Acta Medica Scandinavica. Vol. LXXXVIII, fasc. II-IV, 1936.

From the Medical Clinic (Director: Professor Ingvar) of the University at Lund, Sweden.

The Sedimentation Rate of the Red Blood Cor- puscles in Expansive Affections of the Brain.'

BY

ERIK ASK-UPMARK, M. D.

Introduction.

The sedimentation of the red blood cells was, although observed already by the ancients, rediscovered and introduced into medicine by FBhraeus (1918,1921). It has been studied by numerous investigators in the most different clinical and experimental conditions and has gained a well-known and well-deserved position in the clinical medicine.

In neoplastic diseases the sedimentation rate has been studied, among others, by Adams-Ray (124 cases of carcinoma), by Holboll (190 cases of carcinoma and sarcoma), by Lickiiit (200 cases of carcinoma), and by Wulff (301 cases of malign tumours). The results, which have been reviewed in the paper of Wulff, may be summarized thus: in most. cases of malign tumours the sedi- mentation rate is pathologically increased; in several of the cases, however, entirely normal figures are met with, particularly so in instances of carcinoma cutis, carcinoma mammae, and carcinoma ventriculi.

Nobody has apparently hitherto investigated the sedimentation rate in brain tumours. With regard to the widely different cyto- logical character, operability and prognosis of the different cerebral

1 Submitted for publication January 27, 1936.

284 ERIK ASK-UPMARK.

neoplasms i t was considered as of interest and possibly of impor- tance to take up this matter for analysis. The difficulties repeatedly encountered in the differential diagnosis between for example a malign glioma of the hemisphere and a less malign lesion, e. g. a meningioma seem to make such an investigation desirable. The present study represents an attempt to analyse the behaviour of the sedimentation rate in a series of expansive intracranial affections, mainly brain tumours.

Material.

The material was represented by 93 cases of intracranial lesions of expansive character (mostly tumours), examined in the Medical Clinic a t Lund. In 89 instances the diagnosis was histologically verified either by operation or by autopsy; in 4 cases (acromegaly and craniopharyngioma) it was considered that the diagnosis was sufficiently ascertained by the typical clinical and roentgenological symptoms. Cases previously submitted to radiological therapy were excluded and so were all cases with increased temperature but for a few instances in whom the temperature was slightly elevated (not exceeding 3 7 O . 5 when a t its maximum).

Observations.

The sedimentation rate (S.R.) of the red blood corpuscles was determined ad modum Westergren (1924) and recorded after one and two hours. Since the level reached in one hour usually may be considered as significative the present investigation will consider only this figure. The different observations may conveniently lie summarized in the following tables.

Table 1. Review of the material.

Supratentorial turnours. Sedimentation rate

Tumour Sex S.R.: S l O > 1 0 5 2 0 > 20 Med. Max. Min. Malign gliomas, . F 1 5 4 23 45 7

M 12 5 5 12 48 2

T H E S E D I M E N T A T I O N R A T E OF T H E R E D BLOOD CORPUSCLES. 285

Sedimentation rate Tumour Sex S . R . : I l O > l o 1 2 0 > 2 0 Med. Max. Min.

Meningiomas . . 10 20 3 10 20 2

- F 3 1 M 4 3 -

Benign gliomas . .

- F + M 7 4

F 3 1 - 8 12 5 M 5 - 3 6 1 -

Vascular tumours

- F + M ' 8 1

F 1 M 1

6 - - 2 - -

- - - -

Carcinoma ...... Tuberculoma. ... Pinealoma ......

Tumour

Myeloma ......

FM 1 - 2 47 95 10

1 - - - - M 1

Tumours of the pituitary region.

Sedimentation rate Max. Min. Sex S . R . : I 10 > l O l 2 0 > 2 0 Med.

1 156 - - - - ... . F 20 - - 1

1 5 5 - - 1 - 16 - - 2 - 14 16 13

- Craniopharyngeoma . . M - Chromophobe adenoma M - - Chromophile adenoma F -

Together FM - - M

.......... 4 2

Intratentorial tumours.

Sedimentation rate Tumour Sex S . R . 5 1 0 > l o 5 2 0 > 2 0 Med. Max. Min.

12 3 Neurinomas ...... F 3 - 1 13 35 4 Brain stem gliomas FM 3 - 1 9 26 2 Cerebellar ........ FM 10 2 1 6 22 2

- - Meningiomas .... FM 1 1

It will be seen from the table that in the malign gliomas the sedimentation rate was increased above 20 in 9 cases of 32 and above 10 in 19 cases of 32, whereas it remained below 10 in 13 cases.

286 E R I K A S K - U P M A R K .

An increase of the S.R. above 10 appears to be by far more common in females.

In the msningiomas the S.R. did in no case exceed 20 and did exceed 10 in only 4 cases out of 11. Similar figures are to be noted for the benign gliomas (1 case out of 9 exceeding 10, the others 5 10) and for the vascular tumour group (2 cases, in both of whom the S.R. was below 10). It will be observed that the tumour presenting the fastest S.R. among the meningiomas as a matter of fact was a sarcoma of 'a histologically very malign type.

In the carcinomas and carcinosis the S.R. was as low as 4 in 2 instances whereas the maximum reached was 48 (carcinoma pulm. c. metastat. cerebri). It is however obvious that a perfectly normal S.R. may be present even in cases with extensive metastases. This was confirmed by a study of 12 verified intrathoracic tumours with metastases elsewhere than in the brain; in 2 cases the S.R. was limited to 2.

The tuberculomas may obviously behave differently with regard to their S.R. The case in which the least considerable S.R. was to be noted (10) was represented by a nurse, aged 21 who had a lo- calized meningoencephalitis of the right cuneus and a fairly large tuberculoma in the cerebellum. The highest S.R. (95) was on the other hand registered in a man aged 40 who suffered from pul- monary tuberculosis and amyloidosis as well as from a large tuber- culoma of the brain stem.

Most instances of acoustic tumours had a normal sedimentation rate but in one case the S.R. was 35/64 (a female, aged 34 whose temperature was slightly elevated and who had gone through a delivery 2 months previously).

The infratentorial neoplasms of the central nervous structures had generally a fairly normal S.R. In one case, however, the S.R. was 26 (malign glioma of pons in boy of 7) in another case S.R. was 22 (female, aged 31, angioma, delivery 3 weeks ago, slightly elevated temp.) and in a third case S.R. was 14 (boy of 13, angina?).

The tumours of the pituitary region all presented a S.R. exceed- ing 10and reaching a level of 55 in one case of chromophobe adenoma. A myeloma(?) of the sphenoid bone had a S.R. of 156.

THE S E D I M E N T A T I O N RATE OF THE RED BLOOD CORPUSCLES. 287

Sex Ag6 F 65 F 57 F 56 F 55 F 55 F 53 F 53 F 50 F 47 F 39 M 66 M 61 M 60 M 59 M 57 M 56 M 55 M 54 M 53 M 52 M 52 M 5 1 M 51 M 50 M 47 M 45 M 44 M 43 M 43 M 42 M 22 M 19

Sex Age F 61 F 34 F 32

I. Supratentorial tumours.

Malign gliornas ( 3 2 cases).

Table 2. Individual observations.

F 32 Suprasellar region

Localization Left hemisphere Lob. temp. Lob. front. Lob. temp. Hemisphere Lob. temp. Hemisphere Sept. pelluc. et lob. front. Sept. pelluc. e t corp. callos. Lob. front. Hemisphere Lob. front. Lob. temp. Hemisphere Lob. temp. et occ. Lob. front. Lob. temp. Hemisphere Lob. temp. Lob. front Lob. temp. Lob. temp. Lob. front. Lob. front. Regio insula Thalamus and centr. semiov. Lob. temp. Lob. front. Hemisphere Lob. occ. Cornu Ammon. Lob. par.

Meningiomas (11 cases).

Localization Bilateral olfactory Parasagital Fossa Sylvii

S.R. 15 36 19 45 33 20 20 23 11

7 23 16

4 18 2 5 7 5 5

48 25 16 11 36

4 28

3 11 9 4 6 5

S.R. 20

8 3 9

288 E R I K A S K - U P M A R K .

Sex M M M M M M M

Sex F F F F M M M M M

Age 56 51 49 37 32 30 25

Age 60 36 34 31 48 47 29 23 23

Localization Parasagital Olfactory Parasagital Fossa Sylvii (sarcoma) Left hemisphere Lob. occ. e t cerebelli Ventric. lat. dext.

Benign gliomas ( 9 cases).

Localization Astrocytoma Astrocytoma lob. temp. Oligodendroglioma lob. par. Astrocytoma lob. front. Oligodendraglioma lob. occ. Oligodendroglioma lob. front. Astrocytoma lob. front. Oligodendroglioma sept. pelluc. Astrocytoma

Vascular tumours ( 2 cases).

Sex Age Localization F 46 Angioblastoma

S.R. 18

7 3

20 4 2

13

S.R. 12 6 5

10 1 2 6 2 2

S.R. 6 -

M 44 Aneurysma permagn. a. cer. med. 2

Carcinomas ( 4 cases).

Sex Age Localization S.R.

M 56 Carcinosis pulm. e t mening. 4 M 60 Cancer basis cranii 4

M 49 Ca. pulm. c. metastat. cerebri 48 M 46 Ca broncti. c. metastat. cerebri 18

Tuberculomas ( 3 cases).

F 21 Lob. occ. e t 'cerebelli F 17 Lob. par. e t mening. M 40 Brain stem

10 36 95

T E E SEDIMENTATION RATE OF T H E R E E D BLOOD CORPUSCLES. 289 11. Pineal and pituitary region (7 cases).

M I;' F M M M M

F M

E' F F F

Sex F M M nf

F E' F F F M M M M M M M M

M F

45 Pinealoma 1 52 Myeloma (1) corp. OSS. sphen. 156 51 Acromegaly 16 46 Acromegaly 13 38 Acromegaly 16 62 Chromophobe pit. adenoma 55 47 Craniopharyngioma 20

111. Infratentorial turnours.

Meningiomas ( 2 cases).

42 M. regio n. acust. 3 53 M. regio vermis sup. 12

Neurinomas ( 4 cases). 40 N. n. acust. 4 38 N. n. acust. 5 34 N. n. acust. 7 34 N. n. acust. 35

Tumours of the brain stem ( 4 cuses!.

Age Localization S.R. 7 Malign glioma of pons 26 54 Glioni. pont. et corp. quadr. 2

13 Astrocytoma of the aqueduct 4 24 Gliosis of the aqueduct 3

Tumours of the cerebellum ( 1 3 cases).

31 30 30 25 23 57 27 24 21 20 19 13 12

Angioma Glioma Angioma Tuberculoma Papilloma Ependymoma Astrocytoma Astrocytoma Astroc ytoma (angioma?) Medulloblastoma Angioma Glioma Neuroepithelioma

22 3 3 13 2 3 2 3 5 2 5 14 2

IV. Varia.

26 Subdural haeniatoma 36 51 Brain abscess 37

10 - Acfa med. scandinav. Vol. L X X X V I I I .

290 E R I K A S K - U P M A R K .

It will be seen that a S.R. exceeding 20 mm in 1 hour was to be recorded in 9 cases of malign gliomas of the cerebral hemi- spheres, in 1 case of metastatic carcinoma, in 1 tuberculoma, in 1 chromophobe pituitary adenoma, in 1 myeloma of the sphenoid bone, in 1 malign glioma of the brain stem, in 1 acoustic neuri- noma, in 1 cerebellar angioma, in 1 subdural haematoma, in 1 brain abscess.

A S.R. exceeding 10 although not exceeding 20 was to be noted in 10 cases of malign gliomas of the cerebral hemispheres, in 4 supratentorial meningiomas, in 1 cerebral astrocytoma, in 1 case of metastatic carcinoma, in 1 craniopharyngioma, in 3 acromegalies and in 3 infratentorial tumours (1 meningioma, 1 tuberculoma, 1 glioma).

The S.R. did not exceed 10 in the rest of the material, repre- sented by 13 malign gliomas of the cerebral hemispheres, 7 meningio- mas, 8 benign cerebral gliomas, 2 vascular tumours of the hemisphere, 2 metastatic carcinomas, 1 tuberculoma, 1 pinealoma and 17 infra- tentorial tumours (1 meningioma, 3 acoustic neurinomas, 3 gliomas or gliosis of the brain stem, 10 cerebellar tumours including various gliomas, angiomas, papilloma, ependymoma and neuro- epithelioma).

If these different conditions are considered from clinical point of view i t is obvious that certain kinds of tumours are to be consi- dered as more malign with regard to the general course and duration of the disease. To this clinically malign group may be reckoned the multiform glioblastomas (malign gliomas) of the cerebral hemispheres, the metastatic tumours, the tuberculomas, thc me- dulloblastomas and (probably) the neuroepitheliomas of the ccre- bellum, the brain abscesses, the subdural haematomas. On the other hand the following conditions are to be considered as com- paratively benign, particularly with regard to their generally more slow development: the meningiomas, the astrocytomas, the oligo- dendrogliomas, the vascular tumours (angiomas etc.), the epen- dymomas and (possibly) the papillomas. The pinealomas and the tumours of the pituitary region may in one sense belong to this more benign group but owing to their particular localization and general biological character they may be considered, in this con- nection, as a group by themselves. If this distinction is made the S.R. will be found to behave in the following way.

T H E SEDIMENTATION RATE OF T H E RED B L O O D CORPUSCLES. 291

Table 3.

8:xpansive lesion Sedimentation rate I 1 0 > 1 0 5 20 > 20 In all

More malign group. ............... 18 12 15 45 Pineal-pihitary group ............ 1 4 2 7

Together ........................ 51 23 19 93

More benign group .............. 32 7 2 41

It will thus be observed that when a sedimentation rate exceed- ing 20 is present the lesion is, in most instances, of malign character, whereas a sedimentation rate not exceeding 10 may be found as well in the more malign as in the more benign group of conditions, although more frequently in the latter. A moderately increased S.R. (> 10 but not exceeding 20) may be observed in any of the conditions here analysed, although apparently somewhat more often in the malign group. The ))pituitary group)) (chromophobe adenoma, chromophile adenomas, craniopharyngioma) is too small as to allow any definite conclusions but it is remarkable that the S.R. not infrequently seems to be high.

Comment and Discussion.

The normal sedimentation rate of the erythrocytes is indicated as 1-3 mm an hour in men and 4-7 mm in women with the border levels of 4-7 mm in man and 8-11 in women (Wester- gren). In the present investigation 10 mm an hour has been selected as the upper border of the normal level and case$ exceeding 10 mm as presenting an increased S.R.

It is obvious that an increased sedimentation rate in cases of intracranial tumours may be due to different causes.

1) I t may be occasional to the intracranial lesion and depend upon a pathological conditiori elsewhere in the body, e. g. a respira- tory infection. The elimination of all instances presenting any obviously increased temperature was an attempt to exclude this factor as far as possible although it may be readily admitted that, on the one hand, an infection may be present and influence the S.R. in spite of a normal temperature, and that on the other hand an increased temperature, not least in these conditions, may be of central origin so that thus a t least certain cases hence eliminated

292 ERIK ASK-UPHARK.

should have been included in the present material. In the case of brain abscess the temperature was normal; other cases of brain abscess were excluded from consideration on account of fever. The cases of tuberculomas with tuberculosis present elsewhere in the body may belong to this group and so may the metastatic tumours here considered. In two cases of verified hypernephroma of the kidney symptoms of brain tumour were present, reasonably due to metastases; the S.R. did in both instances exceed 50 but since no cytological diagnosis of the brain tumour was obtained these cases were excluded from consideration.

2) A factor which should be given due attention is the influence of age upon the S.R. Evidence has been presented to the effect that in old age an increased S.R. may be encountered in spite of a normal temperature (Broman 1935, examination of 341 cases of cataract treated in the Ophthalmological Clinic a t Lund). This alteration of the S.R. may be due to a silent infection, so common in this period of life, or to other factors but the observation remains a fact. Since most cases in the present material presenting an increased S.R. were older than 50 i t might be possible that this factor of age had been of importance. It may however be said that the investigation of Broman concerned older individuals (average age 70) than the present study, that in several of Bromans obser- vations the temperature was increased as well, and that in the present material a normal S.R. might well be encountered in the older individuals and an increased S.R. in the younger.

3) The character of the lesion is apparently of importance. The predilection for the increased sedimentation rates to occur within the more malign group of lesions is obvious and may be seen in table (3). As Bailey (1933) puts it, we should not forget that glioma is *the cancer of the brain), and particularly goes that for the malign multiform glioblastomas. The common occurrence of an increased S.R. in malign tumours elsewhere in the body is thus entirely in line with the observations in the present investigation. It is interesting to note the level of the S. R. in the case of subdural haematoma; this man, incidentally, emphatically denied every trauma in the history.

4) Whether the localization of the lesion is of any importance for the behaviour of the S.R. is uncertain, particularly on account of the limited size of the material. It may or may not be due to the

T H E SEDIMENTATION RATE OF T H E RED BLOOD CORPUSCLES. 293

same source of error that the importance of the cytological character, as mentioned sub (3), was less apparent in the infratentorial group than in the supratentorial lesions. As to the localization i t must however be considered as rather striking that the lesions of the pituitary region did present an increased S.R. If the case of mye- loma in basis cranii is excluded (in which S.R. was high) the S.R. was increased as well in the chromophile as in the chromophobe adenomas and also in the craniopharyngeoma. This observation may be due to the limited number of cases available but it is also possible that the alteration of the S.R. might be of central origin. To the best of my knowledge an affection of the S.R. by means of a central mechanism has hitherto not been considered in the lite- rature but it is impossible not t o remember the paramount im- portance of the region in question for so many other visceral functions of the body (e. g. temperature regulation, blood pressure, etc.). A certain evidence in the same direction may be represented by the comparatively high S.R. in one case of bilateral meningioma of the olfactory groove, since i t has been demonstrated (Ask- Upmark 1935) that these meningiomas are liable to involve the functions of the parahypophysial regions of the brain. More rese- arch will of course be necessary to settle these questioiis definitely.

From practical diagnostical point of view it may hence be concluded

a) that if the S.R. is increased above 10 and particularly above 20 in a case of brain tumour presenting a normal temperature i t is likely that the tumour is of malign character in the sense of this word here used;

b) that if the S.R. is normal this is no evidence against such a malign character;

c) that an increased S.R. occasionally may be encountered also in tumours of comparatively benign character, particularly perhaps in those involving the pituitary region.

The result of the investigation will apparently be of particular importance when it deals with the distinction between the different tumours of the cerebral hemispheres. If the S.R. is obviously increased in such a tumour a malign glioma is, ceteris paribus, the most likely diagnosis although metastatic tumours are to be considered as well (mainly in older individuals) and tuberculomas

294 ERIK ASK-UPMARK,

remain another possibility (mainly perhaps in younger individuals); subdural haematomas and abscess of the brain are, moreover, to be remembered in this connection.

It may finally be questioned whether not more evidence about the character of the lesion might be obtained if the S.R. was de- termined in blood from the internal jugular vein, punctured ad modum Myerson. Investigations in this direction have been sche- duled in our clinic.

Summary. 1 . The sedimentation rate of the erythrocytes was determined

ad modum Westergren in 93 instances of verified expansive lesions of the brain.

An increase of the sedimentation rate above 20 mm in 1 hour was registered particularly in the malign gliomas of the cere- bral hemispheres but also in metastatic tumours, tuberculomas, brain abscess and subdural haematoma.

A sedimentation rate not exceeding 10 mm in 1 hour may occur not only in the conditions already mentioned but also in a series of comparatively more benign conditions (meningiomas, astrocytomas, oligodendrogliomas, angiomas).

The tumours of the pituitary or parapituitary region did not infrequently present an obvious increase in the sedimentation rate in spite of the clinically comparatively benign character of these instances. The possibility that this may depend upon a central influence upon the sedimentation rate is briefly mentioned.

From practical point of view i t may be said that if a tumour is diagnosed in the cerebral hemisphere and if the case has no fever an increased sedimentation rate will speak, ceteris paribus, for a clinically more malign condition, whereas a fairly normal sedimen- tation rate does not exclude the presence of such a condition.

2.

3.

4.

5.

References.

Adams-Ray: Acta chirurgica scandin. 11 6. Ask-Upmark: -4cta neuro- logica scand. 1 9 3 5 , suppl. 6. Bailey: Intrac.rania1 tumours, Thomas, Springfield 1933. Broman, T.: Personal communication, 1935 . Fihraeus: Hygiea 1918; Acta medica scandin. 55 , 1921. Ilolboll: Bibliothek for Lager 122 . Lickint: Med. Klinik 1928, 11. Westergren: Ergebn. d. inn. Medizin u. Kinderheillcunde 26, 1926. Wulff: Acta radiologica, 1 3 , 1932.