CHRONIC RECURRENT GUILLAIN-BARRÉ SYNDROME

R E P O R T O F 3 CASES

ANTÔNIO RODRIGUES DE MELLO * — MARCOS R. G. DE FREITAS *!¡

LEILA CHIMELLI ***

S U M M A R Y — T h e classical Gui l la in-Barre s y n d r o m e is an acute o r subacute p o l y r a d i c u l o ­

neuropa thy w h o s e main cl inical features are progress ive weakness of the l imbs, decrease or

absence o f tendon ref lexes , and senso ry changes . A l t h o u g h in mos t of the cases there

is comple te r e cove ry in w e e k s o r months , s o m e patients have a s l o w and progress ive

re laps ing course and present th icken ing of the per iphera l nerves . In this paper we descr ibe

three cases o f the chron ic and re laps ing var ie ty o f Gui l la in-Barré s y n d r o m e , two of which

had prominent hype r t roph ic changes in the per ipheral nerves wi th on ion bu lb format ions

T h e cl inical and pa tho log ica l features o f this disease are rev iewed. The three patients

improved wi th the use of s teroids .

Síndrome de Guillain-Barré crônica recorrente: registro de 3 casos.

R E S U M O — A s índ rome de Gui l la in-Barré clássica é pol i r rad icu loneuropat ia aguda ou

sub-aguda, cu jos pr incipais aspec tos c l ín icos s ã o : fraqueza progress iva dos membros , redução

ou ausência de re f l exos tend inosos e a l terações sensi t ivas. E m b o r a na maior ia dos casos

haja recuperação comple t a em semanas ou meses , em alguns pacientes o curso é lento,

p rogress ivo ou rec id ivante e há espessamento dos nervos per i fé r icos . N o presente ar t igo

desc revemos três casos da var iedade c rôn ica e recidivante da s índ rome de Guil lain-Barré,

dois dos quais t inham al terações h iper t róf icas p roeminen tes nos nervos per i fér icos com

fo rmações em b u l b o de cebola . Os aspec tos c l ín icos e pa to lóg i cos desta doença são revis tos .

Os três pacientes me lhora ram c o m o uso de es teróides .

The Guillain-Barré (GB) syndrome is a polyradiculoneuropathy whose main

clinical features are progressive weakness of the limbs, decrease or absence of tendon

reflexes, sensory changes and, less frequently, cranial nerve involvement2. The

cerebrospinal fluid (CSF) shows albuminous-cytologic dissociation, and there is electro­

physiological evidence of slow nerve conduction. In the peripheral nervous system

the main pathological finding is demyelination 2,20. While in most patients the illness

is acute or sub-acute with complete recovery in weeks or months, some cases have

a slow and progressive relapsing course, and present thickening of the peripheral

nerves 2,8,3. In spite of the clinical presentation and the variety of names given by

various authors 9.21 to the latter forms, they share with the classical GB syndrome

electrophysiological, humoral and pathological findings.

In the present paper three cases of the chronic and relapsing variety of GB

syndrome are described, which are also unusual for some morphological findings

in the peripheral nerves.

Traba lho das Disc ip l inas d e N e u r o l o g i a e d e Neuropa to log ia , Facu ldade de Medic ina ,

Univers idade Fede ra l F l u m i n e n s e : * P ro fe s so r Emér i to da U N I R I O ; Professor Ad jun to

d e N e u r o l o g i a ; *** Pro fesso r A d j u n t o de Neuropa to log ia .

Rua Gastão Ruch 16, apto. 1402 - 24220 Niterói RJ - Brasil

C A S E R E P O R T S

Case 1 — L W M , a 12-year-old gir l , presented in June 1958 weakness and paraesthesia of all 4 l imbs s tar t ing in the l o we r l imbs w h i c h p rog re s sed rapidly . She denies any tox ic or a lcoho l ic inges t ion and there is no s imilar case in the family . N e u r o l o g i c a l examinat ion s h o w e d tetraparesis , r educed tendon ref lexes, and s l ight distal superf ic ia l hypoes thes ia in a rms and l e g s ; cranial ne rves w e r e normal . CSF examina t ion s h o w e d 14 ce l l s /mma, prote ins 138 m g / d l . R o u t i ne b l o o d tests were normal . She recovered comple t e ly after 30 days . In 1972 at the age o f 26 she had a recurrence . The re w a s genera l ized deep areflexia, superficial hypoes thes ia in the lateral aspect of the feet . The cubital nerves were th ickened and the brachial p lexus was pa lpable and vis ible on bo th s ides. E l e c t r o m y o g r a p h i c f ind ings sugges t ed a per iphera l nerve d isorder . She improved again but in 1974 she had a n e w recurrence w h i c h improved wi th dexamethasone . Three months later, after the s teroid had been d i scon t inued there was a n e w recur rence wi th unilateral per iphera l facial palsy . T h e r e w e r e three other recur rences in June and D e c e m b e r 1975 and in D e c e m b e r 1981, f o l l o w i n g reduct ion of the s te ro id dose . T h e C S F examinat ion in 1981 s h o w e d 1.7 ce l l s /mm^, 216 m g / d l protein, and 16% of g a m m a g lobu l in . A t this occas ion the b i o p s y of a supraclavicular mass s h o w e d an en larged nerve, wh ich was examined h i s to log ica l ly . The spec imen cons is ted of a th ick nerve w h i c h w a s p roces sed fo r paraffin e m b e d d i n g . Long i tud ina l sec t ions s tained wi th haematoxi l in and eosin ( H E ) s h o w e d ex t r eme ly l a rge nerve f ibres su r rounded b y numerous Schwann cell nuclei . On transverse sec t ions it s h o w e d concen t r i c pro l i fe ra t ion of Schwann cells w i th the appearance of on ion bu lbs ( F i g . l a ) . L y m p h o c y t e s , main ly a round b l o o d vessels w e r e a lso seen ( F i g . l b ) . T h e appearances w e r e those of a hype r t roph ic ch ron ic in f lammatory neuropa thy . T h e patient d ied soon after last recurrence wi th cardio-respi ra-to ry failure. P o s t m o r t e m examinat ion was not pe r fo rmed .

Case 2 — O A , a 52-year-old b l a c k female w a s seen in Apr i l 1986. S y m p t o m s had started in 1981 wi th paraesthesiae in hands and feet f o l l o w e d b y l imb weakness w i th d i f f icul ty in walk ing . She improved cons ide rab ly on prednisone . Since then and fo r abou t 6 years she presented s imi lar ep isodes , usual ly p receded b y a c o l d . W i t h the s teroid therapy there w a s

partial r emiss ion of the weakness , and b e t w e e n the relapses she exper i enced on ly little d i f f icu l ty in wa lk ing . The re is no h i s to ry o f t o x i c or a lcoho l ic inges t ion and no d iabe tes . N o similar cases occur red in the fami ly . N e u r o l o g i c a l examinat ion — Coarse postura l t remor in hands, a tax ic t y p e of gait wi th suppor t . Tet rapares is p redominan t ly distal and m o r e marked in l o w e r l imbs , genera l ized hypo ton ia , p rop r iocep t ive a taxia of all l imbs , superf icial and deep hypoes tes ia in l o w e r l imbs . Cranial nerves normal . Per iphera l nerves pa lpable bu t no t th ickened. CSF examina t ion — In January 1983: 0 c e l l s / m m 3 , p ro te ins 150mg/d l ; in M a y 1986: 26 cells/mm-3 (60% p o l y m o r p h s and 40% m o n o n u c l e a r ) , prote ins 325mg/dl . R o u t i n e b l o o d and ur ine tests w e r e normal . E l e c t r o n e u r o m y o g r a p h y s h o w e d severe invo l ­vement o f distal neu roconduc t ion . Sural nerve b i o p s y — A segmen t of nerve, 2 c m in lenght w a s f ixed par t ly in 10% formal in for paraffin e m b e d d i n g and par t ly in 3% g lu ta ra ldehyde in 0.05 M N a cacody la t e buf fe r for Ara ld i t e e m b e d d i n g and fo r teasing. Paraff in sec t ions stained wi th H E s h o w e d apparent ly normal nerve f ibres w i th s o m e increase in number of Schwann cel ls . N o in f lammatory cel ls w e r e seen. One mic ron thick Ara ld i te sec t ions stained w i t h to lu id ine b lue s h o w e d some clusters of small mye l ina ted axons ins ide s ingle Schwann cells ind ica t ing regenera t ion . S o m e concen t r i c pro l i fe ra t ion o f Schwann cell c y t o p l a s m su r round ing mye l ina ted f ibres wi th thin mye l in sheath w e r e also seen ( F i g . 2 ) . Th i s w a s

conf i rmed in thin sec t ions whe re s o m e Schwann cel ls devo id o f a x o n s ( F i g . 3a) and naked axons ( F i g . 3b) c o u l d b e obse rved . O n l y f e w unmyel ina ted f ibres w e r e present . S ingle teased f ibres s h o w e d segmenta l demyel ina t ion and a g rea t var ia t ion of in ternodal lenght . The features w e r e sugges t ive o f a ch ron i c demye l ina t ing neuropa thy wi th s igns of remyel ina-t ion, axona l regenera t ion and beg inn ing of o n i o n b u l b format ion . W i t h prednisone , even after reduc t ion o f the dose , s ignif icant improvemen t w a s obta ined and she w a s ab le to wa lk wi thou t suppor t .

Case 3 — M V C , a 67-year-old whi te female w a s seen in N o v e m b e r 1936. In 1981 she pre­sented cervical pain i r radia t ing to the left a rm ( l ike a s h o c k ) , when she w a s submit ted to m y e l o g r a p h y and s u r g e r y of the cerv ica l sp ine w i th t empora ry improvement . In 1983 she had a l o w b a c k pain radia t ing t o pos te r io r surface o f r igh t t h igh and weakness of this l imb . A l aminec tomy w a s pe r fo rmed wi th s o m e re l ief o f the pain f o r a l imi ted pe r iod . T h i s w a s fo l l owed b y weakness o f all l imbs, a symmet r ic , w i t h d i f f icu l ty in wa lk ing . T h e pain was ma in ly in the left l imbs . S o m e re l ief w a s ob ta ined wi th ca rbamazepine and ch lo r imi -pramine . T h e r e is no h i s to ry o f toxin , a l coho l i sm o r diabetes . N o s imi lar cases in the fami ly are repor ted . Neu ro log i ca l examina t ion s h o w e d distal a m y o t r o p h y in all 4 l imbs wi th s l igh t de fo rmi ty o f the left hand, pe s equinus, bi lateral s t eppage gai t (w i th suppo r t ) , distal te t raparesis m o r e severe in the l o w e r l i m b s genera l i sed hypo ton ia , bi lateral Babinsk i

s ign ; left b ic ipta l re f lexes were present , o ther t end inous ref lexes w e r e absen t ; superficial hypoes thes ia b e l o w the knees and the wris ts , loss o f v ib ra to ry sense in l ower l imbs . Cranial nerves were normal . Cubital nerves w e r e un i fo rmly pa lpable and th ick ( m o r e on the lef t ) . R i g h t pos te r io r aur icular nerve w a s thick. C S F examinat ion s h o w e d 1 cel l /mm3, totel prote ins 48mg/dl , I g G 5.6mg%. E l e c t r o n e u r o m y o g r a p h y s h o w e d a great reduc t ion in sensi t ive and m o t o r nervo conduc t ion in all 4 l imbs . Sural ne rve b i o p s y — A t w o c m nerve was f ixed and p rocessed as desc r ibed in case 2. Paraff in sec t ions stained wi th H E s h o w e d thick nerve f ibres, increase in n u m b e r of Schwann cell nuclei and no in f lammatory cel ls . One micron

t ransverse Ara ld i t e sec t ions stained wi th to lu id ine b lue s h o w e d that a lmost all the f ibres were sur rounded b y Schwann cell cy top l a sm concen t r ica l ly prol i fera ted wi th the appearance of on ion bu lbs ( F i g . 4a ) . Clusters of regenera ted axons w e r e seen as wel l as th inly mye l ina ted axons indica t ing remyel ina t ion . Ultrathin sec t ions examined wi th the e lec t ron m i c r o s c o p e s h o w e d similar features ( F i g . 4b ) wh ich w e r e those of a hype r t roph ic t y p e o f ch ron i c neuropa thy . T h e pat ient w a s pu t on 60mg predn isone per day, and 30 days after she cou ld walk wi thout suppor t wi th great improvemen t o f the s t renght and sensat ion in all 4 l imbs .

C O M M E N T S

Currently, the diagnosis of chronic recurrent GB syndrome is based on the following criteria 5 , 2 i : sensory-motor polyneuropathy with slow evolution; progressive or recurrent course; severe reduction of nerve conduction velocity; increased protein level in the CSF; absence of any systemic disease or exposure to toxic substances; and finding of segmental demyelination of peripheral nerves. Although Prineas and McLeod 21 and Dalakas and Engel 5 described the illness at all ages from 3 to 60 years, the patients reported by Dyck et al.9 were in their 5th and 6th decade of life. On the other hand there is agreement on the absence of sex predominance. The possibility that a genetic predisposition plays a role in the disease is supported by the findings of Aaams et al.i who observed that their 14 patients belonged to the HLA types A l , B8, D W E and D R W 3 , and those of Stewart et al.23 w h o found a high incidence of the type HLA DRW3.

The main clinical feature is a mixed polyneuropathy, sometimes with predomi­nance of weakness in proximal muscles. This pattern was seen in our case 2, while in the remaining two cases the distal muscles were the most severely involved. Cranial nerve involvement is not as common as in the acute form 5>9,21 ) and was seen only in our case 1 who presented unilateral 7th nerve palsy. Postural tremor of the upper limbs has been described in some patients by Prineas and M c L e o d 2 1 and Dalakas and Engel 5 ; in our case 2 there was hyperkinesia which disappeared after treatment with steroids. The tremor is attributed to involvement of proprioceptive pathways 5,21. Bilateral extensor plantar reflex, present in our patient 3, had been previously observed by Prineas and M c L e o d 2 1 in one of their cases.

According to Dyck and Arnason 8 the evolution of the syndrome can follow 3 courses: steadily progressive or relapsing; the progressive course may stabilize and the patient may eventually recover; a relapsing course in which the attacks may be separated by periods of normality. The recurrence can be spontaneous or may follow the reduction or the withdrawal of the steroid therapy 15-17. Regarding the number of recurrences, the patient described by Nattras in 1921 18 presented only two episodes, while that described by Austin 3 in 1958 had 20 such episodes over a period of 5 years. The patient reported by Pollard and Selby 19 had two recurrences, both of which followed an injection of tetanus toxoid. Our patients 1 and 2 suffered multiple episodes (7 in 23 years and 5 in 17 years, respectively), which followed the withdrawal of steroids. On the other hand, the progressive course shown in our three patients was also present in the cases described by Bonduelle and Gruner 4 , Torvik and Lundar 24, and by Freitas and Nascimento i 2 .

In addition to the presence of inflammatory cells, oedema and segmental demy­elination and remyelination, other features described in chronic GB syndrome include thickening of peripheral nerves and, at histological and ultrastructural level, hyper­trophic neuropathy 8. The latter abnormality was present in two of our three cases. Hypertrophic neuropathy, first described by Nattras is, is however present in a mino­rity of cases 9« 2i. The return of nerves to normal size in the cases described by Austin 3 was probably due to improvement of the oedema which was present, in addition to changes of hypertrophic neuropathy. These onion bulbs have been inter­preted by many authors as the result of repeated episodes of demyelination 2 5 . Axonal degeneration has also been reported in cases of chronic and acute GB syndrome 9,ii. Feasby et al .H described 5 patients with a variant of acute GB polyneuropathy who had severe axonal degeneration in distal nerves without inflammation or demyelination. Although we did not find fibres undergoing axonal degeneration we could observe indirect signs of this change such as Schwann cells devoid of axons and small clusters of myelinated axons indicating regeneration. The differential diagnosis of hypertrophic forms with slow evolution have to be made with hereditary diseases like Dejerine--Sottas and Charcot-Marie-Tooth diseases 7. However, in these two forms there is a family history, dysmorphic changes and they do not improve with the use of steroids.

The use of steroids made the course of chronic GB syndrome more favou­rable 3,5,6,9,10,16,17,21. Remission can be spontaneous or with the use of this drug. Prineas and M c L e o d 2 ! observed among their patients spontaneous remission in 12 occasions and 35 followed steroid therapy. Three out of the 4 patients studied by Hinman and Magee is, had spontaneous recovery and one recovered after the use of steroids. Dyck et al.io separated their 28 patients in two groups: 14 with and 14 without prednisone and the improvement was much more conspicuous in the group

which used the drug. Our three patients had steroids. All improved and two of them became steroid dependent. It has recently been suggested plasmapheresis as an effective method in the treatment of this disease H.22. However, some more studies are necessary with more patients to evaluate the real efficiency of this therapeutic scheme.

Acknowledgements — W e should l ike to thank Miss R i t a C. Cunha and Miss Suely M.

Cunha for the technical assistance, and Miss R o s e l y C. Cunha and Mr. R i c a r d o Barre to

for the pho tog raph i c w o r k .

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