Diagnostic Considerations in Gdain-Bar6 Syndrome

Arthur K. Asbury, MD

Guillain-Bar& syndrome (GBS) is a recognizable entity for which the basis for diagnosis is descriptive in our pres- ent state of knowledge. Diagnosis rests upon pattern recognition of the clinical picture plus other features includ- ing elevated cerebrospinal fluid protein level, electrophysiological changes of marked slowing of cohduction ve- locities, prolonged distal latencies, dispersion of' the evoked responses, and frequent evidence of conduction block, together with pathological changes, when known, of low-grade inflammation and demyelination-remyelination in peripheral nerve. The precise diagnostic limits of GBS remain uncertain.

Asbury AK: Diagnostic considerations in Guillain-Barrk syndrome. A n n Neuro l 9(suppl): 1-5, 198 1

Acquired demyelinative neuropathies fall into two major groups: an acute form, called Guillain-Bark syndrome (GBS), and a chronic form. The entire group of acquired demyelinative neuropathies con- stitute about 40% of all cases of polyneuropathy in adults [23] and share a distinctive pattern of- clini- cal, electrophysiological, and pathological features. Diagnosis rests upon pattern recognition of the clini- cal picture plus other features including elevated ce- rebrospinal fluid protein level, electrophysiological changes of marked slowing of conduction velocities, prolonged distal latencies, dispersion of evoked re- sponses, and frequent evidence of conduction block as well as pathological changes, when known, of low-grade inflammation and demyelination-remy- elination in peripheral nerve. The course of GBS is acute and monophasic, whereas the chronic forms pursue either a slowly progfessive [6] or a relaps- ing [24] course. Cases with an intermediate course occur frequently enough to blur the diagnostic de- limitation of GBS from the more chronic types of acquired demyelinative neuropathy.

It is generally accepted that GBS is immuno- logically mediated [2, 141 and, by extension of the logic, that chronic acquired demyelinative neu- ropathies may be as well. What specific alterations of immunological circumstance are necessary to initiate the sequence of events culminating in de- myelination of human peripheral nerve are unclear.

Historical Aspects Our concern here is only with GBS. Although a con- siderable amount was written during the nineteenth century on acute ascending paralysis and synonymous

conditions, it was not until 1916 that Guillain, Barri, and Strohl [ 101 characterized clearly the condition which has more recently borne the name of at least two of them. They emphasized the motor distur- bance, areflexia, minimal sensory loss, increased protein level in cerebrospinal fluid with absence of cells, and favorable prognosis. Although no one would argue with this general formulation, particu- larly since it was based on observation of only two patients, it was not long before many more cases were reported and controversy erupted. Opinion differed as to the limits of the diagnosis, with much of the argument focusing on the degree of sensory loss that was acceptable, the frequency and severity of sphitlcter disturbance, the level of pleocytosis in ce- rebrospinal fluid that was allowable, and the mortality rate, if any. Although some of these points do not seem too controversial at present, the diagnostic limits of the disorder are still uncertain.

An inflammatory component in GBS was recog- nized early by authorities writing in French and German [ l , 13, 211. This factor was generally over- looked in English-language writings on GBS until relatively recently [ 3 ] , and it was commonly held for many years that the pathological affection of root and peripheral nerve in GBS was of a bland nature. The thorough and detailed study of Haymaker and Ker- nohan in 1949 minimized the inflammatory features [ 1 11. Whether because of this concept of GBS or be- cause of other factors, the clinical range of disorder subsumed under the heading of GBS gradually ex- panded in the English-language literature in the 1940s and 1950s.

In 1960, Osler and Side11 [20] published a paper

From the Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA. Presented at the Conference on Guillain-Bark Syndrome spon- sored by the Kroc Foundation, Santa Ynez Valley, CA, Sept

Address reprint requests to Dr Asbury, Department of Neurol- ogy, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104.

22-26, 1980.

0364-5134/81/S10001-05$01.25 @ 1980 by the American Neurological Association 1

ent i t led “ T h e Guillain-Barr; syndrome: t h e need for exact diagnostic criteria.” T h e y poin ted o u t that GBS was a t risk of becoming a meaningless te rm, synonymous with acute polyneuritis of any type, a n d they se t down twelve diagnostic criteria which se- verely restricted t h e definition o f t h e disorder . The effect of their paper was salutary i n tha t i t helped t o stimulate a host of subsequent studies 12, 5, 15-19, 22, 25, 26, 281, m o s t of which arrived at a broader concept of the disorder. T h e reader should n o t e that t h e diagnostic criteria and definitions for GBS ar- rived a t by all these authors depend u p o n the i r initial assumptions; thus t h e a rgument is circular. Devel - o p m e n t s in t h e past dozen years have included ac- cumulat ion of a body of ev idence indicating a likely immunological basis for GBS, based i n large par t on t h e close analogy with experimental allergic neuritis. I n addition, a characteristic s e t of electrodiagnostic features have c o m e t o be recognized, thus s t rength- en ing t h e certainty of clinical diagnosis.

With t h e occurrence of m o r e than a thousand cases of GBS i n t h e Uni ted States i n t h e wake of the mass inoculation program for swine flu i n late 1976, publ ic a t tent ion and subsequent epidemiological surveil- lance of t h e condi t ion have been heightened. O n e outcome was an effort, sponsored by t h e Nat ional In- s t i tute of Neurological and c o m m u n i c a t i v e Disor- ders and St roke ( N I N C D S ) , to characterize the dis- order clearly e n o u g h for field studies. T h a t r e p o r t [4] was published previously i n Annuls of Neurology and is restated in its ent i re ty in the following sect ion.

D e f i n i t i o n of Guillain-Barrk S y n d r o m e and Criteria for D i a g n o s i s Guillain-BarrP syndrome is a recognizable entity for which the basis for diagnosis is descriptive in our present state of knowledge. The features which allow a diagnosis include clinical, laboratory, and electrodiagnostic criteria. The problem is not with recognition of a typical case, but with knowing the boundaries by which the core disorder is de- limited. The following criteria are established, in light of current knowledge and opinion, to define those limits.

The presence of preceding events is frequent, but they are not essential to the diagnosis. Most commonly, preced- ing events are viral infections, but the association of Guillain-Barre syndrome with preceding surgery, inocula- tions, and mycoplasma infections is also known. In addi- tion, Guillain-Barre syndrome occurs more frequently than by chance in the setting of preexisting illnesses such as Hodgkin’s disease, lymphoma, or lupus erythematosus. Many patients with Guillain-Bar6 syndrome will have no history of any of these events, and the diagnosis should be made independent of them.

1. Features Required for Diagnosis A. Progressive motor weakness of more than one

limb. The degree ranges from minimal weakness

of the legs, with or without mild ataxia, to total paralysis of the muscles of all four extremities and the trunk, bulbar and facial paralysis, and external ophthalmoplegia.

B. Areflexia (loss of tendon jerks). Universal areflexia is the rule, though distal areflexia with definite hyporeflexia of the biceps and knee jerks will suffice if other features are consistent.

11. Features Strongly Supportive of the Diagnosis A. Clinical features (ranked in order of importance)

1. Progression. Symptoms and signs of motor weakness develop rapidly but cease to progress by four weeks into the illness. Approximately 50% will reach the nadir by two weeks, 80% by three weeks, and more than 90% by four weeks.

2. Relative symmetry. Symmetry is seldom abso- lute, but usually, if one limb is affected, the opposite is as well.

3. Mild sensory symptoms or signs. 4. Cranial nerve involvement. Facial weakness

occurs in approximately 50% and is frequently bilateral. Other cranial nerves may be in- volved, particularly those innervating the tongue and muscles of deglutition, and some- times the extraocular motor nerves. On occa- sion (less than 5 % ) , the neuropathy may be- gin in the nerves to the extraocular muscles o r other cranial nerves.

5 . Recovery. It usually begins two to four weeks after progression stops. Recovery may be de- layed for months. Most patients recover func- tio nall y .

6. Autonomic dysfunction. Tachycardia and other arrhythmias, postural hypotension, hyperten- sion, and vasomotor symptoms, when present, support the diagnosis. These findings may fluc- tuate. Care must be exercised to exclude other bases for these symptoms, such as pulmonary embolism.

7. Absence of fever at the onset of neuritic symp- toms.

Variants (not ranked) 1. Fever at onset of neuritic symptoms. 2. Severe sensory loss with pain. 3. Progression beyond four weeks. Occasionally,

a patient’s disease will continue to progress for many weeks longer than four or the patient will have a minor relapse.

4. Cessation of progression without recovery or with major permanent residual deficit remain- ing.

5 . Sphincter function. Usually the sphincters art: not affected, but transient bladder paral- ysis may occur during the evolution of symp- toms.

6. Central nervous system involvement. Ordi- narily, Guillain-Barri syndrome is thought of as a disease of the peripheral nervous system.

2 Annals of Neurology Supplement to Volume 9, 1981

Evidence of central nervous system involve- ment is controversial. In occasional patients, such findings as severe ataxia interpretable as cerebellar in origin, dysarthria, extensor plantar responses, and ill-defined sensory lev- els are demonstrable, and these need not ex- clude the diagnosis if other features are typ- ical.

B. Cerebrospinal fluid features strongly supportive of the diagnosis 1. CSF protein. After the first week of symptoms,

CSF protein is elevated or has been shown to rise on serial lumbar punctures.

2. CSF cells. Counts of 10 or fewer monohuclear leukocytes/mm3 in CSF.

Variants 1. No CSF protein rise in the period of one to ten

weeks after the onset of symptoms (rare). 2. Counts of 11 to 50 mononuclear leukocytes/

mm’j in CSF. C. Electrodiagnostic features strongly supportive of

the diagnosis Approximately 8OC6 will have evidence of nerve conduction slowing or block at some point during the illness. Conduction velocity is usually less than 60$ of normal, but the process is patchy and not all nerves are affected. Distal latencies may be in- creased to as much as three times normal. Use of F-wave responses often gives good indication of slowing over proximal portions of nerve trunks and roots. Up to 209;. of patients will have normal conduction studies. Conduction studies may not become abnormal until several weeks into the ill- ness.

I l l . Features Casting Doubt on the Diagnosis 1. Marked, persistent asymmetry of weakness. 2. Persistent bladder o r bowel dysfunction. 3. Bladder or bowel dysfunction at onset. 4. More than 50 mononuclear leukocytes/mm3 in

5 . Presence of polymorphonuclear leukocytes in

6. Sharp sensory level.

CSF.

CSF.

IV. Features That Rule Out the Diagnosis 1. A current history of hexacarbon abuse (volatile

solvents; n-hexane and methyl n-butyl ketone). This includes huffing of paint lacquer vapors or addictive glue sniffing.

2. Abnormal porphyrin metabolism indicating a diag- nosis of acute intermittent porphyria. This would manifest as increased excretion of porphobilinogen and 8-aminolevulinic acid in the urine.

3. A history or hnding of recent diphtheritic infec- tion, either faucial or wound, with or without myocarditis.

4. Features clinically consistent with lead neuropathy (upper limb weakness with prominent wrist drop;

5 . 6.

may be asymmetrical) and evidence of lead intox- ication. The occurrence of a purely sensory syndrome. A definite diagnosis of a condition such as poliomyelitis, botulism, hysterical paralysis, or toxic neuropathy (e.g., from nitrofurantoin, dap- sone, or organophosphorus compounds), which occasionally may be confused with Guillain-Bar& syndrome.

Clinical Variants and Diagnostic Formulation These criteria, as set forth by the Ad Hoc NINCDS Committee 141, were by intention somewhat restric- tive because they were designed for use by both neurologists and nonneurologists in case identifica- tion during field studies of GBS. Uncertain cases and categories of polyneuritis were systematically ex- cluded by these criteria for fear of contaminating the GBS case group under study. This approach is adequate for its purpose, but it avoids the questions we must address: what are the real nosological limits of GBS, and which of the suspected variants share a common pathogenesis with the core disorder? For now the answers to these questions must remain an educated guess because our knowledge of the patho- genesis is imperfect and because we lack a reliable laboratory diagnostic marker which is independent of the clinical features. Despite these protestations of ignorance, a reasonably satisfactory diagnostic pro- cess may be formulated.

The sequence of logic is to consider first the clini- cal features and temporal evolution. If these are typi- cal (see I and I1 in the Criteria) and without variant features or features that rule out the diagnosis (see IV in the Criteria), one can feel confident about the diagnosis of GBS on clinical grounds alone, even early in the course of the disorder. This point has particular practical importance because laboratory studies frequently are not helpful in the early stages. The cerebrospinal fluid is almost always normal in the first 48 hours of symptoms, and often the protein content does not rise until after a week. Similarly, characteristic electrodiagnostic findings may not be evident until well after the clinical features are estab- lished, and on occasion may never appear in an otherwise typical case.

If clinical features are unusual, one must rely more heavily on laboratory studies and wait until later in the course of the disorder before accepting the diag- nosis of GBS. Specific examples are necessary to il- lustrate this point; these examples include the clinical “variants” which are most frequently discussed at rounds and conferences, The term ziariant is used in this context to refer to cases and not to indi- vidual features (as it is used in IIA and IIB in the Cri- teria).

Asbury: Diagnosis of Guillain-Barri- Syndrome 3

EXAMPLE 1: OPHTHALMOPLEGIA, ATAXIA, A N D AREFLEXIA (MILLER FISHER SYNDROME) [8]. When this constellation of findings comes on rapidly, the accumulated experience indicates that the course is usually benign and recovery is fairly complete within weeks to months. Cerebrospinal fluid protein con- tent becomes elevated in most patients, with few or no cells, and electrodiagnostic features in some cases have indicated a demyelinative process of peripheral nerve ([ll] and Sumner AJ, personal communica- tion, 1980). Transitional cases with degrees of motor weakness link this syndrome with GBS [7, 91. Taken together, these considerations should allow the syn- drome of ophthalmoplegia, ataxia, and areflexia to be included within the nosological limits of GBS.

EXAMPLE 2: SENSORY LOSS A N D AREFLEXIA. In order for this clinical picture, without motor weak- ness, to be acceptable as GBS, the onset must be rapid, distribution widespread and symmetrical, re- covery complete or nearly so, and cerebrospinal fluid protein content elevated, with few or no cells; also, the electrodiagnostic results should be characteristic of a demyelinative process in the peripheral nervous system. If any one of these criteria is not fulfilled, the case should be excluded; otherwise, cases of sensory neuronopathy [27] would be mistakenly diagnosed as GBS.

EXAMPLE 3: POLYNEURITIS CRANIALIS. On occa- sion, patients with rapid simultaneous onset of sym- metrical cranial nerve dysfunction alone-usually bilateral facial palsy-may be considered as having a variant of GBS. For such cases to be acceptable, cra- nial nerves I and I1 must be uninvolved, a typical course of illness and recovery must ensue, the cere- brospinal fluid protein content must be elevated, and a typical electrodiagnostic pattern of demyelination must be demonstrated, preferably in subclinically affected spinal nerves as well as in cranial nerves. Failure to fulfill any of these criteria is a basis for excluding the case from the category of GBS.

EXAMPLE 4: PURE PANDYSAUTONOMIA. Although autonomic dysfunction frequently marks the course of typical GBS, i t remains uncertain whether cases of pure pandysautonomia with rapid onset and full re- covery bear any relationship to GBS. Young et al [29] suggested that their case might represent a vari- ant of GBS. Because there was no histological or electrophysiological evidence of myelinated nerve fiber involvement in their patient, the potential link to GBS remains only a hypothetical possibility.

EXAMPLE 5: CHRONIC ACQUIRED DEMYELINATIVE NEUROPATHY. At the moment there is no clear

method of delimiting GBS from more chronically evolving demyelinative neuropathies, either progres- sive or relapsing, except by an arbitrary clinical judgment as to temporal evolution. As discussed in the opening paragraph of this review, the duration is important because approximately half of all cases of demyelinative neuropathy are chronic, with evolu- tion over more than three months [23]. Our own ex- perience bears this out. Resolution of the puzzle con- cerning GBS and chronic demyelinative neuropathy awaits future advances.

Supported in part by US Public Heath Service Grant NS-08075 and the Muscular Dystrophy Association, Inc.

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Asbury: Diagnosis of Guillain-Barre Syndrome 5