pathological changes in the central and peripheral nervous ... · pathological changes in the...

Diabetologia 4, 34-43 (1968)

Pathological Changes in the Central and Peripheral Nervous System of Young Long-term Diabetics

II. The Spinal Cord and Peripheral Nerves

EDITH RESKE-1NIELSEN and K~UD LUNDB~EK

Department of Neuropathology and Second Clinic of In ternal Medicine, Kommunehospital, Aarhus University School of Medicine, Aarhus, Denmark

l~eceived July 10, 1967

Summary. A study of the spinal cord and peripheral nerves of 15 long-term, juvenile diabetic patients has revealed the following changes : -- 1. atrophy of the spinal cord, sometimes with fibrosis of the leptorneninges; -- 2. degeneration of the ganglion cells of the anterior and posterior horns; -- 3. demyelinization and axon cylinder loss in the posterior columns and the peripheral nerves, increasing in severity towards the periphery; -- 4. severe neurogenic atrophy of the muscles; -- 5. mild abnormalities in the blood vessels of the spinal cord in some of the cases, which were more pronounced in the peripheral nerves ; -- 6. severe hyalinosis in the muscle capillaries. -- On the whole, the vascular changes were not severe enough to explain the presence of the ganglion cell and nerve fibre abnormalities observed in the spinal cord and peripheral nerves of young, long-term diabetic patients.

Modifications pathologiques du syst4me nerveux central et pdriph~rique de su]ets ~eunes, diabdtiques depuis longtemps. I I . La moelle @ini~re et les nerfs p~riphdriques

Rdsumd. Une 6tude de la moelle dpinibre et des nerfs pgriphdriques de 15 patients jeunes, diab6tiques depuis longtemps, a rdv61d les modifications suivantes : -- 1. Atro- phic de la moelle dpini~re, parfois avec fibrose des lepto- mdninges; -- 2. Ddg6ndrescence des cellules ganglionnaires des cornes antdrieures et postdrieures; -- 3. Ddmy61inisa- tion et perte des cylindraxes des cordons postdrieurs et des nerfs pdriphdriques, devenant plus graves vers la pdriph6rie; -- 4. Grave atrophic neurogbne des muscles; -- 5. Ldg@res anomalies des vaisseaux sanguins de la moelle dpinibre dans certains eas, plus prononcdes dans les nerfs pdriphdriques; -- 6. Hyalinose grave dans les

capillaires musculaires. -- Au total, les modifications vasculaires ne sent pas assez graves pour expliquer la pr@sence des anomalies des cellules gangliormaires et des fibres nerveuses, observdes dans la moelle @ini@re et les nerfs p@riphgriques de patients jeunes, diab6tiques depuis longtemps.

Pathologische Verdnderungen am zentralen und per@he- ten Nervensystem ]ugendlicher Diabetiker. I I . R~c/cenmar/c und per@here Nerven

Zusammenfassung. Bei Untersuchungen des Riicken- marks und der peripheren Nerven yon 15 jugendlichen Langzeitdiabetikern ergaben sich folgende Ver~nderun- gen: 1. Atrophic des l%iickenmarks, z.T. mit Fibrose der Leptomeningen; -- 2. Degeneration yon Ganglienzellen der Vorder- und Hinterh6rner; -- 3. Markschwund and Verlust von Achsenzylindern in den I-Iinterstriingen and, nach distal zunehmend, in den peripheren Nerven; -- 4. Sehwere neurogene Muskelatrophie; -- 5. Bei einigen F~llen Gef~13veranderungen, die irn Bereich des Rficken- marks leicht, an den peripheren Nerven starker ausgepr~gt erscheinen; -- 6. Sehwere Hyalinose der Muskelkapilla- ren. -- Zusarnmenfassend 1/~l~t sich sagen, daI3 die Gef~fL verfinderungen nieht ausgepri~gt genug waren, um die an Riickenmark und peripheren Nerven beobachteten Seha- digungen yon Ganglienzellen und Nervenfasern bei jugendlichen Langzeitdiabetikern zu erkl~ren.

Key-words: Neuropathy, eneephalopathy, spinal cord, peripheral nerves, juvenile diabetes, long-term diabetes, angiopathy, microangiopathy.

I n an earlier report, we presented the results of histological studies of the bra in in a series of juvenile, long-term diabetic pa t ien ts (RESK~-NI~LS~N et al., 1966). The present paper gives the results of studies of the spinal cord, the peripheral nerves and the muscles from some of the cases inc luded in the previous report as well as from other pa t ien ts in the same cate- gory. Here, as in the report on eneephalopathy, we are dealing exclusively with juvenile diabetics dying after many years of diabetes.

The purpose of the present s tudy was to elucidate the still unse t t led problem of the significance of vascular abno rma l i t y in the deve lopment of diabet ic neuropa thy , as well as to revive the half-forgotten quest ion of the localization of the disorder of the nervous system appear ing clinically as diabet ic neuropa thy .

Material and Methods The Pa t i en t s

Clinical observat ions on the 15 pa t ients in this series are shown in Table 1. Seven of the pa t ients were men, eight were women. The average age of onset was l l years (range 2 - -29) ; 11 of the cases were diagnosed before puber ty . The average dura t ion of diabetes was 23 years (range 15--36 years). All the pa t ients had severe and widespread vascular disease. Re t i nopa thy was observed in all cases and was severe in six, four of them being b l ind or near ly blind. Clinical signs of neph ropa thy were present in 13 cases, hear t disease in seven, and hyper tens ion was found in 10. Four teen of the pa t ients showed signs or symptoms of neurological disease; n ine had paraesthesia and four had muscle

Vol. 4, No. 1, 1968 E. •ESKE-•IELSEN and K. LUNI)B~IC: Pathological Changes. II . 35

weakness. Areflexia was present in all but one, eight revealed reduced sensitivity, nine reduced vibratory :sense and eight reduced motor conduction velocity. Three patients also showed pronounced signs and symptoms of cerebral disease, which in two of them included a spastic gait.

Pathological Report Autopsy of the brains, the spinal cords, the peripheral

nerves and the muscles

All the material was fixed in four per cent neutral formalin. Nine of the spinal cords, which included the cauda equina, showed a slight a t rophy and four of them had blurred leptomeninges. In nine cases inspec- t ion of the transverse section revealed a faded pattern.

For histological examination the cervical, thoracic and lumbar segments of the spinal cord, the eauda equina and the following bilateral speciments of nerves and muscles were used: nervus isehiadicus, nervus peroneus superfieialis, nervus eutaneus dorsalis pedis and nervus ulnaris, musculus semimembranosus, musculus peroneus brevis, musculus extensor digitorum brevis and musculus flexor carpi ulnaris. In some cases pieces of other nerves and muscles from both the upper and lower extremities were also removed. All specimens were removed with great care, precaution being taken to avoid artificial trauma. In addition to the stains routinely used in the study of the central nervous system such as hematoxylin-eosin, VAN GIES0N, gallocyanin-chromalum (EINA~SON), toluidine blue, and Mahon, special techniques were also employed including lipid (scarlet-red) and elastic tissue stains, a modified MclVLtNus, a modified ZIEI{L-I~[IELSEN, an axis-cylinder stain (DAVENPORT), and HALE'S technique for de- monstration of acid mucopolysaccharides as modified by ]~INEHAaT and ABUL-IIAJ.

placed nuclei. In the cytoplasm, PAS-positive and fat- positive granules were seen. A mild degree of glioses was present. (Fig. 2, 3, 4)

In the white matter the myelin sheaths as well as the axons were swollen with unequal calibre, and frag- mented with loss of nerve fibres. There was mild, diffuse gliosis and corpora amylacea. Most of the spinal cords revealed elective degeneration of the posterior columns with loss of axons (Fig. 5). In two of the cases (No. 2 and 3) degeneration of the lateral columns was also observed.

The vessels of the grey and white matter showed only mild changes. In five cases, hyalinosis of the arterioles could be seen. Only one case showed a characteristic homogeneous PAS=positive thickening of the walls of the small vessels with narrowing of the lumina. (Fig. 6)

The anterior and posterior roots showed varying de- grees of loss and degeneration of myelin sheaths and axis cylinders. The myelin sheaths were swollen with varying calibre. The changes were most pronounced in the posterior roots. The degeneration of the anterior roots paralleled the alterations in the motor ganglion cells. As a rule the posterior roots were more degenerated than the posterior columns, and there was often SCnWANN cell proliferation. In few cases the small vessels of the anterior and posterior roots showed hyalino- ses, but the degenerative alterations were mild. (Fig. 7,8)

Peripheral nerves from the upper and lower extremities revealed the same pathological changes as the roots, but they were much more pronounced. In many eases, total demyelinization and severe loss of fibres were seen. The large and small vessels showed mild or

Histological Examination

Brains from patients not previously described showed essentially the same types of lesions as those seen in the cases published earlier (I{ESKE-NIELSEN et al., 1966).

The spinal cord

The leptomeninges were normal or showed slight fibrous thickening. In a few eases the anterior spinal ar tery and its ramifications revealed proliferation of the intima, containing phagocytes with fat droplets and PAS-positive granules in the cytoplasm. In two of the cases, vessel changes were very severe; the sub- endothelial space or the entire wall was filled with fat and the vessel lumina were narrowed, but without thrombi (No. 1 and 2). (Fig. 1)

The anterior and posterior horns showed slight or moderate loss of ganglion cells. The remaining ganglion cells revealed degeneration with swollen and/or dis-

Fig. i. Small artery with fat-laden phagocytes in the intima. The lumen is narrowed and eccentrically placed

(Scarletred. High magnification)

3*

Fig. 2. Anterior horn with degenerated ganglion cells and Fig. 4. Sensory ganglion cells with degeneration (Gallo- gliosis (Gallocyanin-ehromalum. Medium magnification) eyanin-ehromalum. I-Iigh magnification)

Fig. 3. Motor ganglion cells with degeneration (Gallo- Fig. 5. Posterior columns with loss of axons and degenera- eyanin-ehromalum. High magnification) tion of the myelin sheaths (Mahon. Medium magnification)

Vol. 4, No. 1, 1968 E. RESKE-NIELSEN and K. LUNDBzEK : Pathological Changes. II. 37

moderate pathological changes. A considerably thickened intima with homogeneous, PAS-positive material and pycnotie nuclei was found in only one case. The nerve lesions and vascular changes gradually increased in severity from proximal to distal. (Fig. 9, 10, 11)

Fig. 6. Small arteriole with enormously thickened, homogeneous and deeply PAS-positive wM1. The lumen is

nearly occluded (PAS-stain. High magnificat/on)

Fig. 7. Spinal nerve with loss and degeneration of myelin sheaths (Mahon. tIigh magnification)

Fig. 8. Spinal nerve with loss and degeneration of axis cylinders (Davenport. High magnification)

The muscle specimens showed neurogenic atrophy with fields of varying age and size. The changes ap- peared to be dependent upon the degree of degeneration of the peripheral nerves. They were most pronounced in the specimens from the legs and the feet where the most severe lesions were seen. Sometimes the muscle fibres had almost disappeared and only clumps of muscle nuclei and a few very thin fibres remained. In many places the muscles were substi- tuted by fat. ?r with hyalinization and va- cuolization of the muscle fibres and the presence of a few necrotic segments, was seen in only one ease (No. 4), and here both upper and lower extremities were in- volved. (Fig. 12)

The capillaries of the muscles were more numerous than normal. The walls revealed both diffusely and focally thickened basal membranes with increased PAS-positivity. (Fig. 13, 14)

38 E. RESKE-NIE5S~ and K. LUSrDB~:: Pathological Changes. II . Diabetologia

Fig. 9. Peripheral nerve with loss and degeneration of myelin sheaths (Mahon. High magnification)

The arterioles sometimes showed fibrillar thickening. Vessel changes were extremely pronounced in the muscles of the feet.

:Fig. 10. Peripheral nerve with loss and degeneration of axis cylinders. The small vessel is normal (Davenport.

High magnification)

Correlations

In Tables l, 2 and 3 the patients have been listed according to the severity of the neurological symptoms. In spite of considerable pathological changes in both motor and sensory peripheral neurons in all the patients, only half of them had sensory symptoms (paraesthesia), and only four of them had motor symptoms (muscle wegkness).

On the other hand, all of the cases except one, presented objective signs of peripheral neuropathy; 14 patients having reduced tendon reflexes and four a t rophy of the muscles.

Pathological changes in the white mat te r of the spinal cords were, as was to be expected, most pronounced in the posterior columns.

Degeneration of the lateral columns was seen in only two cases, and was probably secondary to ence- phalopathy (case no. 2 and 3).

Fig. 11. Small artery with clumps of PAS-positive material in the thickened intima (PAS-stain. High magnifi-

cation)

Vol. 4, No. 1, 1968 ]~. RESXE-NIELSEN and K. LVNDB2EK: Pathological Changes. If. 39

I t has not been possible to demonstrate any correlation between the degree of vessel degeneration and pathological alterations in the spinal cord and peripheral nerve roots. I t is striking tha t the changes in the nervous system were symmetrical, diffuse and remark- amy uniform, whereas the alterations in the vessels were focal, variable and, in general not very pronounced.

studies tha t include examination of the spinal cord. Cases reported in the old literature, i.e. before the in- troduction of insulin, are discussed in detail in the paper by WOLTHAN and WILDE~ (1929). Most of these reports describe findings in only a single ease. In some of these cases degenerative changes were noted in the spinal cord, similar to those of tabes dorsalis or of subaeute, combined degeneration.

Fig. 12. Cross-section of muscle with severe neurogenie atrophy (Hematoxylin-Eosin. Medi-

um magnification)

Except for the fact tha t the two cases with severe vascular changes in the spinal cord had manifested a pronounced neuroencephMopathie syndrome during life, there was no correlation between symptoms and vascular abnormalities.

In the muscles, especially of the feet, there were very severe changes in the capillaries with enormously thickened, PAS-positive walls. In spite of this, myogen atrophy was seen in only one case, a patient who had had severe peripheral neuropathy for several years. Neuro- genie atrophy on the other hand was present in every case.

Discuss ion

The voluminous literature on diabetic neuropathy contains surprisingly few comprehensive histological

Fig. t3. Cross-section of muscle with severe capillary angiopathy. Muscle fibres appear as empty rings. (PAS-

stain. High magnification)

WO~,T~AX and WINDOW'S own material consisted of the spinal cord and peripheral nerves from three diabetic patients. They found tha t changes in the spinal cord were not very pronounced, whereas those in the peripheral nerves were severe and associated with pronounced thickening of the wails of the Mood vessels. They concluded tha t diabetic neuropathy is a disease of the peripheral nerves - - " the degenerations noted in the spinal cord are unimportant" .

This conclusion was widely accepted and in the following years very little was published on the his- to]ogy of the nervous system in diabetes mellitus. In the 1940's and 1950's, when it was reMized tha t the various, so called, complications such as retinopathy, nephropathy and gangrene were in fact parts of a gen- eralized diabetic vascular disease, the question was raised whether neuropathy was also to be accepted

4:0 E. RESKE-NIELSEN and K. L~DB~K: Pathological Changes. II. Diabetologia

under the heading of diabetic angiopathy. Many clinical facts were consistent with this concept, and FAGE~- BErG (1959) found a good correlation between the histological changes in the vasa nervorum of the lower

Fig. 14. Longitudinal section of muscle with numerous capillaries. The walls are enormously thickened and deeply PAS-positive. (PAS-stain. High magnification)

extremities and the symptoms and signs of clinical neuropathy. However, other evidence, clinical as well as experimental, has shown tha t a nonvascular element must also be present in the pathogenesis of diabetic neuropathy.

In the meant ime the problem of the localization of the defect inside the nervous system was nearly forgotten. Except for a few ease reports, only one extensive and well-documented s tudy of the histology of the spinal cord, nerve roots and peripheral nerves in young or middle-aged patients with diabetes mellitus has ap- peared recently (DoLMA~, 1963). Most of the 36 patients described by this author were old, 26 being over 60, and 17 over 70 years of age. However 5 patients were younger - - 27--45 years - - and had suffered from diabetes for many years (18--33 years). Except re- garding vascular changes, no distinction was made in the report between old patients with short or long du- rat ion of diabetes and juvenile, long-term diabetics. I t appears from the tabulation of data, however, tha t neuropathologicM changes were well-marked in the

young patients. In half of the 36 cases, the spinal cord showed reduction of myelin sheaths with severe dam- age to axis cylinders in the dorsal columns, but not in the lateral funiculi. The posterior roots were atrophic in cases with degeneration of dorsal columns ; the motor roots were normal. Pa tchy demyelinization was seen in many peripheral nerves. Axis cylinders were also affected, but less severely. These changes increased towards the periphery. Neurogenic a t rophy was seen in muscle specimens from 9 of the 25 patients. The in- traneural and perineura] arteries often showed cellular hyperplasia and PAS-positive hyalinization. Capillary thickening was seen only in the juvenile diabetics. Similar, although less pronounced, vascular changes were noted in 7 hypertensive, non-diabetic patients (age not mentioned).

In the present s tudy of long-term juvenile diabetics changes which are more severe and extensive than those reported by DOL~A~ have been found. The overM] picture of the changes in the spinal cord is that of a diffuse, symmetrical degeneration, affecting the grey as well as the white substance. The root changes were not confined to the posterior roots. The posterior root changes were more severe than those of the posterior columns. The mild or moderate changes observed in the ganglion cells of the anterior horn might be due in par t to retrograde degeneration.

The myelin sheath and axon cylinder degeneration in the peripheral nerves was even more severe than that in the spinal cord, and as in DOLMA~'S cases increased towards the periphery, but we cannot conclude, as WOLT~AX and WILD~g did, tha t in comparison the spinal cord changes are "unimportant".

Except for two cases with severe neuro-encephalo- patic symptoms, vascular changes in the spinal cord were mild or absent. Vascular changes were more pronounced in the peripheral nerves, especially in the smallest vessels; and were very severe in muscles.

I t is known today tha t nervous system abnormalities may be present at the start of clinical diabetes in young patients, and some abnormalities have been shown to be reversible (STm~ESS, 1961; G~EOERSV.~, 1964, 1967). Certain biochemical changes suggesting an abnormali ty of the sorbito] pa thway of nervous tissue have been demonstrated in acute experimentM diabetes in animals (GAB~AY et M., 1966; ST~WAnT et a]., 1966). On the other hand, clinical signs and symptoms of diabetic neuropathy increase in incidence with the duration of diabetes and are correlated to the incidence of re t inopathy and nephropathy.

Findings in the present s tudy resemble those ob- tained in our s tudy of brains from juvenile, long-term diabetics, i.e. a severe nervous system disease with relatively mild abnormalities of the vascular t r e e (R~sK~-NIELS~ et al., 1966).

The changes observed in ganglion cells and nerve fibres cannot be due simply to ischemia alone. As in the brain, a dual pathogenesis seems likely, viz. a metabolic disturbance of nervous tissue combined with

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§ + + § + § § + + + + + § § § + • + § § + + + + + + § + + + +

+ 0 O O + 0 + 0 O + 0 O O 0 O

O 0 0 0 0 0 0 0 0 0 0 0 0 0 0

+ + + + § + + § + + + + + + + +

+ + § 2 4 7 + + + + + + § + + + + + § + +

+ O O O § O + O 0 + 0 0 0 0 0

0 0 O O O O 0 O 0 O O O O O O

+ v

§ + + + 0 0 ~ + + + + r § + +

+ + + § § § § § + + § § § + § § + + § + §

+ § § 2 4 7 + § + § § § + § + + + § § § + § §

+ + + § § + + + + + + + § + + + + + +

+ + + 0 0 + O O O 0 + O 0 0 0

+ + + 0 0 0 0 0 0 0 0 ~ 0 0 0

d @ N

ga �9

#a

Vol. 4, No. 1, 1968 E. 1%ESKE-NIELSEN and K. LUNDB2EK: Pa tho log ica l Changes. I I . 43

Table 3. Histological abnormalities of the muscular vessels and muscle fibres. Third columns: neurogenic atrophy. Sym-

bols: as in Table 2

m

Muscles

Upper ex t remi t ies

�9

~ ~ ~

~ =~ o ~ ~

Lower ex t remi t ies

@

O

1 SVJ + ++ ++ �9 + + + + + + +

2 JPC1% o ++ + o (+) + + + + + +

3 B G N (+) + ++ o o + + + + + +

4 I~IK o + + + ++ + o + + + + + +

5 Epa o o + o o + +

6 K G L ~ o o (+) o o + +

7 BEH o ++ + o (+) +++ ++

8 ESC ~ o o + o o o +

9 EIS o + + + ++ o (+) + + + + + +

10 MMJ a o + + + ++ o o + + + ++

11 E V A a o ++ ++ o o + + + + + +

12 K C H a o + + o + + + + + + +

13 IT a o + + o o + + + + + +

14 E A A + + + o o ++ ++

15 K M J o + + o o + +

a h y p o p h y s e c t o m i z e d .

a s lowly d e v e l o p i n g a n g i o p a t h y . N e u r o p a t h y in t h e c l inical sense w i t h p e r m a n e n t s igns a n d s u b j e c t i v e s y m p t o m s u s u a l l y a p p e a r s o n l y a f t e r m a n y y e a r s of d i a b e t e s w h e n i n c a p a c i t a t i n g v a s c u l a r a b n o r m a l i t i e s are also p r e s e n t in m a n y o t h e r o rgans .

J~ef ere'ace8

DOLlVIAN, C.L. : The mo rb i d a n a t o m y of d iabet ic neuro- p a t h y . Neuro logy 13, 135--142, (1963).

FAGERBERG, S .E . : Diabet ic n e u r o p a t h y . Ac ta reed. s t and . 164, suppl . 345 (1959).

G•BBAY, K.I-t . , L .O. ME~OLA, and R . A . FIELD: Sorbi tol ~ p a t h w a y : presence in ne rve and cord wi th subs t r a t e o accumula t ion in d iabetes . Science 151, 209--210 (1966).

G~GERSEN, G.: Motor -ne rve func t ion and dura t ion of d iabetes . L an ce t 1964 II, 733.

-- Diabet ic n e u r o p a t h y : Inf luence of age, sex, metabo l ic o control and dura t ion of d iabe tes on m o t o r conduc t ion o velocity. Neurology 7, 972--980 (1967).

-- V ib ra to ry pe rcep t ion t h r e sho ld and m o t o r conduc t ion o veloci ty in d iabet ics and non-diabet ics . Ac ta reed. + s t and . (To be publ ished) .

~ESK]~-NIELSEX, E., K. LVND•eEK, and O. g. RA~'AELSEN : o Pa thologica l changes in t he cent ra l and per iphera l ner- o vous sys t em of young long- te rm diabetics . I. Diabet ic

encephMopa thy . Diabeto logia 1, 233--241 (1966). O STEINESS, I. : Inf luence of d iabet ic s t a tus on v ib r a to ry o pe rcep t ion dur ing isehemia. Ae ta reed. s t and . 170,

319--338 (1961). o STEWART, M.A. , W.1%. SHERMAN, and S. AN~HO~Y: Free o sugars in a l loxan ra t nerve. Bioehem. b iophys , res.

Comm. 22, 488--491 (1966). o WOLT~AN, H . W . , and 1%.M. WILDER: Diabe tes mell i tus . o Pa thologica l changes in t h e spinal cord and per iphera l

nerves. Arch. in tern . Med. 44, 576--603 (1929). O

Dr. EDITI~I gESKE-NIELSEX o D e p a r t m e n t of Neuropa tho logy , and o 2nd Clinic of I n t e r n a l Medicine

K o m m u n e h o s p i t a l e t Aarhus Un ive r s i t y School of Medicine Aarhus , D e n m a r k

pathological changes in the central and peripheral nervous ... · pathological changes in the...

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