histopathological studies of the arachnoid and radicular nerves in various diseases

Folia Psychiatrica et Neurologica Japonica, Vol. 18, No. 1, 1964

HISTOPATHOLOGICAL STUDIES OF THE ARACHNOID AND RADICULAR NERVES IN VARIOUS DISEASES

BY

Tetsuji FUJIWARA

The 3rd Medical Division, Faculty of Medicine, Kyoto University, Kyoto (Director: Prof. M. MAEKAWA)

INTRODUCTION

Since the classical work of KEY and RETZIUS~) on the leptomeninges of the central nervous system appeared in 1876, various kinds of papers have been published in this field up to the present time, and it appears that there are few new data, anatomical as well as pathological, to add. Recently, Prof. M. MAEKAWA and his co-workers observed the relation between the pathological changes of the spinal arachnoid and psychosomatic diseases, and have reported a number of investigations in this field. From this point of view, the spinal arachnoid in various kinds of diseases has been examined and a clinico-pathological correlation has been investigated in full detail. The present paper describes several pathological findings dealing with the arachnoid and the radicular nerves in the spinal cord, and discusses the pathogenesis of these findings. Forty cases without any particular nervous diseases were chosen from among the patients who were admitted to, as well as those who died at the MAEKAWA clinic, and who were well-known in clinical pictures and laboratory findings.

MATERIAL AND METHODS

On treating the histological materials, the author followed MORIMOTO'S method substantially2-5). That is, the spinal cord from cervical to coccygeal segments with three membranes, radicular nerves and posterior root ganglia were excised as early as possible from postmortem materials. In order to keep the arachnoid and subarachnoid space from shrinkage, the materials were first fixed for 24 hours in 10% formalin, then for an adequate time in 96% alcohol and embedded in celloidin, and serial sectioning was carried out at 20-30 p thickness. These sections were treated with hematoxylin-eosin stain, van Gieson stain, Nissl stain, Holzer stain and Tirman-Schmelzer stain, and further, in other fixative methods, Pal-Weigert and Marchi stains were done.

RESULTS

The table shows the main clinical features, autopsy findings of 40 patients who had various kinds of illnesses, including hypertension of various origins, malignant

Received for publication Jun. 7, 1963.

Histopathological Studies of the Arachnoid and Radicular Nerves

Gastric cancer, Pulmonary and hepatic tuberculosis, Fibrinous adhesive pericarditis

25

No operation

Table. Main clinical features and autopsy findings of the 40 cases with various kinds of diseases.

- _ _

Case 1 $t;- I Clinical Features Main Pathological Findings Other Findings

a) Hypertensive Diseases

58F HT. since 3yrs., Paroxysmal loss of consciousness 15, 4 days and 1 hour before

B.P. 225/130

Cerebral hemorrhage (intra- ventricular and subarachnoid), Arteriosclerosis, Slighi nephros.

Cerebral hemorrhage, Arteriolosclerotic nephros., Arteriosclerosis

70F HT. for the past 15 yrs., Apo- plexy 2 ms. before, Urinary and fecal incontinence, Palpi- tation

B.P. 200/95 Paroxysmal atrial tachycardia

69M HT. for the past few yrs., Slight hemiparesis of the left side since 10ms.

Cerebral softening in lenti- cular nucleus, Paratracheal abscess, Intense arterios.

B.P. 200/96

57M HT. from the age of 30, Edema since one year

Cerebral softening, Arteriol- osclerotic nephros., Syphilitic arteri tis

B.P. 240/ Wa.R. (+)

B.P. 210/110 Anxiety

neurosis

68M HT. of 30 yrs. standing, Con- gestive heart failure, Auri- cular fibrillation

Cerebral softening, Arteriol- osclerotic nephros., Arterios, Adhesive pericarditis

57M

__ 47M

HT. since 2 yrs., Shoulder stiffness, Diplopia, Malignant phase

Arteriolosclerotic nephros., Arterio- and arteriolosclerosis

B.P. 225/110

HT. since 5 or 6yrs., Malig- nant phase since 3 ms.

B.P. 245/160

Arteriolosclerotic nephros., Arteriosclerosis, Chronic ton- sillitis, Hemorrhagic fibrinous pericarditis

52M Bronchial asthma, Chronic nephritis and HT. since 30 yrs., Duodenal ulcer 15 yrs. before, Congestive heart failure since 6 ms.

Malignant nephros., Arteriol- osclerosis

B.P. 184/110

46M HT. since 1 yr., Malignant phase since 1 m.

B.P. 260/ 160

Arteriolosclerotic nephros., Arterios., Gastric ulcer

Secondary contracted kidney, Arteriosclerosis, Chronic ton- sillitis

32M Acute nephritis at the age of 20, Uremic state since 1 m.

B.P. 150/100 NCA M yelography

15M Secondary contracted kidney, Serofibrinous pericarditis

B.P. 190/ 120

Acute nephritis at the age of 22, Bronchial asthma from the age of 22, Cardiac failure since 3ms.

b) Malignant Tumors

Hypotension form the youth, Gastric cancer, Hemorrhagic No operation Epigastralgia since 4 ms. gangrenous enteritis

lassitude, Anemia and pulmonary emphysema since

26 T. Fujiwara

14 66M Partial gastrectomy

Emaciation and gastric complaints since 6 ms., Operation 4 ms. before

HT. since 20yrs., Apoplexy 20 yrs. before, Gastric complaints since Ibms.

Gastric cancer, Pulmonary tuberculosis, Adhesive pericarditis

Gastric cancer, Arteriosclero- tic nephros., Biliary cirrhosis

15 82M

- ._

52F

Gastroentero- stomy 1 yr. before

16 Left hemiplegia since 6 yrs., Emaciation since 6 ms., Opera- tion 2ms. before

Gastric cancer, Systemic abscess (pulmonary, renal hepatic, cerebral, tonsillar and myocardial)

Total gastrectom y

17

__ 18

61M Abdominal distension and epigastralgia since 3 ms.

Hepatoma, Perforation of stomach, Mitral insufficiency

No operation

50M No operation Wa.R. (+)

Gastric complaints since 1 4 yrs., Syphilis in the past

Renal disease at the age of 7, 20 and 36. Dull pain in epigastrium since 20 yrs., abdominal distension since 8 ms.

Hepatoma and hepatic cirrhosis, Syphilitic arteritis

Hepatoma and hepatic cirrhosis, Portal thrombosis, Chronic gastric ulcer, Sclerosis of aorta

19

~

20

61M

__ 61M

No operation

Bronchial asthma since 20 yrs., HT. since 3yrs., Jaundice since 3 ms.

Pancreatic head cancer, Left hydronephrosis, perinephritis and renal stone

No operation B.P. 210/140

c) Diseases of the Cardiovascular System

21

- 22

1 OM Operation of ventricular septal defect 2 yrs. before, Portal hypertension

High ventricular septal defect, Myocardial degeneration, Liver cirrhosis

~~

Rheumatic polyarthritis 3 yrs. before, Mitral insufficiency since that time

Pulmonary tuberculosis 2 yrs. before, Rheumatic arthritis since 2yrs., Cardiac decompensation

Acute polyarthritis 15 yrs. before, Progressive cardiac complaints after that time, Mitral insufficiency, Cardiac decompensation

Pericarditis 8 yrs. before, Pericardiectomy 2 yrs. before, Cardiac decompensation

Postoperative mitral insufficiency, Fibrinous endo- and epicarditis

25F Died a few hours after operation

23 65M NCA Myelography

Aortic insufficiency, Athero- sclerosis of aorta and coronary artery

Postoperative state of mitral insufficiency, Constrictive pericarditis

24

- 25

~

26

29F Operation for mitral insufficiency 1 yr. before

29M

- 67M

Postoperative constrictive pericarditis, Congestive cirrhosis of liver, Adhesive pleuritis

Streptomycin effective in pericarditis

Angina pectoris since 2 yrs., Myocardial infarction and cardiovascular syphilis

Syphilis 25 yrs. before, Wa.R. (+)

Hyalinous degeneration of ventricular septum, Syphilitic aortitis

Coronary sclerosis, Myocardi- al infarction, Cerebellar hemorrhage, Cystitis and pyelitis

27 73M Diabetes mellitus since 20 yrs., Apoplectic seizure 6 ms. before, Since that time cranial nerve symptoms, Cheyne- Stokes respiration and paroxysmal tachycardia

B.P. 150/100

Histopathological Studies of the Arachnoid and Radicular Nerves 27

Gastric ulcer since 25 yrs., Frequent hematoemesis since 1 m.

d) Peptic Ulcer

Round gastric ulcer, Tonsil- lar abscess

28

-- 29

____ 30

49M

51M

29F

NCA since 2 yrs.

Gastric Complaints since 1 yr., Operation for perforated gastric ulcer 1 week before

Purulent peritonitis. Esophagojejunostomia, Pulmonary abscess

Acute nephritis at the age of 9, HT. and chronic nephritis since 5 yrs. before, Gastric complaints since 2 ms.

32

33 ~ _ _

Duodenal perforation and purulent peritonitis, Arterio- sclerotic nephrosclerosis

26F Systemic lymphnodes swelling

69M Progressive disturbances in I Ydcing and sensation since

since a few ms.

e) Diseases of the Blood

Reticulum cell sarcomatosis (mixed type), Gall stone

Multiple myeloma, Post- operative raminectomy (D8-DI2)

32F Exsudative pleuritis at the I age of 19, Anemia since 6 ms. 31 ~~

Operation 6 ms. before

Aplastic anemia, Atrophy of all hormonal glands

36

-__ 37

46M

63M

39 84M Thrombophlebitis.of the leg 3 yrs. before, Faintness and paroxysmal tachycardia 20 days before, Apoplexy few days before

Multiple myeloma, Gastric ulcer

Epigastralgia since a few yrs., Lumbago since 1 yr.

f ) Miscellaneous Diseases

35 125F- ~~

Anorexia nervosa since 3 yrs. Severe atrophy of hormonal system, Hyperplasia of Iym- phatic tissues

M yelograph y, Died after

pneumoence- phalography

Banti’s syndrome, Herpes zoster 1 yr. before

Splenomegaly, Liver cirrhosis, Thrombosis of portal vein

NCA

~

Bloody sputa and dyspnea since 2ms.

Multiple pulmonary embol- ism, Myocardial infarction

Arterios. of basilar artery, Fatty heart

B.P. 240/110 NCA

HT. since 10 yrs., Disturbance in gait, Vertigo

Cerebral hemorrhage, Arteriosclerosis, Coronary sclerosis

B.P. 128/70 Paroxysmal sinus

or auricular fibrillation

Liver cirrhosis, Gallstones, Arteriosclerotic nephros., Gastric ulcer

Paroxysmal disturbances of consciousness since 6 ms.

Abbreviations: HT. = hypertension, Arterios. =arteriosclerosis, Nephros. =nephrosclerosis, B.P. =blood pressure, yrs. =years, ms. =months, NCA=neurocirculatory asthenia.

28 T. Fujiwara

tumors, cardiovascular diseases, peptic ulcers, diseases of the blood and miscellaneous other diseases. With the exception of 3 cases of terminal cerebral hemorrhoge none of them had the diseases peculiar to the central nervous system. The author describes first the pathological findings of the spinal arachnoid, secondly, the spinal roots or radicular nerves, and finally, some pathological findings observed in the vascular system.

1) The spinal arachnoid, which is analogous to the cerebral, is an avascular mem-

brane consisting of two laminae. The outer parietal surface is in close relation to the inner surface of the dura and is covered by flattened mesothelial cells of a single layer, i.e., outer-layer cells, supported by a delicate framework of connective tissue fibers. This inner or visceral layer is in relation to and connects to the pia by delicate trabeculae. This layer consists of coarse and dense connective tissue fibers, which may be called inner-layer cells. Depending upon which cellular component of these two layers is mainly responsible for the proliferation of the arachnoid,, the arachnoid shows fairly complicated findings.

Findings in the spinal arachnoid.

a ) As special forms of the arachnoid proliferation, the arachnoid cell-clusters, arach-

noid villi and pacchionian bodies are first described. The outer-layer cells, i.e., the young mesothelial cells covering the outer surface of the arachnoid proliferate frequently into a few layers or in a semicircular or oval shape with concentrically arranged nuclei. This change is often described as arachnoid cell-clusters or “zellige Flecke”. The cytoplasma of these cells is indefinitely outlined and pale in color, and their nuclei are oval and dark in color. These cell-clusters have no connection with the dura and are found everywhere around the whole circuit of the spinal cord, but relatively more frequently at the funnel-shaped part in which the spinal roots penetrate the dura. One occasionally sees changes in which the cell-clusters proliferate more extensively than the above-mentioned ones, accompanied by collagenous connective tissue of the arachnoid, and sometimes they may penetrate into the dura. This change, known as arachnoid villi or “zellige Knotchen”, is frequently found at the funnel-shaped part. A hypertrophied form of this change is the so-called pachionian bodies, though the typical form is rarely found in the spinal cord (Fig. 1).

Physiological proliferation of the outer-layer cells.

b) Occasionally, the associated proliferation of both the mesothelial cells of the

arachnoid and the ones covering the inner-layer of the dura shows the typical adhesive arachnoiditis, supported by the thickened fibrous tissue of the inner-layer of the arachnoid (Fig. 2). The massive mesothelial cell proliferation of the arachnoid accompanied by the slightly thickened fibrous tissue is peculiar in the arrangement, namely concentrically or onion-skin like, and the nuclei of the extreme outer layer are smaller and longer than those of the extreme inner layer which are larger and more rounded (Fig. 3). This change is frequently seen in the dorsal surface but very rarely in the ventral surface.

Pathological proliferation of the outer-layer cells.

c) This form of change, regarded chiefly as the proliferation of the inner-layer cells,

is most often seen in the dorsal surface of the thoracic segments, occasionally extending to the lateral surface, but scarcely seen in the ventral. This change can be more or less divided into two types depending upon hte stage of inflammation. Firstly, there is a form in which the dense fibrous thickening rich in cell elements is seen and

The fibrous thickening of the arachnoid.


Fig. I . Case 31. Pacchionian body near the funnel-shapcd part of the dura.

Fig. 2. Case 25. Diffused proliferation of the outer-layer cells of the arachnoid accompanied by fibrously thickened connective tissue of the inner-layer.

lymphocytes or plasma cells arc seen here and there among the interlacing coarse fibrocytic fibers (Fig. 4) . In association with the severe arachnoid proliferation the subarachnoid space frequently disappears owing to the concomitant proliferation of the pia. In such cases, rnesothelial cells of the arachnoid also occasionally proliferate diffusely or zonally, in contrast to the oval or spherical arrangement of cell-clusters. In cases in which myelographic examinations were carried out before death, histiocytic giant cells were seen in the subarachnoid interstitial tissue. not accompanied by arach-

30 1'. Fujiwara

Fig. 3. Casc 2s. Concentrically proliferatccl cells of the outer-layer of the arachnoid. The conncctive tissue c?f the inner-layer is scarccly pro1 i fcrated .

Fig. 4. Case 16. Dense fibrous thickening of connective tissue of the Relatively rich cell elements are seen among the inter- inner-layer cells.

lacing coarse fihrocytic fibers.

noid proliferation (Fig. 5 ) . The second type is composed of il dense meshwork 0 1 fibers which appears relatively acellular, unlike the rich cellular elements and poorly prcliferated fibers observed in the first type (Fig. 6 ) . Occasionally, those changes were seen in which the findings observed in the first type and that in the second type are alternately piled up in strait form, and also in which connective tissue fibers of the

Histopathological Studies of the Arachnoid and Radicular Nerves 3 1

Fig. 5 . Case 10. Histiocytic giant cells in the subarachnoid interstitial tissue.

Fig. 6. Case 25. Dense but relatively acellular meshwork of lbers which obliterate completely the subarachnoid cavity.

arachnoid become edematous and proliferative vertically to the spinal axis. d ) This change was chiefly seen near the anterior spinal artery or in the ventral

surface extending from middle thoracic to the lower thoracic segments, but exception- ally in one case (Case 6) in the upper thoracic segments and in another case (Case 3 ) in the dorsal surface. In this form of degeneration the thickened arachnoid generally appears acellular, becomes hyalinous and those various changes are occasionally seen

The hyalinous thickening of the arachnoid.

32 T. Fujiwara

in which the arachnoid proliferates zonally and locally or diffusely, or in others hyalinous and fibrinous thickening are zonally piled up. In the center of these changes, calcified bodies, vascular changes similar to necrotizing angiitis or rounded homogenous substances are sometimes seen (Fig. 7 ) . In sore cases it occurs that the thickened arachnoid is adherent to the pia and/or the dura. and many erythrocytes are detected in the arachnoid owing to the invasion of the capillaries from the pia.

Fig. 7. Case 32. Hyalinous proliferation in the ventral surface. In the center of the proliferation rounded homogenous substances are seen.

2 ) Periradicular proliferation at the funnel-shaped part of the dura or in the radicular nerves.

At the funnel-shaped part, where anterior and posterior spinal roots pierce the dura, the connective tissue layers of the dura, arachnoid, and pia become continuous with the connective tissue of the nerve roots, namely a perineurium, epineurium and endoneurium. The changes in this area are found to be of two types.

a ) Granular proliferation. This type of change refers to a granular change in which the cell component, con-

tinuous and probably identical with outer-layer cells of the arachnoid, proliferates locally or diffusely around the spinal roots and/or extending to the inner connective tissue of the roots. These changes are usually recognized even under low power by their dark-staining reaction as compared to the surrounding tissues. The granulation is composed of the cells with pale-staining and indefinitely outlined cytoplasrna, with big darkly stained nuclei of oval or rather irregular appearance (Fig. 8 ) . When the change is slight, the clusters of such cells are found focally or more or less diffusely only around the perineurium, but as proliferation proceeds these cells tend to invade far into the more inner connective tissue and finally to cause the degeneration of the nerve fibers in association with the proliferation of the cells of the myelin sheath. Among these cells there are found cells with small, rather round nuclei, presumed to be the interstitial cells other than those of the outer-layer of the arachnoid. Occa- sional round cells are seen in a few cases, but in acute intensive form, round cell


Fig. 8. Case 29. Granular proliferation at the funnel-shaped part of the dura. The granulation is composed of the cells with pale-staining and indefinitely outlined cytoplasma. with large darkly staining nuclei of oval or rather irregular appearance.

infiltration including lymphocytes and plasma cells are found in this area (Case 3 8 ) . Polymorphonuclear cells were not found in any cases. Predilection sites in the spinal roots are usually a t the beginning or proximal part of the funnel-shaped part and less frequently in the distal part. This change can be found both in the anterior and posterior roots but there are cases in which changes of the anterior roots are more intensive than those of the posterior, and vice Vera. Predilection segments are, generally speaking. the thoracic, but there are also some differences between cases in which changes are tively more intense in the middle thoracic segment or sometimes in the lumbal than the other. PAL-WEIGERT’S stain for myelin sheath shows irregularity, ballooning, and localized fragmentation at this site in severe cases. In hematoxylin-eosin stain, more eosinophilic fibers are often detected in the site of such changes, which shows the probable degeneration of axon.

b) Fibrous and hyalinous proliferation. In this change, the interstitial tissue around or in the spinal roots at the funnel-

shaped part, refering mainly to the inner-layer of the arachnoid, proliferates fibrously or hyalinously, accompanied by the proliferation of the interstitial cells with rather small nuclei in the epi- and/or endoneurium, contrasting to the previously-mentioned granular proliferation of the cells with larger nuclei (Fig. 9 ) . In such changes. hematoxylin-eosin stain does not show the eosinophilic fibers, and myelin sheath stain also does not show the degeneration of the nerve fibers. N o definite predilection segments are found. The other changes observed at the funnel-shaped part include frequent appearances of small calicified bodies in older age, extension of the perineural space, and degeneration of the blood vessels, which later will be stated.

c ) Findings following subarachnoid hemorrhage. In the spinal roots a t the funnel-shaped part of a fresh case (Case 3 9 ) , who

34 T. Fujiwara

Fig. 9. Case 20. Fibrous proliferation at the funnel-shaped part.

died 3 or 5 days after cerebral hemorrhage, non-coagulated erythrocytes were seen along the perineural space from the cervical to the lumbosacral segments, and extended to the entrance of the spinal ganglia. Numerous erythrocytes of normal shape were seen, of course, in the subarachnoid space. In one case (Case I ) , one who had 3 seizures, 2 weeks, 4 days, and one and a half hours before death respectively, a number of fresh and broken erythrocytes accompanied by numerous lymphocytes, plasma cells and phagocytes containing hemosiderin were seen in the perineural space and the interstitial tissue of the nerve roots. In the subarachnoid space over the spinal cord, the fresh erythrocytes and the old ones organized, within the fibrous meshwork, were seen. In the older case (Case 2 ) , who had had a seizure two months before, the remaining phagocytes containing hemosiderin were seen in the interstitial tissue of the spinal roots extending to the entrance of the spinal ganglia, but erythrocytes or hemosiderin-laden cells had already disappeared from the subarachnoid space.

N o cellular reaction was seen.

3) a ) To summrrize, the perimedullar proliferation of the spinal arachnoid from the

standpoint of each disease group is as follows: In the hypertensive group (Cases 1 - 1 I ) , no changes were seen in Cases 2 and 8,

slight changes in Cases 3, 6 and 10, intense changes in Case 5 (lower thoracic), Case 7 ( lumbar) , Case 9 (upper and middle thoracic, upper lumb.) and Case 1 1 (up. th., up. lumb.), Case 4 (Wassermann positive) was remarkable in the thoracic segments. Case 6 showed relatively remarkable hyalinous proliferation in the ventral surface. Case 1 showed perimedullar reaction due to subarachnoid hemorrhage.

In the tumor patient group (Cases 12-20)? no changes were seen in Cases 12, 13, 14, 17 and 19, slight changes in Case 20 (up. th.), moderate changes in Case 15 (up. th., low. lumb.), Case 16 (up. th.), and severe changes in Case 18 (mid. th.) which had a positive Wassermann.

Summary of findings of the spinal arachnoid. Perimedullar proliferation of the spinal arachnoid.


In the cardiovascular disease group (Cases 21-27), slight changes were seen in Case 27 (up. th., lumb.), moderate changes in Case 21 (up. th.), Case 22 (low. th.) and Case 26 (mid. th ) , and severe changes in Case 23 (up . & mid. th.), Case 24 (up. & mid. th.) and Case 25 (up . & low. th., lumb.).

In the peptic ulcer group (Cases 28-30), moderate changes were seen in the middle thoracic segments of all three cases.

And in the blood disease group (Cases 31-34), slight changes were seen in Case 31 (md. th.), moderate changes in Case 32 (up. th.). Case 34 (up . & mid. th.), and Case 33 which had a laminectomy showed a severe adhesive Dicture in the operated region. Localized hyalinous proliferation in the ventral surface was seen in the middle thoracic segments of Case 32.

In the miscellaneous disease orgup (Cases 35-40), no changes were seen in Case 40. slight changes in Case 38 (up. lumb.), Case 39 (low. th.) and moderate changes in Case 35 (up. & mid. th.) and Case 37 (mid. th, low. lumb.), and severe changes in Case 36 (low. cervical, up. th . ) . In addition, in the cervical region of Case 38 was seen a remarkable hypertrophy of the dura without any accompanying arachnoid proliferation; and in the middle thoracic region of Case 37 remarkable hyalinous thickening was seen locally in the ventral surface.

b ) Periradicular proliferation in the radicular nerves. This form of change of the arachnoid or interstitial tissue in the funnel-shaped

part of the dura, or in the radicular nerves, is summarized as follows: At the beginning, on the granular proliferation in the radicular nerves of hyper-

tensive patients (Cases 1 - 1 I ) the cases which show some changes (Cases I , 2, 5, 6 and 8) and the ones which show no changes (Cases 3, 4, 7, 9, 10 and 1 1 ) are almost equal, and the lesions of these change-cases are seen in both anterior and posterior roots but are apt to localize in a few segments and d o not extend over many segments, with the exception of Case I which showed a reaction extending over all segments after subarachnoid hemorrhage. These changes were found in the proximal as well as distal part of the radicular nerve, but predilection sites were rather the proximal. In cases which show changes, slight granular proliferations were seen in Case 2 (mid. th . ) , Case 5 (mid. th., up. lumb.) and moderate in Case 6 (up. th., up. lumb.) and Case 8 (mid. th.. up. lumb.). Further, the pathological findings of the spinal cord in the hypertensive patients will be reported in detail in the next paper..;2)

In the tumor group (Cases 12-20), localized and moderate granulations were seen in Cases 18 (up. & mid. th.) and 10 (up. th.), but in the other seven cases no changes or even very slight ones were seen.

In the cardiovascular disease group (Cases 21-27), Case 24 showed locally severe changes in upper thoracic segments, Case 26 of cardiovascular syphilis showed relatively intense changes in the middle thoracic, and the other cases didn’t show any changes. But in this series it is characteristic that the hyalinous proliferation of the inner-layer of the arachnoid was remarkable.

In the peptic ulcer group (Cases 28-30). moderate or severe granulations were seen in Case 28 (mid. th.), in Case 29 (up. & mid. th.) with neurocirculatory asthenia and in Case 30 (low. th., up. lumb.) with renal hypertension.

In the blood disease group (Cases 31-34), granulation was seen in the upper to the middle thoracic segments of Case 34 having a gastric ulcer, but very little or no change was seen in the other cases.

36 T. Fujiwara

In the miscellaneous disease group (Cases 35-40) , severe granulation in the anterior roots extending from the middle cervical into the upper thoracic segments and slight changes in both anterior and posterior roots of the middle thoracic were seen in Case 38 complicated by hypertension and severe neurocirculatory asthenia. Moderate granulation was seen in the lower cervical and upper thoracic segments of Case 3 9 with cerebral hemorrhage and paroxysmal auricular fibrillation. The other cases didn't show any changes.

4 ) It is an established theory that the arachnoid does not contain any kind of blood

vessels but when proliferative and adherent to the pia and/or dura, the arachnoid was occasionally found to contain many erythrocytes and capillaries. Thc changes of the blood vessels observed in the subarachnoid space are briefly mentioned as follows:

Arteries: lntimal and medial proliferation, thrombosis and endoarteritis obliterans (Case 20 & Fig. 10) were seen in the anterior spinal artery of the aged and hypertensive cases, as well as in the radicular arteries but with fewer slight changes. Such changes were found in nearly the same degree from the cervical to the coccygeal segments. In cases of malignant hypertension, small arteries and precapillaries in the spinal cord substance and the subarachnoid roots show hyalinosis. In addition, in the small arterioles of the subarachnoid space and nerve roots, medial calcification (Case 3 7 ) , remarkable medial thickening (Case 37, Fig. I I ), remarkable intimal and medial thickening of "onion-skin" like appearance (Case 35, Fig. 12) were seen. The hyperplasia of giant cell appearance was also seen in the media of the small artery of Case 14. In three cases of positive Wassermann tests (Cases 4, 18 and 26) perivascular cut?' was seen.

Veins: A few changes found in the subarachnoid space include congestion.

Findings in the blood vessels.

Fig. 10. Case 20. Anterior spinal artery. Intense intimal thickening is very similar to the endoarteritis obliterans. The media is not so thickened.


sometimes marked zonal and edematous thickening of venous wall. but rarely perivascular round cell infiltration.

Fig. I I . Case 13. A small artery in the subarachnoid space. Slightly thickened intima and intensely proliferated media. Cellular elements are highly rich, but perivascular cuff is not seen.

Fig. 12. Case 35. A small artery in the subarachnoid space. Edematous swelling and onion-skin-like proliferation of intima and media.

38 T. Fujiwara

COMMENTS

The painstaking and systemic studies on the microscopic structure of the arachnoid by KEY and RE-rziuslI built the basis of our modern conceptions of this field and its value is unchanged in its principle even today after 90 years have elapsed. Since that time many excellent studies have been published in this field‘;.iJ-’”’.

The author described the changes of the leptomeninges, especially of the arachnoid and interstitial tissues in the radicular nerves and classified these findings from a standpoint of cellular components, either outer or inner, in various kinds of illnesses.

I ) The arachnoid cell-clusters (“zellige Flecke”) , arachnoid villi (“zellige Knotchen”)

and pacchionian bodies are, as already mentioned, found in the spinal arachnoid as well as in the cerebral. These structures are seen in all ages, but fewer in the young. increasing with advancing age. Regarding pacchionican bodies, which are regarded as a hypertrophied form of arachnoid villi, the author finds that no definite boundaries can be fixed between them, and that they are less typical and fewer in number than in the brain. These three special structures are presumed to have the same entity a t the point of the mesothelial cell proliferation covering the outer surface of the arachnoid. though the first two forms are presumed to have no function as a matter of fact, as HASSIN!’) stated before.

These structures were first observed in psychotic patients by M A Y E R ’ ~ ) , and considered as pathological findings. Later, WEED^) regarded these changes as senile degeneration. and G O L M A N N ~ ‘ ~ ’ , SCHULTZ et al.lti) and SCHLEUSSlNd’8’ regarded them as physiological findings. GOLMANN considered “zellige Flecke” as non-differentiated mesenchymal cells or unripe forms of endothelial cells, and that there is no ground for conceiving it as only senile alteration, and that these structures may form a reaction apparatus which fights against invasion of pathogenic agents to the central nervous system and that these mesothelial cell-clusters are, so to speak, a look-out for the central nervous system which can react rapidly to the invasion of pathogenic agents.

Recently, on the phylogenesis and ontogensis of the cerebral and spinal pacchionian bodies there are interesting reports from C ~ H A R A ~ ! ’ ) , S A D A N A G A ~ ~ ~ ~ ~ ~ , N I S H I N A ~ ~ ’ , and especially of KIHARA’*-’) on the ground of the extravascular pathway of cerebrospinal fluid from the subarachnoid cavity. KIHARA. who systemically studied the extravascular pathways from the spinal subarachnoid space, classified them morphologically into two kinds: that is, granula meningica spinae, which exists in the spinal cord and cor- responds with pacchionian bodies in the brain, includes two kinds of pathways: one is granula paravenosa which is the pathway to the venous system, and one is granula praelymphocapillaria which is the lymphatic channels. This granula praecapillaria is a small fleck which consists of argynophilic reticulum and is most often seen at the perineural space at the funnel-shaped part, and does not exist in the brain.

The meaning of the pacchionian bodies on cerebrospinal fluid absorption has been discussed by various investigators, such as KEY and RETZIUS~ ), WEED^) ELMAN’):%) and HAS SIN!^). Judging from the reports of KlHARA and GOHARA on the extravascular pathway from the spinal subarachnoid space, the opinion of KEY and RETzlus is not exact, because they claim that from the spinal subarachnoid cavity the mode of escape of the fluid is by way of the perineural roots spaces, although from the cerebral it’s by way of the pacchionian bodies. That is, the meaning of the pacchionian bodies

Specific structures in the arachnoid.


in the spinal arachnoid on the cerebrospinal fluid absorption is less important in comparison with that in the brain, and it is probable that the pathway of escape through the perineural channels along spinal nerve roots and then into lymphatic channels is rather important.

The author examined 3 cases of apoplexy (Cases 1, 2 and 39) which ruptured into the ventricles and then into the subarachnoid space. As previously mentioned, the fact that fresh erythrocytes and hemosiderin-laden cells invade from the perineural space at the funnel-shaped part into spinal ganglia seems to indicate that these pathways are naturally present, admitting that this happened under abnormal high fluid pressure due to hemorrhage.

2) The perimedullar findings of arachnoid which were observed by the author are

summarized as follows: the mesothelial cell proliferation has no specific relation to any certain kind of illness, but the fibrous proliferation is apt to be seen often in cardiovascular diseases, then in peptic ulcers and hypertensive groups, and less often in tumor cases, hyalinous thickening is seen mostly in the ventral surface, extremely localized, and has no predilection segments and no special relation to any specific type of illness.

Though it may not be easily decided whether these findings are inflammatory or degenerative in etiology, almost all of them are presumed to be inflammatory from their histological findings; in consequence, the term circumscribed arachnoiditis may be quite appropriate. But as PETT et al.24) has already pointed out, the term “arachnoiditis” is not adequate in the sense that there does not exist an inflammatory process which occurs primarily in the avascular arachnoid. But as the findings of the author include frequently the “arachnoiditis” which are localized in the arachnoid, except those with an intense proliferation of arachnoid accompanied by pial and/or dural thickening, the term circumscribed arachnoiditis is considered to be quite adequately used.

The so-called circumscribed adhesive arachnoiditis in the classical sense is presumed to occur from the following causes: (1) infection (bacterial, viral, etc.) including syphilis and tuberculosis, (2) trauma, (3) accompanied by tumor in the central nervous system, (4) postoperative and ( 5 ) unknown causes. According to ELKING- TON^^), cases of unknown etiology are present in high percentage, mounting to 44%. The author suggests that rheumatism or allergy relates etiologically to these findings on the ground that the fibrinous proliferation is occasionally seen in the cardiovascular, especially in valvular diseases. And further, viral origin of arachnoiditis must be a great possibility, as HORSLEYW described at first, and BROCK et al.*7) and T E R P ~ suggested with their cases, but the author’s cases could not disclose a close relation between arachnoiditis and viral infections.

Though there are many etiological classifications of arachnoiditis, there are but few histopathological ones regarding cellular components in the spinal arachnoid. DAVIS et al.”) classified proliferation of cerebral arachnoid into hyperplastic, fibrous and inflammatory types. WINKELMANN et aL3()) subdivided pathological changes in the cerebral pacchionian system into 5 groups (aplastic, hypoplastic, hyperplastic, fibrotic and infiltrative). The author classified spinal arachnoid proliferation into ( 1) mesothelial cell proliferation, (2) fibrous proliferation and (3) hyalinous proliferation. However, the intense fibrous proliferation often accompanies, more or less, mesothelial

Perimedullar proliferation of the spinal arachnoid.

40 T. Fujiwara

cell proliferation; and mesothelial cell proliferation rarely accompanies fibrous ones. And there are cases in which hyalinous proliferation is presumed to be a chronic form of fibrous proliferation. But also in some cases of hyalinous proliferation it is certain that there exists a degenerative nature.

3 ) Anatomically at the funnel-shaped part the dura, arachnoid and pia envelop the

spinal roots forming a small funnel-shaped sheath for a short distance, uniting and transferring to the sheath of the intervertebral ganglia and the peripheral nerves. The degeneration often seen at this area is, as already mentiond, a granular proliferation which consists of the mesothelial cells of the arachnoid. Arachnoid cell-clusters or arachnoid villi are occasionally seen in this area, especially increasing as age advances. As it appears that granular proliferation has a specific clinical meaning, it is described somewhat in detail.

This change is almost identical with the one which was at first termed “syphilitic granulation tissue” by RICHTER-~) and on which the most importance was etiologically placed. According to VEITH~*), granular inflammation in the radicular nerve is found in chronic infections, chronic infectious diseases and malignant tumors. These alterations are non-specific granular interstitial inflammation (radiculitis) which are mainly localized in the distal part of the radicular nerves and have a tendency to form scars in epi- and perineurium, sometimes extending into endoneurium. These changes were less often seen in the proximal part, and peripheral nerves were never involved. A close relationship between each illness and predilection segments was not found. Degenera- tion of the myelinated nerve fibers was not detected even in sites of remarkable granular proliferation, and the nerve cells in the spinal ganglia showed no alterations. E L S T E R ~ ~ ) found non-specific granular inflammation regularly in the interstitium of the radicular nerves of the hypertensive patients of various origins, stating that this granulation was regarded as the arachnoid cell in nature and his findings were essentially identical with that of VEITH. These findings were found throughout the length of the spinal cord but more remarkable in the lumbosacral than in the thoracic segments. Predilection sites were in the proximal and distal part, and the intermediate part was scarcely involved. KUMPF~‘) found arachnoid cell-clusters, extremely similar to that of the spinal nerve, also in accompaning sheaths of all the cranial nerves. These findings become more remarkable as age advances and as infections are more frequently ex- perienced. SCHALTENBRAND~‘) states that there does not seem to be a relationship between these findings and any specific type of disease.

On the contrary, the author’s series showed considerably different results from the above-mentioned authors’ findings. While ELSTER found regular granular proliferation in the hypertensive cases, in one half of the author’s cases no changes were seen, slight changes in two cases, and moderate or severe changes in two other cases. The findings most common to these four cases are that sites of changes were in the upper lumbar and middle thoracic segments. In malignant tumor patients moderate changes were seen in only two cases out of nine, in spite of the advanced ages and chronicity of the illnesses; but one case (Case 20) was complicated by bronchial asthma and another case (Case 18) was a Wassermann positive patient suffering from syphilis. Intense changes were seen in the thoracic segments of peptic ulcer, less intense changes were seen in the upper thoracic of bronchial asthma, neurocirculatory asthenia and allied conditions. Thus, it is interesting to note that these findngs were found in high per-

Periradicular proliferation at the funnel-shaped part of the dura.


centage in the so-called functional or psychosomatic illnesses such as peptic ulcer, bronchial asthma, neurocirculatory asthenia and some of the essential hypertension, and not so often in tumor, chronic infections, and others cases of hypertension. A relation between the findings of arachnoiditis or radiculitis and clinical features has been discussed by Prof. M A E K A W A ~ ~ ~ ) and his co-workers80-4’) on physiological grounds, by KONISHI 43*7) on myelographic grounds and by MORIMOTO~-~) on histological grounds. As SAWAMI et al.51) recently reported on researches in this field systemically, and as the author reports the histopathological studies of the spinal cord in essential hypertension in the following papersz), details are omitted here.

Three main possibilities are considered on the pathogenesis of the granular proliferation at these sites: (1) inflammation caused by pathogenic agents which invade the cerebrospinal fluid from a neighboring focus, (2) reaction of the coarse connective tissue to pathogenic agent reached by the centripetal way along the peripheral nerves, and (3) allergic reaction including rheumatic reaction. Histologically the author’s series did not show any kind of acute inflammation, with the exception of occasional appearances of small lymphocytes and plasma cells. But polymorphonuclears are never seen. However, Case 38 was an exception and showed intense accumulation of small round cells at this site, but this finding is not clear enough from clinical pictures. As there are no specific findings histologically for allergic reaction, allergic causes can not be concluded from histological findings alone either in positive or negative senses. Though these findings of histology suggest an inflammation which chronically progresses from the beginning, no specific causes can be concluded from these findings alone.

From the fact that granular proliferations were occasionally seen in the so-called functional diseases, clinical features, especially laboratory findings, are necessary to be considered.

MAEKAWA et al.48) found a slight increase of a- and 8-globulins in sera of neurocirculatory asthenia, and N A K A J I M A ~ ~ ~ ~ ~ ) found an increase of a-, 8- and y-globulins in the cerebrospinal fluid of neurocirculatory asthenia. SAWAMI et al.51), from the ground of systematic examinations, found that many of the patients of psychosomatic diseases tend to show decreased albumin, increased a-, 8- and y-globulins in the serum, elevated blood sedimentation rate and increased mononuclear cells, and suggested that these findings show an inflammatory nature, especially of chronic, and further, that virus is the most probable cause judging from the fact that many of these patients show leukopenia without accompanying hepatic or splenic changes. These data are highly suggestive that the author’s findings indicate inflammation, especially of viral origin. It is possible that viruses such as enteroviruses reach this site by way of a centripetal lymphatic channel or reach the cerebrospinal fluid via the blood stream and arouse reaction at this site when the fluid is absorbed; but a more precise decision on the pathogenesis of these findings remains a task for future research..

SUMMARY AND CONCLUSIONS

1) The spinal arachnoid and radicular nerves, especially at the funnel-shaped part, were systemically examined in forty cases which had various types of disease, excluding diseases of the nervous system. The alterations were classified into the following, from the standpoint of which the cellular component mainly constitutes the lesion.

42 T. Fujiwara

2 ) The perimedullar proliferation of the arachnoid surrounding the spinal cord is classified into (1) proliferation of mainly outer-layer cells; and (2) proliferation of mainly inner-layer cells. The latter is further classified into fibrous and hyalinous thickening. The periradicular proliferation of the radicular nerves, especially in the funnel-shaped part, is divided into the following two types: (1 ) granular; and (2) fibrous and hyalinous proliferation.

The perimedullar mesothelial cell proliferation is not found especially in any particular kind of disease. This is found less in young people and tends to become more remarkable as age advances.

The perimedullar fibrous thickening is most often seen in cardiovascular diseases including neurocirculatory asthena, peptic ulcer, less often in hypertension. A few examples are seen in malignant tumor patients, and in blood diseases. The lesions are localized mostly in the dorsal surface and more often in the thoracic segments. The perimedullar hyalinous changes are localized, mostly in the ventral surface. The relationship between these alterations and diseases is not clear.

5 ) The granular proliferation, related to the outer-layer cells of the arachnoid in nature, is most typically and frequently seen in the peptic ulcer group, less often in bronchial asthma, neurocirculatory asthenia and allied conditions and in positive Wassermann test cases, but seen only in one half of the hypertensives and not seen in tumor patients. The fibrinous and hyalinous proliferation are remarkable in cardiovascular diseases, but not clear in other diseases.

6) The pathogenesis of the periradicular granular proliferation is discussed, and from the clinical features it is stated that virus origin must be one of the most probable causes.

The author wishes to thank Prof. MAEKAWA for his helpful criticism and many suggestions throughout this study. The author’s thanks are due to Drs. S. HAYASE, H. SAWAMI, N. KONISHI, and Y. YAMADA for their advice and histopathological guidance. The author is particularly indebted to Dr. 0. MORIMOTO for his generous advice and permission to examine his pathological materials.

3 )

4)

REFERENCES

Key, A. and Retzius, G.: gewebes, Stockholms. 1875. Morimoto, 0.: Idem.: Ibid. 12: 50, 1958. Idem.: Ibid. 12: 87, 1958. Morimoto, 0. and Maekawa, M.: Weed, L. H.: Idem.: Brain 58: 383, 1935. Idem.: Hassin, G. B.: Golmann, S. W.: Spatz, H. and Stroescu, G. G.: Lutz, P.: Acta Anat. 11: 162, 1950/51. Schultz, A. and Knibbe, H. J.: Schaltenbrand, G.: Handbuch d. mikroskopischen Anat. d. Menschen IV. Nervensystem, I1 Teil. Springer, Berlin 1955.

Studien in der Anatomie des Nervensystems und des Binde-

Folia Psychiatrica et Neurologica Japonica 12: 34, 1958.

Ibid. 12: 231, 1958. Jour. Med. Research 31: 21, 51, 93, 1914.

Bull. Hopkins Hosp. 31: Nr. 356, 1920. Arch. of Neur., 23: 65, 1930.

Zeitschr. f. d. ges. Neurol. u. Psychiat. 135: 323, 1931. Nervenarzt 7: 425, 481, 1934.

Frankf. Z. Path. 63: 455, 472, 1952.


49) 5 0 ) 51)

Kihara, T.: Saishin-igaku 11: 1, 1956. (in Japanese) Millen, I. W. and Woollam, D. H. M.: Meyer, L.: Arch. path. Anat. 17: 209, 1859. Schleussing, H.: 1958. Giihara, C.: Acta Anat. Nippon. 28: No. 3, 1952. (in Japanese). Sadanaga, M.: Kumamoto Igk. Z. 31: 669, 1956. (in Japanese). Idem.: Nishina, H.: Acta Anat. Nippon. 34: 483, 1959. (in Japanese) Elman, R.: Bull. Johns Hopkins Hosp. 34: 99, 1923. Pett, H. and Kalm, H.: Handbuch d. Inneren Medizin IV Aufl. Neurologie 111. Springer, Berlin 1953. Elkington, J. St. C.: Brain 59: 181, 1936. Horsley, V.: Brit. Med. Jour. 1909 I, 513. Brock, S., Bell, A. and Davison, C.: J. Am. Med. Ass. 106: 441, 1936. Terp, A.: Nord. Med. 43: 1026, 1950. Davis, L. and Haven, H. A.: J. Nerv. Dis. 73: 129, 286, 1931. Winkelman, N. W. and Fay, T.: Arch. Neur. and Psych. 23: 44, 1930. Richter, H.: Zeitschr. f. d. ges. Neurol. u. Psychiat. 6B: 1, 1921. Veith, G.: Arch. Psychiatr. u. Z. Neur. 182: 400, 1949. Elster, K.: Ibid. 187: 69, 1951. Kumpf, W.: Diss. Erlangen 1952. Maekawa, M.: Idem.: Jap. Circulation J. 18: 1, 1954. Idem.: Cardiac neurosis, Shindan-to-chiryosha, Tokyo, 1955. (in Japanese) Idem.: J. Jap. Psychosomat. SOC. 2: 89, 1962. (in Japanese) Maekawa, M. and Hayase, S.: Maekawa, M., Hayase, S. and Mashiko, N.: Hirakawa, S.: Ibid. 24: 155, 1960. Hayase, S. and Konishi, N.: Shinryii 15: 199, 1962. (in Japanese) Konishi, N.: Jap. Arch. of Inter. Med. 1: 65, 1954. (in Japanese) Idem.: Ibid. 1: 168, 1954. (in Japanese) Idem.: Ibid. 1: 299, 1954. (in Japanese) Idem.: Ibid. 2: 792, 1955. (in Japanese) Idem.: Ibid. 3: 523, 1956. (in Japanese) Maekawa, M., Kumagai, N., Sawami, H., Tomita, S., Konishi, N. and Okazaki, H.: Jap. Circulation J. 19: 141, 1955. (in Japanese) Nakajima, K.: Idem.: Sawami, H., Konishi, N. and Fujiwara, T.: Psychiatr. Neurol. Jap. 64: 139, 1962. (in Japanese) Fujiwara, T.:

Brain 84: 514, 1961.

Handbuch d. spez. patholog. Anatomie u. Histologie: XIII-2, Bd. A,

Ibid. 32: 257, 1957. (in Japanese).

Acta Med. Univ. Kioto 28: 2, 1950.

Jap. Circulation J. 18: 92, 1954. Ibid. 23: 19, 1959.

Jap. Arch. of Inter. Med. 6 : 247, 1959. (in Japanese) Ibid. 6: 263, 1959. (in Japanese)

Jap. Circulation J. 27: 873, 1963.

histopathological studies of the arachnoid and radicular nerves in various diseases

Documents