Several pathologic and pathophysiologic events account for the clinical signs and the course of GBS: (a) an immune-mediated destruction of the myelin surrounding the peripheral and cranial nerves, effected mostly, but not exclusively, by the cellular arm of the immune system (13); (b) an early, humorally mediated and complement dependent damage to myelin (14); (c) varying degrees of axonal damage that are most often secondary to very active inflammation but may also result from a primary immune attack on axonal elements in which there is poor and prolonged recovery (15) (“axonal GBS” or ASMAN); and (d) a rapid and reversible electrophysiologic “conduction block” (16).

The immunologic nature of GBS seems undoubted, prompting studies of the cellular and humoral roles in experimental allergic neuritis (EAN), a model that closely resembles the disease in humans. The pathology in GBS and EAN consists mainly of lymphocytic infiltration of peripheral nerves, predominantly in perivascular regions, with adjacent demyelination of segmental type (loss of the myelin segments between adjacent nodes of Ranvier). Macrophages produce the stripping and destruction of myelin from the axonal surface. The lymphocytic infiltration occurs multifocally along the length of the nerve in both GBS and EAN and it may also affect dorsal root ganglia and the proximal portions of autonomic nerves. It has been proposed that extensive inflammation and myelin destruction can damage the underlying axons as they course through the zone. As mentioned, the distinction between demyelination and axonal disruption is often difficult but it assumes clinical importance because mild cases, with only demyelination, improve in weeks through a mechanism of remyelination, whereas those with axonal interruption require longer to recover, and are more likely to be left with residual weakness. As also mentioned, a primary axonal form of GBS occurs in which there is little inflammation and axonal disruption arises without primary destruction of myelin.

A considerable body of data suggests that plasma (humoral) factors participate in the pathogenesis of GBS. The earliest immunologic change that can be detected is deposition of complement on myelin surfaces. Cell-free serum from patients with GBS or animals with EAN can induce demyelination in cultured nerve tissue. Several histo pathologic reports indicate that some early cases may show a paucity of inflammation. Serum from animals with EAN and from patients with GBS also have been shown to induce electric conduction block and demyelination when injected into nerves in animals. Specific antibodies to peripheral nerve tissue have been isolated from a proportion of patients with GBS but not from control subjects.

The postinfectious nature of many, if not most, cases of GBS has been appreciated for many years and it has been presumed that the immune response to the infecting agent cross reacts with elements of normal neural tissue—a monophasic and self-limited autoimmune reaction. Direct evidence for this mechanism has been difficult to obtain, but it is supported by the singular relationship of preceding infection by the enteric bacterium, Campylobacter jejuni to acute GBS. Antibodies directed against this organism bind to specific ganglioside epitopes on peripheral nerve (in this case GM1) and are believed to generate the immune damage. There are certainly many cases of GBS that arise without an obvious prior infection and several case control series have attempted to show that there is no such relationship. It should be pointed out that in many instances there is only serologic evidence of recent infection without, for example, a febrile enteritis. The other infectious agents that have been regularly implicated in GBS are mainly EBV, CMV, and mycoplasma. Many cases of GBS following CMV are associated with antibodies to GM2, another neural ganglioside.

More than half of patients with GBS have a history of recent acute infection, usually a mild respiratory syndrome. A number of cases follow other well-defined illnesses such as mononucleosis, acute exanthemas, or surgery. When Epstein-Barr virus or CMV precede GBS, they often cause mildly abnormal liver function tests. These latter two infections are particularly likely to be seen in health care personnel. A preceding atypical or mild pneumonia suggests mycoplasma infection. As mentioned, Campylobacter jejuni enteritis is perhaps the most frequent identifiable pathogen that precedes GBS, accounting for up to 20% of cases in some series. An uncertain proportion of such cases occur without the typical enteritis and are detected only by serologic testing. It has been observed that Campylobacter may be associated with a severe axonal form of illness (AMSAN or AMAN), but there seems little question that more typical and less severe cases, as well as variant illnesses such as Fisher syndrome, also may follow (17,18). In certain populations, symptomatic acute human immunodeficiency virus infection precedes GBS in up to 15% of cases (19). Postsurgical GBS is a less certain entity. Prior to the appreciation of what is now called critical illness polyneuropathy, postoperative GBS was said to occur 2 to 3 weeks after intracranial, abdominal, thoracic, and orthopedic operations as well as following epidural or spinal anesthesia; we have encountered several such cases (20,21). However, the incidence of this complication probably has been overestimated because many cases that follow postoperative sepsis are more likely to be of the “critical illness polyneuropathy” variety (Chapter 11).

In the most typical cases of GBS, the main clinical sign is weakness, usually appearing symmetrically in the legs, most often proximally. (The term ascending paralysis signifies weakness that begins in the legs and progresses to the arms, not weakness in the feet.) Bifacial paresis arises in about one half of patients and may be delayed in appearance, and oro-lingual-pharyngeal weakness is a feature in one third. The weakness in all parts evolves over 3 to 21 days (mean 2 weeks in untreated patients) and does not usually remit until a plateau of maximal weakness occurs.

Distal paresthesias with mild sensory loss are typical early in the illness; sensation is increasingly diminished in the distal limbs as the illness progresses, but it may be indistinct in the first several days. Patients with GBS exhibit few objective signs besides weakness and areflexia. Sensory signs early in the illness may be confined to mild or moderate glove and stocking loss of vibration and pain sensibility.

The deep tendon reflexes are usually lost in paretic limbs after several days of illness. In contrast, a brisk direct muscle percussion with a small hammer causes a local fascicular contraction.

Pain concentrated in the back or sciatica occurs in 10% to 25% of patients and is typically worse at night; it is described as a “charley horse” or deep aching pain similar to that experienced after exercise (22). The management of this pain is a major issue in the ICU and is addressed in the following. When it precedes weakness by several days, the diagnosis of lumbar spine disease or a painful muscle disorder may suggest itself. A separate acral dysesthetic pain may arise within days but is more often a delayed phenomenon and is managed differently.

One of the greatest problems in ICU practice is the identification and care of the approximately 5% of patients with a rapidly evolving and aggressive form of disease. They reach their worst clinical state in 1 to 3 days, resulting in quadriplegia and respiratory failure. In most other ways these cases resemble typical GBS. Feasby and colleagues showed that many of these patients have an acute axonal disruption with a paucity of inflammation of nerves, and coined the term “axonal GBS,” which has come into wide use (15). In our experience and that of others, these patients have prolonged and incomplete recoveries (23); others have disagreed that the tempo of onset is related in this direct way to outcome (24); but there is no question that patients with signs of axonal degeneration on EMG have a more severe form of illness (see Treatment).

Dysautonomia of varying degrees occurs in approximately 20% of cases. Its various manifestations are more prominent in the most severely affected patients, including those with the axonal form of illness. For example, transient urinary sphincter dysfunction occurs in 15% of patients, particularly urinary retention that may occur early in the course of the disease and raise the possibility of spinal cord compression or myelitis. Respiratory muscle weakness, the main ICU issue in GBS (also discussed in greater detail in the following), occurs in one third of patients and is apparent within the first 2 weeks of illness with few exceptions.

Several variant illnesses of GBS are known; the most striking is a pattern of ophthalmoplegia and severe ataxia described by Fisher (25). Other unusual patterns or signs include cases of “descending” paralysis, beginning with ocular, facial, and pharyngeal paresis that simulates botulism or myasthenia gravis; ophthalmoplegia or ptosis; and predominantly or purely ataxic, motor, or sensory forms (26, 27 and 28). About 3% of patients have abortive regional forms of the illness with preserved power and reflexes in either the arms or legs. The signs are relatively symmetric in all these variant cases. Failure of protective airway reflexes and the need for intubation are the main reasons these patients come to the attention of intensivists; diaphragmatic weakness is less common than in typical generalized GBS.

The electrophysiologic abnormalities associated with GBS provide confirmation of the diagnosis and are useful in distinguishing GBS from clinically similar diseases. They are more sensitive, and become abnormal earlier in the illness than does the classical laboratory abnormality of GBS, elevation of spinal fluid protein concentration. These tests also delineate a group of patients with early and severe axonal damage who typically require more intense and prolonged respiratory and ICU care.

Early in the illness, nerve conduction velocity is slightly slowed but it may be normal
in mildly affected patients. Conduction block, the most specific EMG sign of demyelinating neuropathy, alluded to earlier, consists of a drop in the muscle action potential amplitude when proximal is compared to distal stimulation of the nerve. Abnormalities of the “late responses” are also sensitive indicators of early GBS. The main late responses (F-waves) are obtained by supramaximal stimulation of motor axons that propagates in a retrograde fashion toward the spinal cord and causes a discharge of motor neurons that can be recorded 25 to 35 msec later. In relation to axonal damage, inexcitable nerves or severely reduced motor action potential amplitudes, below 1 µV, or values that are less than 20% of the lower limit of normal, are predictive of prolonged illness and poor outcome (29). However, there are exceptions in which the inexcitability of nerves reflects severe focal demyelination with potential for recovery rather than indicating axonal disruption (30).

The electrical manifestation of the blink reflexes also can be recorded and are prolonged or absent in most patients with GBS. Somatosensory evoked potentials are typically abnormal in their peripheral nerve portions and rarely show central abnormalities. The severity of abnormalities in conventional electrophysiologic studies, except for early and widespread denervation on needle electromyography examination, only roughly parallels clinical weakness. Furthermore, there is usually a long interval between manifest clinical improvement and the normalization of electrophysiologic studies.

Except for the examination of CSF and the discussed electrophysiologic testing, laboratory findings are of limited value in diagnosis. An increased level of CSF protein is helpful in confirming the diagnosis but may be detectable only after 5 to 10 days of illness. Occasionally, the CSF protein value is normal throughout the illness, including some cases of severe or axonal type. The absence of cells in the CSF supports the diagnosis of GBS, but up to 5% of patients have 5 to 50 lymphocytes/mm³; in all likelihood some of these cases represent other forms of polyneuropathy (e.g., Lyme, CMV, acquired immunodeficiency syndrome, etc.). Oligoclonal bands of CSF protein are present occasionally. Mild, asymptomatic abnormalities of liver function tests occur in about 5%, probably indicating a preceding viral hepatitis. In severe or particularly abrupt cases of GBS, it is interesting but not necessary for clinical work, to culture the patient’s stool for Campylobacter; as mentioned, many of these cases also display circulating antibodies to GM1, a myelin glycolipid component. The sedimentation rate is normal.

The illnesses that simulate GBS are described in standard textbooks of neurology and in a monograph by one of the authors. The ones usually cited are: myasthenia gravis, transverse myelitis, and the rare entities of tick paralysis and porphyria. In the ICU setting, however, illnesses that cause acute areflexic quadriparesis include botulism, diphtheria, hyperalimentation-induced hypophosphatemia (31), and most importantly, the myopathy and polyneuropathy associated with sepsis and critical illness (Chapter 11). Several variants of GBS also may cause difficulty in diagnosis. Difficulty weaning from ventilation after general surgery is occasionally caused by GBS that develops postoperatively for unclear reasons, but the aforementioned critical illness myopathy and neuropathy as well as nutritional factors are more common causes of this problem.

Autonomic dysfunction, although potentially serious and relatively common in mild form (34, 35 and 36), nonetheless may be a somewhat overrated clinical problem because most of its manifestations are inconsequential. We are dubious that autonomic dysfunction can represent the sole initial manifestation of generalized GBS, but putative cases have been reported (37). The status of “pure pandysautonomia” is likewise controversial, but we believe that many of its features conform to those of a postinfectious polyneuropathy.

The main concerns in GBS are cardiovascular changes ranging in seriousness from a fixed tachycardia (invariant R-R interval) usually in the range of 110 to 120 beats/min and reduced sweating, to more threatening manifestations such as profound hypotension or hypertension, as summarized in Table 18.3. Ileus, bladder dysfunction (particularly early urinary retention), various arrhythmias, electrocardiogram (ECG) changes, and paralysis of pupillary accommodation, are other components that arise in individual patients.

Among the less frequent changes, ileus should be emphasized because it impedes nasogastric feeding and may progress to the point of cecal rupture (Fig. 18.1). Its presenting features are abdominal discomfort and repeated “large residuals” following feeding. Often, in our experience, these patients have episodes of otherwise unexplained bradycardia. Interesting, but rare “parasympathetic discharges,” or “vagal spells,” are also known to occur, consisting of facial flushing, bradycardia, chest tightness, dermatographia, and a general sense of warmth, sometimes following a Valsalva maneuver. A number of patients, early in their course, have profound vasodepressor responses to the initiation of positive pressure ventilation. A probable manifestation of this same vagally induced abnormality is a high incidence of hypotension during elective intubation. These problems occur independently of dehydration.