseous areas. The bone marrow contained nucleated red cells pointing to over-activity. Rendu and Widal concluded that the disease was due to primary tuberculosis of the spleen, which conclusion has not, however, been sustained by subsequent investigation. At about the same time two cases were reported by Cabot,11 one by Cominotti12 and one by McKeen.13 Erythremia was first referred to as a clinical entity in connection with a case reported by Saundb}r and Russell,14 in 1903. It was not, however, until the appearance of Osier's papers,15 in 1903 and 1904, that the condition was brought prominently before the profession in this country and its existence established. During the five years which have elapsed since the appearance of Macke/s thesis an increasing number of cases have been reported annually. One hundred and forty-nine apparently unquestionable cases are now on record, which number would undoubtedly be considerably augmented were all the facts known in connection with the thirty addi¬ tional cases which have been included in the questionable list in the summary at the end of this article.
ETIOLOGY The cause of the disease is unknown. Rendu and Widal10 attributed it to primary splenic tuberculosis and considered that the diminished function of the organ caused increased erythroblastic activity of the bone marrow. Collet and Gallavardin,10 in 1901, reported a case of "massive primary tuberculosis of the spleen," in which the blood-cells were not counted, but in which the general physical features of the blood were similar to cases of erythremia. Vaquez,17 in 1899, Turk,18 in 1902 and Osier,19 in 1903, stated their belief that the disease was not due to splenic tuberculosis, but that, on
10. Rendu and Widal: Bull. Med. Soc. d. h\l=o^\p.,1899, iii, ser., page 528. 11. Cabot: Boston Med. and Surg. Jour., March 15, 1900, cxlii, 275; and Dec. 7, 1899, cxli, 574. 12. Cominotti: Wien. klin. Wchnschr., 1900, xiii, No. 39, p. 881. 13. McKeen: Boston Med. and Surg. Jour., June 20, 1901, cxliv, 610. 14. Saundby and Russell: Lancet, London, 1902, i, 515; Brit. Med. Jour., 1907, i, 1165. 15. Osler: Am. Jour. Med. Sc., Phila., 1903, N. S., cxxvi, 187-201; Brit. Med. Jour., 1904, i, 121. 16. Collet and Gallavardin: Arch. de m\l=e'\d.exper. et d'anat. path., 1901, xiii. 191. 17. Vaquez: ``Hyperglobulie et Splenomegalie,'' Bull. Soc. m\l=e'\d.d. h\l=o^\p.,Paris, June 16, 1899, p. 579. 18. Turk: Wien. Ges. f. inn. Med., 1902. 19. Osler: Jour. Med. Sc., Phila., 1903, N. S. cxxvi, 187-201.
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the other hand, it was due to a primary hyperplasia of the erythroblastie bone marrow. According to Weber,20 objection to the view that the excessive forma¬ tion of red cells in the bone marrow is the primary condition in ery¬ thremia has been urged by Lommel, Bence and others. In several cases of (clinically) splenomegalic polycythemia (erythremia) evidence of local or general blood stasis has been found, suggesting that the poly¬ cythemia was secondary. Bence states that the polycythemia in the splenomegalic type can be diminished by oxygen inhalation, but Stern and others obtained negative results by this method. As having a possible bearing on the etiology of the condition, Weber20" suggests that it may be considered analogous to leukemia, or as a result of a reversion to, or persistence of, fetal and early life conditions in which the bone-marrow is red and still actively engaged in the formation of red cells. Nervous excitement, mental worry, toxemia originating in the spleen, lungs or alimentary canal, and compensatory reaction towards some hypothetical disturbance in the gas exchanging functions of the blood have all been suggested as possible causes of the disease.21 Eeckzeh,22 reporting a case of polycythemia occurring in a male-of 24, in which there was progressive compression of the superior vena cava by a malignant tumor of the thymus, was inclined to consider stagnation of the blood, from various causes, as the sole cause of erythremia, but Osier23 does not consider his reasons or experiments convincing, and Behr24 says, "The view that the increase of red cells and the general cyanosis are the result of a simple stasis appears rather forced if we consider that, while such cases of acquired stasis are frequent, yet such cases accompanied by polycythemia are extremely rare." Anders'25 case led him to consider defective venous tone as playing an important rôle in the pathogenesis. A theory, which has the support of Metchnikoff, assumes that some toxin of a hemolytic nature is manufactured by the enlarged spleen and is absorbed into the circulating blood in minute quantities, not sufficient to cause hemolysis, but sufficient to excite reaction in the blood-forming organs. Belonovsky,26 by injecting minute doses of hemolytic serum into the blood of anemic individuals succeeded not only in raising the number of red corpuscles, but also the amount of hemoglobin. 20. Weber: Quart. Jour. Med., Oxford, January, 1908, ii, 85. 21. Allbutt and Rolleston's System of Medicine, 1909, v, 831. 22. Reckzeh: Ztschr. f. klin. Med., 1905, lvii, 215. 23. Osler: Modern Medicine, 1908, iv, 678. 24. Behr: Klin. Monatsbl. f. Augenh., 1911, xlix, 672. 25. Anders: Am. Jour. Med. Sc., 1907, N. S. cxxxiii, 829. 26. Belonovsky: Sur l'Influence de l'injection de diverses doses de serum hemolytique sur le nombre des elements du sang, St. Petersburg, 1902.
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The blood has been examined in several cases for methemoglobin and sulphhemoglobin with negative results. Age : The disease is comparatively uncommon in early life, only 12 per cent, of the patients being under the age of 30, while 64 per cent. occurred between the ages of 40 and 60. The two youngest patients were girls, aged 17, one being reported by Chace (Case 58 in summary) and the other by Sandesky (Case 67), and Reissmann (Case 94) and Hann (Case 108) each reported a case occur¬ ring in a girl of 18. It is true that Guinon, Rist and Simon (Case 152) reported the case of a girl of 10 years with polycythemia, cyanosis and splenomegaly, but in the case in question there was chronic jaundice and the polycythemia and cyanosis were transitory; it cannot, therefore, be regarded as a case of erythremia. At the other extreme of life is the case of a female of 68 reported by McQuitty (Case 102). The cases27 were divided with respect to age as follows : Per cent.
Second decade . 4 Third decade. 8
Fourth decade . 18
Fifth decade . 37
Sixth decade . 27
Seventh decade . 6 Sex: Sex has no noteworthy bearing, although the proportion of male to female patients is about two to one. In the 140 cases in which the sex is stated, eighty-nine occurred in males and fifty-one in females. Occupation: Has no particular bearing beyond the probability that an active life was led by the majority of the patients, judging from those cases in which the occupation is stated. Race : As the nativity is given in but twenty cases, no satisfactory conclusions can be drawn as to the influence of race on the occurrence of erythremia. In the twenty cases in question ten of the patients were Hebrews, three natives of the United States, two each English and German, and one each Irish, Dutch and Polish. Of the remaining 129 cases sixty-six were reported in German publications, thirteen in the United States, seven in Italy, five in France, four in Hungary and one each in the Philippine Islands and Australia.
SYMPTOMS Erythremia is characterized by marked, persistent and absolute increase of the red blood corpuscles; marked increase in the viscosity and total volume of the blood; excessive erythroblastic activity of the bone-
27. All statistics given in this article refer only to the 149 cases in Tables A, B, C and D of summary appended, the thirty doubtful cases in Table E not being taken into account.
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marrow, and, usually, by characteristic changes in the eye-grounds, cyanosis and enlargement of the spleen. Weber20 suggests that the sequence of events is probably as follows : 1. Increased erythroblastic activity in the bone-marrow. 2. Increased viscosity of the blood resulting from this polycythemia. 3. Dilatation of the small blood-vessels so as to lessen the resistance to the abnormally viscid blood. 4. Arterial hypertonia as a result of the great strain thrown on the circulatory mechanism. 5. Cyanosis, when it occurs, is probably due to the inadequacy of the series of compensatory changes which precede it. The physician's advice is usually sought on account of (1) the abnormal color of the skin and mucous membranes (present in 83 per cent, of cases), (2) the symptoms of cerebral congestion, such as head¬ aches (present in 31 per cent, of cases), and vertigo (34.5 per cent, of cases), (3) dyspnea (19.5 per cent, of cases), and (4) lassitude and weakness (19.5 per cent, of cases). Twenty-three per cent, of the patients complained of hemorrhages, 19 per cent, of pain in the left hypochondrium and 14 per cent, of loss of flesh. Occasional symptoms were constipation, vomiting, indigestion and palpitation, each in about 10 per cent, of the cases; swelling of the limbs, cough, edema and clubbed fingers, each in about 6 per cent, of cases ; and disturbed menses, tinnitus aurium, anorexia, fulness of head, sweating and diarrhea, each in about 4 per cent. Cyanosis: In 75 per cent, of the cases summarized by me in the tables at the end of this article distinct cyanosis was present, and in about 8 per cent, of the cases it is stated that the patient, while not dis¬ tinctly cyanosed, was "very red," "florid," "face congested," "plethoric," etc., so that in 83 per cent, of the cases there was some intensification of the color of the skin. Cyanosis was absent or not reported in 17 per cent, of the cases. It was one of the first symptoms in 15 per cent, of the patients. The cyanosis may be general, but is usually more marked in the face and hands. The tongue is nearly always a characteristic bluish red color. The patient may be deeply cyanosed, moderately cyanosed, or there may be merely a florid appearance with great dilatation and engorgement of the superficial vessels. The most common condition appears to be a distinct cyanosis of the face, more marked in the nose, ears, cheeks and lips; duskiness or deep redness of the tongue and mucous membranes; and more or less discoloration of the hands. From this it will be observed that the cyanosis is most common in the exposed portions of the borly..
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Discoloration of the feet was reported in two cases (5 and 124) and of the trunk in two cases (20 and 69). Exposure to cold and mental excitement seems to intensify the cyanosis, while a warm room may cause the blue color to give place to red. The symptoms seem to subside somewhat in summer (Case 12). In a number of cases the patient presented a striking appearance. One of Osier's patients (Case 10) was known as "the blue baby." Aldrich and Crammer's patient (Case 47) was called "the red Indian woman." Other authors spoke of the cyanosis as "extreme," "intense," "startling," "remarkable" and "extraordinary." Skin, Mucous Membranes, Etc. : Vascular engorgement is usually noted in the buccal and pharyngeal mucous membranes, conjunctivae and the interior of the eye and frequently in the superficial vessels. In 25 per cent, of the cases the veins are described as being distended and the conjunctivae was reported injected in 19 per cent. In 3 per cent, of the cases slight pigmentation of the skin is reported. Carbuncle, erythema, bronzing, psoriasis and tâche cérébrale were each reported in one case. Osier drew attention to the fact that a white line could be produced by cutaneous irritation, a sign which some French writers supposed to be connected with functional insufficiency of the suprarenals. Dermatographia and erythromelalgic symptoms have been reported in a few cases. Lungs : Usually either no mention is made of the lungs or they are reported as being normal. Dyspnea, however, is recorded in 19.5 per cent, of the cases, some degree of emphysema in 8 per cent, and cough in 6 per cent. Asthmatic attacks were reported in three cases and exces¬ sive expectoration in two cases. Heart and Circulatory System : In only a very few cases was the cardiac involvement worthy of consideration. No mention was made of the organ in 28 per cent, of the reports; 30 per cent, report the heart normal ; 27 per cent, state that the heart was somewhat enlarged, and 15 per cent, call attention to very slight cardiac irregularities. If, then, a normal heart be assumed in the 28 per cent, of cases in which the organ is not referred to, 58 per cent, of the patients were without demonstrable heart abnormality. Palpitation was reported in 10 per cent, of the cases, tachycardia in four cases and in one case (94) a pulse-rate of 160. With reference to disturbances in circulation, the feet and legs were blue, swollen and painful in 9 per cent, of the cases ; edema and clubbing of fingers and toes each occurred in 5 per cent; arteriosclerosis, varicose veins, thrombosis, gangrene, hemorrhoids and incurvated nails each in
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3 per cent. ; phlebitis in two cases ; cold extremities in one case. Anemia preceded one case. Hemorrhages: Hemorrhage seems to have been a very prominent symptom, occurring in about one-fourth of all cases, as follows : Cases Epistaxis . in 10 Gums swollen and bleeding. in 12 Cerebral hemorrhage. in 3 Hematemesis . in 6 Hemoptysis . in 2 Melena . in 5
Hematuria . in 2 Menorrhagia . in 2 Mucous hemorrhage . in 1 Miscarriage and severe hemorrhage with relief. in 1 Prolonged hemorrhage after extraction of teeth. in 1 Epistaxis was very marked in one case (58). Blood-Pressure: Unfortunately, the blood-pressure was reported in only about 60 per cent, of the cases. In sixty-six reports of cases in which the blood-pressure was taken, twenty-one gave the systolic pressure as below 140, while forty-five reported pressures ranging from 145 to 310, as follows : Cases
Blood-pressure 145 to 170 . 23 Blood-pressure 180 to 200 . 13 Blood-pressure 210, 235, 240 and 310, each one case. 4 Blood-pressure 220 . 3 Blood-pressure 200 . 2
It is interesting to note that in eight cases in which the authors report an absence of splenic enlargement the systolic blood-pressure was comparatively low—110 to 130 in five cases, 140 in one and 150 in two— whereas in twenty cases making no mention of the spleen (from which it may be assumed that the organ was not enlarged) the blood-pressure appears to have been uniformly high, ranging from 150 to 210 in fourteen cases and in six cases (Cases 130, 132, 135, 138, 139 and 142) being reported as from 220 to 310. From this it would appear that, notwithstanding the comparatively low pressure in the eight cases referred to, the blood-pressure is usually above normal in cases showing no splenomegaly (Geisbock's polycythemia hypertoniea). On the other hand, in thirty-eight cases reporting a distinct splenic enlargement, the blood-pressure was below 150 in twenty cases and only exceeded 200 in two cases (82 and 145). Spleen : Some enlargement of the spleen was present in about three- fourths of the patients. The organ was not mentioned in 18 per cent, and was not enlarged in 8 per cent. In the 110 cases in which splenomegaly was reported, forty-six reported marked enlargement, fifty-four slight enlargement as determined
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by palpation, seven cases "percussion enlargement" and in three eases enlargement was found at autopsy. Of the forty-six cases in which there was marked splenic enlargement, twenty-one cases reported the spleen as reaching to the level of the umbilicus and nine as reaching to or below the iliac crest. It is worthy of note that in one case (120) an accessory spleen was found on exploratory incision and in another case (81), what was thought to be a supernumerary spleen was palpated by the examiner. Liver: The liver did not show any increase in size in the majority of the cases; about a third of the patients presented a slight enlargement of the liver, but not to the extent seen in the spleen. A tremendous enlarge¬ ment of the liver was present in one case (90), and a marked enlarge¬ ment in six other cases. Gastro-Intestinal System : In about half of the patients there was disturbance of the gastro-intestinal system. Vomiting was present in 12 per cent, of the cases, constipation in 11 per cent., indigestion in 9 per cent., diarrhea in 4 per cent., anorexia, jaundice, nausea and thirst each in 3 per cent., and stomatitis, hiccough, eructations and ascites each in one case. Temperature: The temperature, as a rule, is not affected. Fever was reported in but five cases and subnormal temperature in but three cases. Generative Organs: There was disturbed menstruation in seven cases, prolapse of the uterus in two cases, atrophy of the uterus in one case and in one case (105) the general condition was worse before com¬ mencing of menstruation and after the menopause. Pain : In over a third of the cases the patient complained of pain in some form, headache being the most constant, occurring in 31 per cent, of all cases. Pain in the left hypochondrium was complained of in 19 per cent., in many cases both headache and pain in the left hypochon¬ drium being present. Pain in the chest was present in four cases; pain in the right hypochondrium and tenderness over the bones each in three cases ; cramps in the legs in two cases ; and neuritis, neuralgia, precordial pain, lumbar pain, pain in the stomach, pain in fingers and toes, shooting pains in the hands, pain between the shoulders and pains in the joints each in one case. Nervous System: The nervous system appears to have been affected in many cases. The following symptoms have been reported : Tinnitus aurium (in 5 per cent.), apprehension, nervousness, excitability, delir¬ ium, irritability, hypochondriasis, disturbed mentality, insanity, insom¬ nia, minus knee-jerks, muscular atrophy, numbness, choreiform attacks, epileptiform attacks, muscular twitching, shivering, tremor, paratysis,
Downloaded From: http://archinte.jamanetwork.com/ by a Monash University Library User on 06/20/2015 WALTER S. LUCAS 609 hemiplegia, aphasia, disturbed speech, paraphasia, "heat in head," "lump in throat," fainting, loss of consciousness, syncopal sensations without loss of consciousness, etc. Eyes: The eye condition in cases of erythremia is especially note¬ worthy and a careful ophthalmoscopic examination should be made. The importance of such an examination does not appear to have been appreciated by most of the authors, the eye being mentioned in only forty-four cases (30 per cent.), and an ophthalmoscopic examination having been made in only twenty-six cases (18 per cent.). White, in reporting a case (Case 119), says: "Judging from the appearance of the fundus oculi, I should say that the condition would always be easy to recognize." According to Holloway,28 on the other hand, the fundus picture in erythremia cannot be distinguished from the changes produced by con¬ genital heart disease with cyanosis, except that, in his opinion, the con¬ genital eases as a group would tend to show more extensive intraocular changes than would cases of erythremia. Behr, in writing on this point, says :24 It must be of great importance for the conception of the symptom-picture if we can establish the specificity of the disease by some special symptom which is only found in primary erythroeytosis but never in simple chronic stasis without polycythemia. By its establishment in the so-called secondary cases we can then remove the principal difference between the idiopathic and symptomatic erythrocy- toses. Such a symptom we possess in the characteristic changes in the fundus of the eye. Disturbances of vision were reported in thirteen cases, Hutchinson and Miller's patient (Case 34) becoming quite blind, although nothing was found in the optic disks beyond a slight hyperemia and engorgement. The conjunctiva is usually injected and in those cases in which an ophthalmoscopic examination was made the retinal veins are almost universally reported as being dark colored and dilated and frequently tortuous. Parker and Slocum's patient (Case 78) had blurring of vision and occasional diplopia ; the veins of the fundus were markedly tortuous and dilated and the retina edematous and deeper red than normal. The same authors reported a second patient (Case 79) entering the ophthalmologic clinic complaining of severe frontal headache, blurring of vision and diplopia. Examination revealed vision O/D 6/7.5, O/S 6/9, retina hyperemic, veins much engorged, tortuous and dark in color. Hall's patient (Case 86) was carefully examined by Jackson29 on a number of occasions during a period of two years, the results being set forth in detail in an excellent article accompanied by a plate showing the appearance of the fundus oculi. This patient when first seen by
28. Holloway: New York Med. Jour., Jan. 13, 1912, xcv, 69. 29. Jackson: Ophthalmology, Milwaukee, 1907, iv, No. 1.
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Jackson showed an indefinite blurring of vision, epiphora, dilatation of the retinal veins, decreased vision unimproved by any lens, and a slight rotary nystagmus. Later the pupils became unequal and the vision still less and the sinus of the left nerve became markedly larger and distinctly bluish towards the periphery. The appearance was, Jackson says, "dis¬ tinct from anything I have ever seen." There was a "considerable blurring of the optic disks, obviously due to edema," in the patient reported by Russell (Case 99). The right disk showed enlarged and tortuous veins and the arteries were also enlarged. The outer part of the disk showed a remarkable group of small arterioles and enlarged vessels were scattered about the retina. Near the macula was a small patch of pigment, "the result of former chorioiditis." The left disk showed a similar appearance to a lesser degree. Hemorrhagic glaucoma was reported in one of Geisbock's patients (129). Double optic neuritis was present in three cases (14, 30, 124). Choked Disk : It will be observed from the foregoing that optic dis¬ turbance was present in a number of cases. In only two instances, however—Pfeiffer's case (101) and the author's first case (124)—has choked disk been observed. Behr,24 in a paper published in 1911, goes very fully into the eye condition in Pfeiffer's patient and says: In the characteristic changes in the fundus we possess a special symptom of marked diagnostic value, and it is to be regretted that only in a very small frac¬ tion of the cases reported was the eye examined. All of the cases reported agree that the veins are much dilated and serpentine and dark colored. The arteries are either normal, or in rare cases also dilated and darker than normal. Frequently the retina is livid blue. As a rule the margin of the papilla is distinct, rarely indistinct and never with bulging of the papilla itself. That the blood-vessels of the conjunctiva are affected is clear. Dr. William T. Shoemaker, of the Pennsylvania Hospital, Philadel¬ phia, macie a very careful examination of the eye grounds in the author's first case (124) and exhibited the patient before the eye section at the College of Physicians. I am indebted to Dr. Shoemaker for permission to quote from his report as follows: Special interest from an ophthalmic standpoint lies in the violent changes in the optic nerve, retina and blood-vessels. These changes are those of typical inflam¬ matory choked disk, identical, it would seem, with those frequently seen with intra- cranial disturbance. Carl Behr,24 in a most important communication on this subject last year, including a case with microscopic examination, says that his case of polycythemia was the first observed with typical choked disk, and, while referring to a number of cases of cyanosis in which optic neuritis, blurring of the disk margins, etc., were noted (Hirschberg, Posey, Harms), he is inclined to think that the changes in these cases Avere not inflammatory but were due to edema, and, in the absence of swelling, represented perhaps the beginning stage of the more pronounced con¬ dition.
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The retinal changes which Behr demonstrated from his case are enlargement of the veins with no other alteration in the vessel walls than loss of elasticity and thinning. The retinal capillaries showed general distention and irregularity with fusiform dilatations. All of the veins were filled with red cells, but Schlemm's canal, on the other hand, showed no enlargement and contained but a limited num¬ ber of red cells. There was a general round cell infiltration. The ehorioidal ves¬ sels were greatly distended and in pronounced cases the sclera may be of a decided bluish color. Whether or not the case shows simple edema around the nerve head or pro¬ nounced choked disk, as in Behr's case (No. 101) or in the case which I show (No. 124) depends, according to Behr, entirely on the equilibrium maintained in the eyes between the fluid thrown from the blood into the tissues and those carried off through the ordinary lymph channels. The choked disk in polycythemia, Behr concludes, originates solely from local edema of the papilla and the peripheral end of the optic nerve, and, he states, this choked disk is in no way different ophthalmoseopically and microscopically from that of intracranial origin. Swan30 claims that one of the prominent symptoms of polycythemia is exophthalmos. In the cases covered by my summary, however, this symptom was reported in only two instances (Cases 78 and 94). Urine : In a majority of the cases the urine showed a small amount of albumin and not infrequently tube casts. In fifty-two cases the urine is not mentioned; in sixteen it was negative or normal; in eighty cases it presented abnormal features as follows : Cases Trace of albumin. 61 Marked albuminuria . 8 Tube casts. 29 Excess of urobilin . 7
Excess of indican . 6 Chronic nephritis . 4 Susar . 2 Blood . 2
Red cells . 2 Polyuria . 2 Oliguria . 1 In addition to the above, urochrome, diacetic acid, acetone, much chromogen, excess of uric acid, leukocytes, diazo reaction (Case 64), eight times the normal amount of iron (Case 113) and a specific gravity of 1,040 were each reported in one case. Glandular System: The glandular system appears to have been affected in only six cases. The submaxillary glands were enlarged in one case, the mediastinal glands in one case (124) and the thyroid gland in four cases (25, 31, 63 and 102). BLOOD Bed Cells: The most important and constant feature of erythremia is the uniform, absolute and persistent increase in the number of erythro- cytes in the circulating blood. This increase varies markedly in differ¬ ent patients and in the same patient at different times. 30. Swan: Internat. Clinics, Philadelphia, 1907, iv, 114.
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In the vast majority of cases the number of red cells reported ranges between six and eleven million, an average of twenty cases being reported in each increase of a million cells from six to eleven millions. That is, twenty cases reported from six to seven millions, twenty cases from seven to eight millions, etc. The highest recorded counts occurred in Seufert's two cases (63 and 64), which showed 15,000,000 and 15,500,000, respectively. Koester's case (Case 40) showed 13,060,000, and in Gibson and Watson-Wemyss's case (Case 111), 13,250,000 cells were present at one time. Thompson's case (61) exhibited 13,000,000, Myer's case (81) 12,880,000, Englebach and Brown's case (38) 12,584,000. Reckzeh's patient (Case 28) had 12,500,000 red cells, Miller's patient (Case 110) 12,010,000 and four cases (3, 56, 65 and 148) reported counts of 12,000,000, making in all thirteen cases in which counts of twelve million or over occurred. These higher counts are particularly interesting when one considers Weber's20 statement that samples of blood showing ten million red cells per cubic centimeter, with coagulation prevented, placed in a cylindrical glass, show a corpuscular sediment of over nine-tenths of the whole column, the plasma forming only a thin layer on the surface, whereas normally cells and plasma are about equal. Hemoglobin : Notwithstanding the high erythrocyte count, the hem¬ oglobin percentage in most cases was estimated as quite low. It seems probable that the hemoglobin is underestimated in many cases, as in some instances the statement is made by the author that the estimated per cent, "is the limit of the scale." In 111 cases in which the hemoglobin percentage was reported all but four stated the percentage to be 100 or over. These four cases reported 80, 85 and 95 per cent. Sixty-eight cases reported percentages ranging between 100 and 150 and thirty-one cases percentages between 155 and 200. One case reported a percentage of 240 (Case 68). Color Index : I have estimated the color index in seventy-nine cases, and, as was to be expected from the comparatively low hemoglobin per¬ centage reported, found it to be between 0.45 and 100 in all but ten cases. Of these ten cases six ranged from 1.02 to 1.20 and four from 1.31 to 1.57. Microcytes and Macrocytes: Were reported in one case (47). Poikilocytes : Present in three cases (28, 33, 47). Degenerated Red Cells: Reported in two cases (78 and 79). Nucleated Red Cells: Nucleated red cells were present to a very limited extent in twenty cases and to a marked degree in two cases (47, 89), in one of these cases being mostly of the megaloblastic type. A few megaloblasts were also present in three other cases (64, 77 and 79).
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Polychromasia : A tendency of the red cells to stain a lighter or darker blue, known as polychromasia, and said to be found in chronic anemia,31 was present in three cases (Cases 33, 38 and 47). This con¬ dition is regarded by Ehrlich as evidence of degeneration, but, on the other hand, some authorities regard such cells as immature and con¬ sequently significant of regeneration. Hemolysis : Eesistance to hemolysis was reported as slightly increased in one case. Color of Blood : Is almost invariably darker than normal. Viscosity : The viscosity of the blood is invariably raised whenever the number of red cells per c.c. is much increased. In one case it was stated as 10.43 (Case 110). Weber20 found the viscosity of a citrated specimen of the venesection blood in two cases to be more than twice the normal. He says : "Supposing the viscosity of normal human blood to be 5.1 to 5.3 (that is to say, 5.1 to 5.3 times that of water), Lommel found the viscosity to be over 11.0 in two cases of polycythemia with splen¬ omegaly, Bence obtained figures varying from 15.9 to 20.9, and Munzer in another case showed figures varying between 12.0 and 23.0 according to the special form of viscosimeter which he employed. In Low and Popper's case the viscosity was 10.4 and in Saundby's case 9.4." Coagulation Time : The blood in erythremia undoubtedly coagulates much more quickly than normal blood.32 In ten eases in which the coag¬ ulation time is stated, four (63, 64, 78 and 94) reported coagulation in one minute or less, three (12, 38, 110) a coagulation time of less than four minutes, and three (60, 75, 81) coagulation in from six to ten and a half minutes. Oxygen Capacity : The oxygen capacity is stated in but four cases, in one instance (35) being diminished, in another (61) being two and a half times normal, in a third (60) being given as 1,480 c.c. with a blood volume of 4,765 c.c, and in the fourth (110) as 3,375 c.c. with a blood volume of 10,200 c.c. Total Volume: According to Weber33 the normal individual is estimated to possess 4.6 c.c. of blood per 100 grams of body weight. It is interesting to note that in the eight cases in which the total volume was estimated it very much exceeded the normal. In Hutchison's two cases (48 and 49) it was greatly increased and in one of his cases reached "the extraordinary figure of 10,750 c.c, or more than three times the normal volume for a patient of same weight."
31. Butler's Diagnostics of Internal Medicine, 1908, p. 617. 32. Normally coagulation is said to occur in five minutes, although Coplin (Manual of Pathology, 1906, p. 404) states that his personal observations indi- cate that a considerably longer time is usually required. 33. Weber: Med. Chir. Tr. London, 1905, lxxxviii, 191; and Tr. Med. Soc. Lon- don, 1907, xxx, 369.
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In Miller's case (60) it was 4,765 c.c. In Thompson's case (61) it was two and a half to three times the normal. In Acland's case (50) "the total volume of the blood by the carbon monoxid method was about two and a half times the normal." Weber's ease (72) exhibited a total volume of 5,600 to 6,000 c.c, while Miller's second case (110) showed a total volume of about 10,200 c.c. White, in reporting a case (119), states that the total volume was three times the normal for a man of his weight and calls attention to the fact that "the red cells being double the normal, the patient had six times the normal number of red cells and four times the normal hemoglobin. Such blood must have nearly reached a volume which would render cir¬ culation very difficult." The specific gravity in this case was given as 1,076. Cryoseopy : The cryoscopy finding is given in but two cases, being about normal in one (72) and —0.56° in the other (42). Glycogen Eeaction: In one case (73) the glycogen reaction was distinct but not marked. Molecular Concentration: Stated in one case (39) as —0.56. Leukocytes : Assuming that, as Butler31 states, the normal variation of leukocytes in health is from five to ten thousand per cubic millimeter, it appears that in 27 per cent, of the patients there was a moderate leukocytosis (10,000 to 20,000) and in 15 per cent, a distinct leukocy- tosis (over 20,000). In four cases the white cells are stated as less than 5,000, one case (31) reporting 1,080, which is probably a typographic error. Differential: The differential count usually shows some increase in the polynuclear cells, this increase being quite marked in three cases (30, 81, 116). McQuitty's case (102), however, showed a marked decrease in the polynuclear cells and a marked increase in the lymphocytes. The eosinophils were markedly increased in two cases (25, 124), in one of which 20 joer cent, was reported, and showed some increase in four other cases (18, 20, 41, 74). Basophils or Mast Cells : These cells, which, as Butler31 states, are found in small numbers in normal blood and more often in leukemia and have as yet no significance, were reported in varying percentages from 0.5 to 4 per cent, in thirteen cases. Myelocytes: Were present in five cases (76, 77, 79, 90 and 99) in small numbers and in number around 4 per cent, in three cases (47, 68 and 144). Blumenthal's case (in doubtful list) showed 36 per cent.
OUTCOME OF CASES According to Osier,23 Vaquez and Quiserne believed that where the polycythemia reached six million it was fatally progressive.
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In thirty-one of the cases, or 21 per cent., the patient died prior to the date of the report. Three of these patients died as a result of splenectomy (Cases 4, 7 and 93), two from tuberculosis, one as a result of secondary hemorrhage following the removal of a uterine fibroid and two as a result of cerebral hemorrhage. Four of these patients passed into a comatose condition prior to death, three became paralyzed and others suffered variously prior to death from vomiting, diarrhea, aphasia, blindness, dyspnea, mediastinal pain, jaun¬ dice and hemorrhages from the stomach and intestines. Thirteen cases were reported as showing no marked improvement under treatment, while three patients (Cases 8, 21 and 22) were worse after being under treatment over a period of from three to six years. Two cases (21 and 80) developed thrombophlebitis and one of these patients also developed a pulmonary infarct. Some improvement was reported as having occurred in twenty-six cases. In eight of these cases the authors state that the polycythemia increased simultaneously with the general improvement. In only two cases (47 and 94) was marked improvement reported.
TREATMENT With the possible exception of the two cases referred to in the previous paragraph, treatment has been uniformly without permanent benefit. Splenectomy : In three cases in which the spleen was removed (4, 7. 93) the patients died in from a few days to six weeks later. In the fourth case (161) the patient died seventeen months later of tuberculosis. Venesection : Venesection is reported as having given temporary relief in seven cases. It was performed nine times in two years in Chamber's patient (56) with marked relief on each occasion, but his patient was discharged "in much the same condition as when she entered the hospital." Venesection was without result in three cases, while in Fuch's patient (27) there was temporary improvement under treatment by venesection and oxygen. In my experience venesection has been at all times a helpful method of treatment, but unfortunately gave but temporary relief. Oxygen: Oxygen was used with some apparent relief in two cases (63 and 64) and was tried without benefit in two cases. Arsenic: Turk (17), Tooth (103) and Miller (110) reported some improvement under arsenic and Levi's patient (98) "left somewhat improved" after treatment by arsenic combined with Roentgen rays. Arsenic, on the other hand, aggravated the symptoms in Watson-Wemyss's case (112) and was without result in six other cases in which it was tried.
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Roentgen Ray: While three cases (33, 47 and 111) showed benefit from the application of the Roentgen rays to the spleen, Case 47 being markedly benefited, this treatment was unsuccessful in six cases. Faradization: Faradization to the spleen did not materially help Senator's patient (76) and Mackey (Case 42) reports that, while far¬ adization in combination with massage helped the leg weakness, it did not diminish the polycythemia, lessen the cyanosis or prevent gradual enlargement of the liver and spleen. Diet and Hygiene : In Milchner's patient (113), in whose urine there was eight times the normal amount of iron, a diet containing a minimum of ferruginous material benefited the patient's general condition. Senator (76) by dietetic and hygienic treatment apparently benefited his patient at first but later an albumin-poor diet, with other treatment, was without much effect. Sodium Nitrite: Osier (Case 9), in referring to a patient who had suffered from headache for four years, states that the headaches were cured by the use of sodium nitrite, but that the patient was under observation for only a few months. Anders (Case 43), in the case of a female of 25, says that the nitrites gave considerable temporary relief from the beginning. Sodium Bromid: Was used by Koester (40) for pain in splenic region and headache with some apparent benefit. General : Nicola reports that under symptomatic treatment, tonics and eliminatives, his patient (Case 77) improved and the cyanosis almost disappeared, but the polycythemia was not affected by the treat¬ ment, nor by potassium iodid or axray. Carlsbad treatment improved the general condition of Geisbock's patient (Case 31). Inunctions of biniodid of mercury over the spleen, in conjunction with large doses of quinin, resulted in diminution of the size of the spleen and subjective improvement in Begg and Bullmore's case (33), although the polycythemia increased simultaneously with the improvement. Biniodid of mercury was reported as being tried without benefit in three other cases. Treatment Without Success : Various other therapeutic measures, as follows, were tried without especial benefit by different authors : Salicylates; tonics; caffein; bromids; sedatives; nitroglycerin; vale- rianates; hydrastis; iron (two cases); diuretin; quinin (five cases); colonie irrigations (two eases); digitalis; sodium cacodylate, adrenalin chlorid (two cases) ; thyroid gland; vinegar (two cases) ; potassium iodid (four cases). AUTOPSIES Autopsies were reported in twenty-three of the cases. Anemic infarcts were present in the spleen in four cases and yellow nodules in three cases.
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There was cirrhosis of the liver in two cases. The lungs showed the presence of emphysema in four of the autopsies and contained infarcts in two instances. There was bronchiectasis in one case; hydrothorax in one case; old tuberculosis in one case; and tuber¬ culosis of other viscera in one case. Enlargement of the heart was reported in six autopsies; evidence of old heart disease in two and fibrous myocardium in one. There was evidence of erythropoietic activity of the bone marrow in ten cases, in most instances the bone marrow being described as red and as having lost its fatty tissue. On the other hand, Saundby and Eussell (Case 6) stated that the bone marrow in their case appeared normal macroscopically. In one case Eosengart34 found evidence of leukoblastic and erythroblastic hyperplasia in the liver and spleen. Softening of the brain and cord was reported in four cases.
DIAGNOSIS The presence of polycythemia with cyanosis and enlargement of the spleen, and with symptoms of cerebral congestion, such as vertigo, sense of fulness of the head, etc., is suggestive of erythremia, particularly if the eye-grounds show the marked change so often seen in this condition. The absence of demonstrable splenic enlargement or of cyanosis, or even of both, does not necessarily negative the diagnosis. Broadly speak¬ ing, in the light of our present knowledge of the disease, erythremia should be borne in mind in all cases of marked persistent and absolute polycythemia of unknown origin. It should be remembered that the increase in the red cells must be absolute and persistent and the condition must not be confused with the "relative" increase which is due to decrease in the plasma occurring in those diseases accompanied by a rapid removal of fluid from the tissues; e. g., acute diarrhea, dysentery, cholera, etc. Erythremia will be less likely to be confused with relative increase in the red cells if it is borne in mind that in the former condition there is an absence of known cause of diminution in the total volume of the blood. Furthermore, in eryth¬ remia, the patients are usually more congested in appearance and the increase in the number of red cells is persistent, whereas in relative polycythemia it is temporary. In erythremia the total volume of blood is above the average; in relative polycythemia it is below the average. It has been claimed that some degree of local relative polycythemia may be induced by obstructing the venous return, the delay allowing a longer time for the blood to leave the vessels, and, according to Weber,33 impeded circulation may even give rise to general absolute polycythemia.
34. Rosengart: Mitt. a. d. Grenzgeb. d. Med. u. Chir., Jena, 1903, xi, 495. 35. Weber: Proc. Roy. Soc. Med., London, 1908-9. Clin. Sec., p. 24.
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Erythremia must also be differentiated from "erythrocytosis," or secondary absolute polycythemia, which condition may be regarded as a compensatory reaction of the organism resulting from some interference with oxygénation. Erythrocytosis is typically seen in congenital heart disease and partic¬ ularly in congenital pulmonary stenosis; also in chronic diseases of the heart and lungs and in certain individuals residing in high altitudes (Toussy reporting 8,500,000 red cells per cubic millimeter). It has also been reported as a result of chronic acetanilid poisoning (Stengel and White36) and in chronic sulphonal poisoning (Fells) (Case 166). Both erythrocytosis and erythremia appear to be of myelogenous origin, deficiency of oxygénation in the former causing erythroblastic over-activity of the bone marrow, while in erythremia the increase in red cells is apparently the primary condition, the stimulating factor being unknown. It is interesting to note that Weil,37 in 1901, found red bone marrow in two cases of congenital pulmonary stenosis and congenital cyanosis, the normal fatty tissue having almost entirely disappeared, and that Mackey, in 1907, confirmed Weil's findings and pointed out that in a case of chronic cyanosis without polycythemia he had found normal bone marrow. It has been observed, according to Weber,35 that there is an increased erythropoietic activity of the bone marrow in animals kept at a high altitude or in an artificially rarefied atmosphere. The hemoglobin value as well as the number of red cells is increased and nucleated red cells appear in the circulating blood. On the other hand, animals inhaling an excess of oxygen show a decrease in the number of erythrocytes. The same author states that other conditions which may give rise to secondary polycythemia (erythrocytosis), by interfering with proper oxygénation, are (1) experimental stenosis of the superior and inferior vena cava, (2) artificial compression of the thorax, (3) diminution of oxygen and increase of carbonic acid gas in the inspired air, (4) clinical or experimental stenosis of the trachea or larynx, and (5) clinical or experimental pneumothorax. According to Weber, Kuhn, by his suction mask (periodical diminution of oxygen pressure in the lungs), was apparently able to produce a decided increase of red cells in some individuals. An increase in red cells is also seen at times in obesity, paralysis of an extremity, ether anesthesia and phosphorus poisoning.
36. Stengel and White: Univ. Penn. Med. Bull., Phila., 1902-3, xv, 462; Jour. Am. Med. Assn., 1905, xlv, 243. 37. Weil: Compt. rend. Soc. de biol., June 29, 1901, liii, 713.
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PROGNOSIS The disease seems to be progressively but slowly fatal. It has extended in some instances over periods of from ten to fifteen years, but, with the possible exception of two cases (47 and 94), none of the patients so far reported have recovered.
SUMMARY In the preparation of the accompanying summary of cases reported m the medical literature, said cases have been tabulated as follows :
Class .-—Sixty-nine cases presenting cyanosis and splenomegaly and in which the systolic blood-pressure did not exceed 150. Class B.—Fourteen cases presenting cyanosis and splenomegaly and in which the systolic blood-pressure exceeded 150. Class C.—Forty-two cases with an absence of either cyanosis or splenomegaly and in which the systolic blood-pressure did not exceed 150. Class D.—Twenty-four cases with an absence of either cyanosis or spleno¬ megaly and in which the systolic blood-pressure exceeded 150. Class E.—Thirty cases considered doubtful. Class F.—Ten cases the details of which were received too late for inclusion under proper classification. Making a total of one hundred and eighty-nine cases. It is difficult, in the light of our present knowledge of the disease, to establish a hard and fast division between cases of polycythemia, probably secondary in form but of obscure origin, on the one hand, and unquestionable cases of primary polycythemia, or erythremia, on the other. It has, therefore, been the endeavor to include in the summary of cases all of those cases of so-called "polycythemia" in which the etiology of the condition presented a reasonable doubt. Of the thirty cases included in Class E some appear to be identical with a case reported by some other author and such cases are included in the doubtful list in order to avoid duplicating cases in Classes A to D. Others present certain features of erythremia but sufficient details are not given by the authors to permit of a definite classification. Still others fail to present the essential features of erythremia. It is quite probable that some of the cases included in the doubtful class would prove to be true instances of erythremia had all the facts on which the authors based their diagnoses been set forth in their reports. For purposes of publication it has been necessary to condense the case reports as much as possible but it has been the aim not to omit any essential features from the condensed report. In conclusion I wish to express my appreciation of the kindness of Dr. Hobart A. Hare in giving permission to report the two cases described herein, as well as for his suggestions and advice in the preparation of this article. I also wish to thank Dr. E. J. G. Beardsley for his encouragement and assistance in many ways. 320 Hathaway Lane, Wynnewood, Pa.
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