Inflammatory Neuropathies

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Chapter 90 Inflammatory Neuropathies

Although children and adults with peripheral neuropathies exhibit similar clinical and electrophysiologic features, the incidence and nature of the underlying disorders responsible for peripheral nerve diseases are widely divergent. Perhaps the most salient difference is that most peripheral nerve diseases in children are immune-mediated and potentially treatable. Table 90-1 lists the principal etiologies for neuropathy in a group of 249 children evaluated over 12 years at a tertiary pediatric referral center by one of the authors. Acquired inflammatory neuropathies were the most common peripheral nerve diseases in this group, followed by the genetically determined neuropathies. Table 90-2 illustrates a more specific classification in these patients of the acquired immune-mediated neuropathies. Acute and chronic inflammatory demyelinating neuropathies were the most common cause of neuropathy in the inflammatory subgroup. Some children with collagen vascular diseases developed neuropathy as a complication of rheumatoid arthritis, systemic lupus erythematosus, or mixed connective tissue disease. Necrotizing vasculitis selectively affecting the peripheral nervous system was also seen. Autoimmune neuropathies presumed to have developed as a consequence of other primary disorders were notable, and included neuropathy associated with graft-versus-host disease after bone marrow transplantation [Adams et al., 1995; Perry et al., 1994], and a chronic immune demyelinating polyneuropathy-like presentation in the course of Lyme disease. Although children with human immunodeficiency virus infection and acquired immune deficiency syndrome were frequently evaluated for neurologic complications, only one adolescent developed an associated peripheral neuropathy [Leger, 1992], presumably as a complication of treatment.

Table 90-1 Etiologies of Neuropathy in 249 Children (1980–1992)

Category Patients (%)
Immune and inflammatory disorders 45
Genetically determined disorders 42
Other causes of neuropathy 13

(From unpublished observations of John T Sladky, MD.)

Table 90-2 Causes of Inflammatory and Immune Neuropathy in 112 Children

Diagnosis Patients (%)
Guillain-Barré syndrome 58
Chronic inflammatory demyelinating polyneuropathy 31
Cases associated with collagen vascular disease 7
Other immune and infectious disorders 4

(Data from unpublished observations of John T Sladky, MD.)

Inflammatory neuropathies, because of their relative frequency and potential to respond to treatment, are important considerations in the evaluation of children with peripheral nerve disease. Guillain-Barré syndrome constitutes the most common category of acquired immune-mediated neuropathies in childhood [Koul et al., 2002]. The pathologic manifestations of Guillain-Barré syndrome are protean, with immunologic-targeted antigens directed toward both axolemmal and myelin-related epitopes [Hughes and Cornblath, 2005; Willison, 2005b; Willison et al., 2008]. The clinical manifestations of the disease are determined by the nature of the pathology and the populations of axons that come under immunologic attack. Although the salient clinical feature of Guillain-Barré syndrome is weakness, any organ system affected by peripheral nerve function may be involved. It is reasonable to conceptualize this syndrome as an inhomogeneous spectrum of clinical features with specific constellations of clinical characteristics clustering in distinct patterns, permitting definitions of subcategories of Guillain-Barré syndrome.

Acute Inflammatory Demyelinating Polyneuropathy

Diagnostic Criteria

As part of a nationwide program to evaluate the possible relationship of swine-flu immunization to Guillain-Barré syndrome, diagnostic criteria were developed under the sponsorship of the National Institute of Neurological Disorders and Stroke and were later modified after analysis of data from several multicenter treatment trials [Asbury and Cornblath, 1990]. Boxes 90-1 and 90-2 provide summaries of the consensus statement describing the clinical characteristics necessary to diagnose Guillain-Barré syndrome, along with those features, including electrophysiologic testing and laboratory measurements, that mitigate for or against the diagnosis.

Box 90-1 Clinical and Laboratory Features in the Diagnosis of Guillain–Barré Syndrome

(From Asbury AK, Cornblath DR: Assessment of current diagnostic criteria for Guillain-Barré syndrome, Ann Neurol 27:S21, 1990.)

Box 90-2 Consensus Electrophysiologic Features Supportive of a Diagnosis of Multifocal Demyelinating Neuropathy of Guillain-Barré Syndrome

Must demonstrate three of the following four features:

CMAP, compound motor unit action potential; LLN, lower limit of normal; ULN, upper limit of normal.(From Asbury AK, Cornblath DR: Assessment of current diagnostic criteria for Guillain-Barré syndrome, Ann Neurol 27:S21, 1990.)

Clinical Features

The clinical presentation of Guillain-Barré syndrome is similar in children and adults [Bradshaw and Jones, 1992; Korinthenberg and Monting, 1996; Rantala et al., 1991; Sakakihara and Kamoshita, 1991; Sarada et al., 1994; Sladky, 2004; Asbury, 2000; Barzegar et al., 2007; Gupta et al., 2008; Kollar et al., 2009; Korinthenberg et al., 2007; Vucic et al., 2009; Wu et al., 1999]. Although there is considerable variability in the nature of the initial symptoms, the overall pattern of the evolution of the clinical syndrome and the ultimate severity of disability usually conform to a triphasic model:

The initial phase is generally relentless and rapid. Between 50 and 75 percent of patients develop maximal weakness within 2 weeks, and 90–98 percent do so by 4 weeks [Asbury and Cornblath, 1990; Korinthenberg and Monting, 1996; Italian Guillain-Barré Study Group, 1996]. In several series describing the natural history in adults and children, the mean duration of the progressive phase was in the range of 10–12 days. A small number of patients continue to progress for longer than 4 weeks. This latter group overlaps to some degree with patients diagnosed with chronic inflammatory demyelinating polyneuropathy. The duration of the plateau phase is similar to that of the progressive phase, averaging 10–12 days but ranging from several days to 4 weeks [Italian Guillain-Barré Study Group, 1996]. Patients who develop severe axonal degeneration have a prolonged plateau phase and tend to have more severe residual weakness [Cornblath, 1990]. In a series primarily of adult patients, about half recovered within 6 months and more than 80 percent by 24 months [Italian Guillain-Barré Study Group, 1996].

A multicenter study of 175 children with Guillain-Barré syndrome has reported similar findings [Korinthenberg and Monting, 1996]. At the height of the disease, 26 percent of patients remained able to walk, but 16 percent required artificial ventilation. The median time from onset of symptoms to first recovery was 17 days; to walk unaided, 37 days; and to be free of symptoms, 66 days. The population in this study was heterogeneous, with many children receiving some form of treatment, including plasmapheresis, intravenous immune globulin, and corticosteroids. A large number of children have a relatively benign course, and a smaller group a more severe and protracted course. At 6 months’ follow-up evaluation, 98 of 106 children (92 percent) were free of symptoms and the others were able to walk unaided. Subsequent reports similarly have emphasized a favorable prognosis [Barzegar et al., 2007; Korinthenberg et al., 2007; Lee et al., 2008; Nagasawa et al., 2006; Ramachandran and Kuruvilla, 2004; Shafqat et al., 2006]. As in series of adult patients, the maximum degree of disability at clinical nadir appears to be the most powerful predictor of incomplete recovery.

In the past, there has been considerable discussion as to whether the natural history of Guillain-Barré syndrome in children is more benign or comparable to adults. The argument may ultimately be unresolvable because of the absence of large prospective controlled treatment trials in children compared with adults [Klegweg et al., 1989]. There are few case series that include descriptions of the natural course of this syndrome in untreated children with similar end-points. Two adult benchmark studies are the North American Treatment Trial and the French Plasmapheresis Treatment Trial.

Table 90-3 summarizes some of the presenting complaints seen in a series of 49 children hospitalized with Guillain-Barré syndrome. This cohort has proved to be typical of other reported pediatric series. Weakness was the most common initial complaint. Pain, particularly in the back and lower extremities, was also prominent and was near-universal in the most severely affected children. A history of difficulty with balance early in the course of the illness was elicited in almost half the children. The classic triad, characteristic of the Miller Fisher variant of Guillain-Barré syndrome (ataxia, ophthalmoparesis, and areflexia), was present in only two children. All children had evidence of progression. Maximal disability was quantitated according to the 1985 Guillain-Barré Syndrome Study Group grading scale (Table 90-4). At the time of maximal neurologic deficit, 25 percent of children were able to ambulate 5 meters without assistance (grade 2). Another 11 children (22 percent) reached a nadir of grade 3 (unable to walk 5 meters without assistance). The largest group of children (39 percent) were bed- or wheelchair-confined (grade 4), and 7 children (14 percent) required mechanical ventilatory assistance (grade 5). There were no fatalities. Autonomic dysfunction occurred in 14 children (28 percent), and included labile hypertension in 9 children and urinary or bowel incontinence in 6 children.

Table 90-3 Clinical Features in 49 Children Younger than 18 Years with Guillain-Barré Syndrome*

Feature Prevalence
Age 7.1 years (mean)
Male-to-female ratio 1.2:1
Weakness 73%
Pain 55%
Ataxia 44%
Paresthesias 18%
Shortness of breath 4%

* Two patients had findings consistent with Miller Fisher syndrome.)

(Data from unpublished observations of John T Sladky, MD.

Table 90-4 Clinical Grading Scale from the U.S. Guillain-Barré Syndrome Plasmapheresis Trial

Score Clinical Criteria
0 Health state
1 Minor signs or symptoms
2 Able to walk 5 m without a walker or equivalent support
3 Able to walk 5 m with a walker or support
4 Bed- or chair-bound (unable to walk 5 m with a walker or support)
5 Requires assisted ventilation (for at least part of the day)
6 Dead

(Adapted from the Guillain-Barré Syndrome Study Group: Plasmapheresis and acute Guillain-Barré syndrome, Neurology 35:1096, 1985.)

The duration of symptoms in children with Guillain-Barré syndrome requiring hospitalization varies in the reported studies. The incidence of admission to pediatric intensive care units for treatment of respiratory failure or other serious medical problems (e.g., infection) or for plasmapheresis ranges between 17 and 68 percent, with the average length of stay about 11 days [Jansen et al., 1993; Ramirez-Zamora et al., 2009; Yata et al., 2003]. The average duration for mechanical ventilation ranges from 17 to 22 days. The mean duration of hospitalization is also quite variable, ranging from 12 to 84 days [Jansen et al., 1993; Jones, 1996]. Time to independent walking reported in a multicenter study in Western Europe [Korinthenberg and Monting, 1996] was somewhat shorter than in other pediatric series, which reported durations of 43 days [Lamont et al., 1991], 52 days [Epstein and Sladky, 1990], and 113 days [Shahar and Leiderman, 2003]. The European study was a questionnaire-based survey that included children from community hospitals along with tertiary referral centers, which the authors thought may represent a less severely affected population. In addition, many of these children received therapies, including corticosteroids, intravenous immune globulin, and plasmapheresis.

Autonomic dysfunction has been reported in 12.5–25 percent of children with Guillain-Barré syndrome [Bradshaw and Jones, 1992; Hung et al., 1994; Lee et al., 2008; Shafqat et al., 2006] and is similar to that in adults [Ropper, 1994; Zochodne, 1994; Korinthenberg et al., 2007; Ryan, 2005; Shafqat et al., 2006]. Symptoms are usually intermittent and include postural hypotension, supraventricular tachycardia, bradycardia, and fluctuating blood pressure. Gastrointestinal complaints are numerous and related to impaired swallowing, gastroesophageal dysmotility, pseudo-obstruction, and constipation. Urinary retention also occurs, and the potential need for catheterization and bladder decompression should be considered in children with more severe symptoms during the acute phase. On rare occasions, cardiac arrest secondary to autonomic dysfunction has been observed in children [Bos et al., 1987; Briscoe et al., 1987].

Although AIDP is often regarded as an entity in which motor symptoms predominate, pain is a common symptom, occurring in up to 79 percent of children [Bradshaw and Jones, 1992; Nguyen et al., 1999; Sladky, 2004] and 72 percent of adult patients [Pentland and Donald, 1994]. The types of pain vary and include paresthesias, dysesthesias, axial and radicular pain, meningismus, myalgia, joint pain, and visceral discomfort. Pain intensity on admission appears to correlate poorly with the degree of initial neurologic disability and is not predictive of prognosis [Moulin et al., 1997]. Patients may also present with or develop pain in a variety of clinical settings, such as the intensive care unit or pediatric ward, or during the more chronic phase of the disease when in rehabilitation or at home. Back and leg pain usually resolves over the first 8 weeks, but dysesthetic extremity pain may persist longer in 5–10 percent of patients, despite motor recovery. Moderate to severe pain requires aggressive treatment. In a recent study of adult patients with Guillain-Barré syndrome, 75 percent required oral opioid analgesics, and 29 percent received parenteral analgesia to provide adequate pain relief [Hahn, 1996]. Despite aggressive therapy, most adults with grade 4 or 5 disease severity reported that their pain was inadequately treated. Few data regarding pain symptoms in children with this syndrome have been published. The principles of pain management for Guillain-Barré syndrome patients are well described [Moulin et al., 1997; Pentland and Donald, 1994].

Clinical Variants of Guillain-Barré Syndrome

Several clinical forms of Guillain-Barré syndrome have been characterized (Table 90-5). Some of the more clearly defined entities are discussed in this section.

Table 90-5 Variants of Immune-Mediated Acute and Chronic Demyelinating and Axonal Disorders Seen in Children

Guillain-Barré Syndrome Subtype Description References*
Acute inflammatory demyelinating polyneuropathy (AIDP) Acute onset of ascending weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; triphasic course, usually with good recovery Hung et al. [1994]; Jones [1996, 2000]; Korinthenberg and Monting [1996]; Ensrud and Krivickas [2001]; Hughes and Cornblath [2005]; Korinthenberg et al. [2007]; Kushnir et al. [2008]; Kuwabara [2007]; Lu et al. [2000]
Acute motor and sensory axonal neuropathy (AMSAN) Acute onset of ascending weakness and hyporeflexia with elevated CSF protein and EMG showing axonal involvement with reduction of CMAP; triphasic course, usually with poor or limited recovery Alma et al. [1998]; Chowdhury and Arora [2001]; Currie et al. [1990]; Reisin et al. [1993]; Hiraga et al. [2005a]; Hiraga et al. [2005b]; Lu et al. [2000]; Vedanarayanan and Chaudhry [2000]
Acute motor axonal neuropathy (AMAN) Clinical syndrome similar to AIDP or AMSAN; elevated CSF protein; electrophysiologic and histopathologic evidence of degeneration strictly limited to sensory axons Griffin et al. [1995]; Ho et al. [1995, 1997b]; Lu et al. [2000]; Paradiso et al. [1999]; Chowdhury and Arora [2001]; Hiraga et al. [2005b]; Kuwabara [2007]; Lu et al. [2000]; Nachamkin et al. [2007]; Ortiz-Corredor et al. [2007]; Vedanarayanan and Chaudhry [2000]; Vucic et al. [2009]; Yuki and Kuwabara [2007]
Miller Fisher syndrome Acute onset of ophthalmoplegia, hyporeflexia, and ataxia with elevated CSF protein and subsequent recovery Hughes et al. [1999]; Jones [2000]; Sladky [2004]; Willison and O’Hanlon [1999]; Koga et al. [2005]; Overell and Willison [2005]; Susuki et al. [2001]; Willison [2001]; Yuki [2001]; Yuki and Koga [2006]
Polyneuritis cranialis Acute onset of multiple cranial nerve palsies (usually bilateral VII and sparing of II) with elevated CSF protein, slowing of motor conduction velocities and recovery McFarland [1976]; Morosini et al. [2003]; Polo et al. [1992]; MacLennan et al. [2004]; Murakami et al. [2006]; Onodera et al. [2002]
Acute sensory neuropathy Acute onset of sensory loss, areflexia, elevated CSF protein, slowing of motor conduction velocities and recovery Sahashi et al. [1985]; Seneviratne and Gunasekera [2002]; Wilmshurst et al. [1999]; Oh et al. [2001]
Acute pandysautonomia Acute onset of multiple dysautonomic symptoms with limited or no motor involvement, CSF protein elevation, and good recovery Chistiansen and Brodersen [2003]; Fagius et al. [1983]; Low [1994]; Nass and Chutorian [1982]; Zochodne [1994]
Chronic inflammatory demyelinating polyneuropathy Subacute or indolent onset of weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; symptoms persist for >8 weeks and may remain chronic or become progressive Connolly [2001]; Korinthenberg [1999]; Nevo [1998]; Ryan et al. [2000]; Hughes [2010]; Hughes et al. [2006]; Jo et al. [2010]; Lewis [2007]; Markowitz et al. [2008]; Rabie and Nevo [2009]; Vallat et al. [2010]
Chronic inflammatory relapsing demyelinating polyneuropathy Acute or subacute onset of weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; symptoms persist for >8 weeks and follow a chronic relapsing course Connolly [2001]; Gorson and Chaudhry [1999]; Hahn [1998]; Hahn et al. [1996a]; Hughes [1994]; Nevo [1998]; Ryan et al. [2000]; Said [2002]; Sladky et al. [1986]; Hughes et al. [2006]; Vallat et al. [2010]
Chronic inflammatory axonal polyneuropathy Subacute or indolent onset of weakness and hyporeflexia with elevated CSF protein and EMG consistent with an axonal neuropathy; symptoms follow a chronic course; sural nerve biopsy is normal Chin et al. [2004]; Feasby et al., [1990]; Hughes [1994]; Uncini et al. [1991]; Hughes et al. [2006]; Vallat et al. [2010]
Guillain-Barré syndrome with acute onset of weakness and hyporeflexia with encephalopathic features Elevated CSF protein and EMG showing neuropathy. Accompanied by encephalopathic and brainstem symptoms and/or myelitis that may have a protracted course, usually with good recovery Bradshaw and Jones [2001]; Brashear et al. [1985]; Feasby et al. [1990]; Maier et al. [1997]; Nadkarni and Lisak [1993]; Uncini et al. [1991]

* References listed are for pediatric case series, if available.

CMAP, compound motor unit action potentials; CSF, cerebrospinal fluid; EMG, electromyography.

Acute Motor and Sensory Axonal Neuropathy

Whether acute motor and sensory axonal neuropathy is distinct from the more common AIDP or part of a continuum of disease remains a topic for on-going discussion. The initial clinical presentations of these disorders are virtually identical; however, children and adults with acute motor and sensory axonal neuropathy with a severe extent of axonal degeneration are more likely to have incomplete recovery. The electrophysiologic hallmark of this syndrome is the decrement or absence of sensory and motor action potential amplitudes, with only minimal slowing of nerve conduction velocities commensurate with the degree of axonal loss. In most instances, pathologic evaluation of the peripheral nervous system from patients within the spectrum of Guillain-Barré syndrome reveals evidence of endoneurial inflammation with primary demyelination and axonal degeneration [Berciano et al., 1993]. Either process can occur in an individual patient, within a particular peripheral nerve or nerve segment [Berciano et al., 1997]. The mechanisms through which the immune system targets specific constituents of the peripheral nervous system remain poorly understood. It is clear that the immune response can be remarkably specific in affecting epitopes associated with myelin, those associated with axolemma, or both [Griffin et al., 1996a, 1996b; Hughes et al., 1999]. There have been a number of studies attempting to associate the presence of circulating immunoglobulins directed against specific ganglioside moieties with specific Guillain-Barré syndrome-related entities. For the most part, there has been only limited correlation between the targeted antigens and the syndrome phenotype. The strongest associations have been reported in the Miller Fisher syndrome with an immune response to the ganglioside GQ1B [Hughes et al., 1999; Saida, 1996; Kusunoki, 2008; Nishimoto, 2008; Asbury, 2000; Hughes and Cornblath, 2005; Yuki, 2000; van Doorn, 2009; Willison et al., 2002, 2008].

Reisin et al. [1993, 1996] reported a series of 44 children with an acute axonal form of Guillain-Barré syndrome. These patients initially had severe reduction in the amplitude of the compound motor action potentials (less than 10 percent of lower limit of normal) and, after 2 weeks of illness, had diffuse, severe denervation on needle electrode examination. Compared to patients with compound motor action potentials that were greater than 10 percent of normal, they were more likely to require assisted ventilation (60 versus 6.2 percent), were more frequently quadriplegic at the peak of their disability (80 versus 18.7 percent), and required longer periods to improve one functional grade (mean, 63.6 days versus 16.6 days) and to become ambulatory (mean, 156 versus 17.6 days).

Acute Motor Axonal Neuropathy

Although first recognized among patients from southern Mexico about 50 years ago as a distinct variant of typical Guillain-Barré syndrome on the basis of disease pathology, the first clear and detailed description of acute motor axonal neuropathy resulted from studies of clustered outbreaks in rural regions of northern China. The clinical presentation is similar to AIDP or acute motor and sensory axonal neuropathy, but is distinguished by the discrete involvement of motor axons with sparing of sensory axons [Lu et al., 2000]. Electrophysiologic hallmarks of the disease are normal sensory nerve conduction velocity studies and diminished compound motor action potential amplitudes, with normal or near-normal motor conduction velocities [McKhann et al., 1991]. Diffuse denervation is present during needle electromyography. Histopathologic examination reveals normal-appearing sensory nerves with degeneration of motor axons within motor nerve roots and motor fibers in the peripheral nervous system [Griffin et al., 1995, 1996a, b; Ho et al., 1995, 1997a; Lu et al., 2000; McKhann et al., 1993]. Just as AIDP and acute motor and sensory axonal neuropathy occur after gastrointestinal infection with Campylobacter jejuni, the association with acute motor axonal neuropathy is even stronger [Hadan and Gregson, 2001; Islam et al., 2010; Kalra et al., 2009b; Kuwabara et al., 2004; Liu et al., 2003; Nachamkin et al., 2007; Nishimoto et al., 2008a; Ogawara et al., 2000, 2003]. Patients who develop acute motor axonal neuropathy in northern China come from rural areas where the ability to purify communal drinking water is often limited or nonexistent [Wu et al., 1999]. Similar findings have been noted in children with Guillain-Barré syndrome who were treated in Buenos Aires, Argentina [Paradiso et al., 1999]. The patients with acute motor axonal neuropathy constituted 30 percent of children with Guillain-Barré syndrome with a high incidence of evidence of prior infection with C. jejuni. Although some authors have suggested that axonal forms of Guillain-Barré syndrome have a more protracted and less complete recovery than in acute inflammatory demyelinating polyneuropathy, most reports have noted that the long-term outcomes are equivalent, or nearly so [Barzegar et al., 2008; Gupta et al., 2008; Kalra et al., 2009a; Korinthenberg et al., 2007; Ramachandran and Kuruvilla, 2004; Ramirez-Zamora et al., 2009; Wierzba et al., 2008].

Miller Fisher Syndrome

Ophthalmoplegia, ataxia, and areflexia characterize this Guillain-Barré syndrome variant, described originally in adults in 1956 [Arakawa et al., 1993; Bradshaw and Jones, 1992; Eggenberger et al., 1993; Jones, 2000; Sladky, 2004; Wong, 1997]. The incidence of Miller Fisher syndrome is probably 2–4 percent in children with Guillain-Barré syndrome-like illnesses (see Table 90-5) [Bradshaw and Jones, 1992; Jones, 2000; Sladky, 2004; Jones, 2000; Korinthenberg et al., 2007; Ryan, 2005]. Cerebrospinal fluid protein elevation is seen in virtually all patients, and in most patients, complete recovery occurs. Brainstem auditory-evoked potentials have demonstrated peripheral and central auditory conduction defects in children [Wong, 1997]. Of interest are recent investigations demonstrating antibodies against the ganglioside GQ1b that recognize similar epitopes from specific C. jejuni strains [Chaudhry et al., 2006; Jacobs et al., 1997a; Jones, 2000, Korinthenberg et al., 2007; Ryan, 2005; Takahashi et al., 2005] and after Hemophilus influenzae infection [Jacobs et al., 2008; Koga et al., 2001; Nagashima, 2007; Nishimoto et al., 2004; Nishimoto, 2008a]. Cross-reactivity with the GQ1b ganglioside, which is present in cranial and other peripheral nerves, may account for the restricted involvement seen in patients with Miller Fisher syndrome [Willison et al., 1993; Willison and O’Hanlon, 1999; Willison 2005a, b, 2007]. This is in contrast to the classic form of Guillain-Barré syndrome, in which molecular mimicry has been described between anti-GM1 antibodies and C. jejuni [Ang et al., 2001a; Carpo et al., 1998; Kuroki et al., 2001; Hughes and Cornblath, 2005, Jacobs et al., 2008; Meyer Zu Horste et al., 2010; Nachamkin et al., 2007]. Successful treatment with intravenous immune globulin has been reported in a 3-year-old boy with Miller Fisher syndrome [Arakawa et al., 1993].

Polyneuritis Cranialis

Polyneuritis cranialis can occur in children, and manifests with the acute onset of multiple cranial nerve palsies (usually bilateral VII and sparing of II), with elevated cerebrospinal fluid protein, slowing of motor conduction velocities, and good recovery [Lyu and Chen, 2004; Polo et al., 1992, 2002]. Bilateral facial weakness, dysphonia, and dysphagia are typical symptoms. Evidence suggests some association with cytomegalovirus infection. One study of 20 cytomegalovirus-associated Guillain-Barré syndrome patients compared the findings with earlier established data of C. jejuni-related Guillain-Barré syndrome patients and found that the patients were significantly younger, initially had a severe course, indicated by a high frequency of respiratory insufficiency, and often developed cranial nerve involvement and severe sensory loss [Visser et al., 1996]. These observations were in contrast to patients with C. jejuni infection, which was more commonly associated with an AIDP phenotype [Hughes and Cornblath, 2005; Jacobs et al., 2008; Meyer Zu Horste et al., 2010; Nachamkin et al., 2007; Nagashima et al., 2004; Nagashima, 2007; Nishimoto et al., 2008a]. Enhancement of multiple cranial nerves seen with postcontrast magnetic resonance imaging (MRI) has also been documented, but clinical symptoms and electrodiagnostic studies reflected abnormalities caused by some, but not all, of the enhancing cranial nerves [Fulbright et al., 1995; Morosini et al., 2003].

Acute Pandysautonomia

Acute pandysautonomia is a relatively rare disorder, even within the group of diseases falling under the Guillain-Barré syndrome rubric. There are no large series of well-studied patients, and the most extensive reports cobble together a handful of subjects that have often been seen at institutions over a protracted time period. The collection of reports available in the literature, as might be anticipated, represents a heterogeneous patient population. The patients, by definition, have in common symptoms of autonomic failure manifestations that have a limited range of expression. Hence, dysautonomia provides the common thread that binds this group into a single entity without connoting a homogeneous underlying pathophysiology. Typically, such patients present with orthostatic hypotension, intestinal dysmotility, bladder dysfunction, syncope, vomiting, and difficulties with urination [Low, 1994]. They may also exhibit hypo- or hyperhidrosis, pupillary abnormalities, sensory deficits, and loss of reflexes. In addition, some patients have been described with symptoms or signs reflecting neurological abnormalities outside the confines of the autonomic nervous system and should probably be excluded from this diagnostic category. Even within this relatively homogeneous clinical group there is considerable heterogeneity in terms of its severity and outcome. In rare circumstances when the disorder has proven fatal, pathological data indicate that some patients have abnormalities quite distinctive from Guillain-Barré syndrome. There are a number of reports of patients who have developed an acute sensory neuronopathy or ganglionopathy that is usually associated with a poor recovery. Fortunately, most children who present with acute autonomic failure recover spontaneously, or respond to treatment with corticosteroids or intravenous immune globulin [Mericle and Triggs, 1997; Ramirez et al., 2004]. Acute dysautonomia most often is observed in the context of associated features that are typical of Guillain-Barré syndrome-like illnesses, making the diagnosis more straightforward. When children present with isolated acute autonomic failure, there is virtually no way to distinguish a Guillain-Barré syndrome variant from a ganglioneuronopathy early in the course of the illness. Empiric treatment is probably of limited risk and may be warranted when the dysautonomia is incapacitating. Most patients will improve relatively rapidly and fully recover.

Guillain-Barré Syndrome with Central Nervous System Manifestations

Although rare, Guillain-Barré syndrome with central nervous system (CNS) manifestations is reasonably well described in adults and children [Bradshaw and Jones, 2001; Maier et al., 1997; Nadkarni and Lisak, 1993; Okumura et al., 2002]. However, the incidence, severity, neuroimaging, and pathologic characterization of peripheral and central nervous system autoimmune disease in children remain elusive. One study reported postmortem findings in 13 adult patients with Guillain-Barré syndrome whose death ranged from 1 day to 12 months from the onset of neurologic symptoms [Maier et al., 1997]. CNS pathologic findings were predominantly secondary to injury to spinal nerve roots and cranial nerves. Evidence of primary inflammation was present, especially within the spinal cord, medulla, and pons, with clusters of mononuclear cells around small vessels. Although features of primary demyelination were identified in the peripheral nervous system in 12 of 13 patients, they were not detected in the CNS in any patients. Nadkarni and Lisak [1993] reported a 28-year-old patient with acute Guillain-Barré syndrome who developed bilateral optic neuritis and extensive CNS white-matter lesions on MRI. This illness was associated with Mycoplasma pneumoniae infection and suggested some degree of overlap with acute disseminated encephalomyelitis. It was hypothesized that certain infections might have a shared epitope that targets the peripheral and central nervous system. The clinical manifestations of CNS involvement in patients with Guillain-Barré syndrome-like illnesses range from nonspecific encephalopathy to more typical features of acute disseminated encephalomyelitis, transverse myelitis, optic neuritis, or brainstem/cerebellar syndromes [Bernard et al., 2008; Martens-Le Bouar and Korinthenberg, 2002]. The CNS component may be obscured by the peripheral nerve disease. The combination of mixed central and peripheral nervous system syndromes in children is rare, although not negligible. In one series, nearly 15 percent of children were thought to have evidence of central and peripheral nervous system disease; however, the actual frequency of Guillain-Barré syndrome-plus syndromes is probably lower. It is likely that such involvement in young children may be clinically difficult to detect, particularly if there is severe generalized weakness with or without respiratory failure.

Clinical Laboratory Evaluation

The diagnosis of Guillain-Barré syndrome is based on clinical features. Confirmatory laboratory studies include cerebrospinal fluid examination, electrophysiologic testing, and occasionally MRI to look for enhancement in spinal roots after contrast administration.

Cerebrospinal Fluid

A characteristic laboratory finding supporting the diagnosis of Guillain-Barré syndrome is albuminocytologic dissociation or a disproportionate elevation of cerebrospinal fluid protein in the absence of significant evidence of inflammation (i.e., >10 mononuclear cells/mm3 of cerebrospinal fluid) after the first week of symptoms of the disease, essentially regardless of the subtype. The presence of significant cerebrospinal fluid pleocytosis (>50 mononuclear cells/mm3) or the presence of polymorphonuclear leukocytes in the cerebrospinal fluid should raise doubt about the diagnosis [Asbury and Cornblath, 1990; Jones, 1996]. The elevated cerebrospinal fluid protein includes both albumin and immunoglobulins. This feature of the illness is due to breakdown of the blood–nerve barrier within the subarachnoid space surrounding spinal nerve roots. Cerebrospinal fluid protein elevation may not be detectable early in the course in about 20 percent of children. If sites of inflammation within the peripheral nervous system are distal to the intraspinal roots, protein elevation within cerebrospinal fluid may be minimal. In most reported pediatric series, the cerebrospinal fluid protein levels have been in the range of 80–200 mg/dL (normal being less than 40 mg/dL) [Briscoe et al., 1987; Epstein and Sladky, 1990; Jones, 1996, 2000; Rantala et al., 1991; Ryan, 2005; Sladky, 2004].

Electrophysiologic Testing

Electrophysiologic testing can help to confirm the diagnosis and also provide useful adjunctive information, including characterizing the pathology and disease subtype more precisely, and potentially contributing information concerning prognosis. The pathologic hallmark of AIDP is multifocal, immune-mediated demyelination within spinal roots and peripheral nerves [Asbury et al., 1969]. The electrophysiologic correlate is the presence of multifocal slowing of nerve conduction or conduction block [Alma et al., 1998; Cros and Trigges, 1996; Hadden et al., 1998; Vriesendorp et al., 1995; Hughes and Cornblath, 2005; van Doorn, 2005; van Doorn et al., 2008; Vucic et al., 2009]. In the case of acute inflammatory demyelinating polyneuropathy, the task of the clinical electrophysiologist is to demonstrate electrophysiologic evidence of multifocal demyelination in sensory and motor peripheral nerves indicative of an acquired inflammatory disorder. This task requires demonstrating asymmetric slowing of nerve conduction along the course of peripheral nerves, disparate conduction velocities among comparable nerve segments, or the presence of conduction block. Asymmetric slowing along the course of a peripheral nerve might be manifest as disproportionate prolongation of the distal motor latency compared with the degree of conduction slowing in a more proximal nerve segment. Alternatively, markedly prolonged F-wave or H-reflex latencies in the face of reasonably normal distal motor latency and nerve conduction velocity in the limb are indicative of slowing of conduction in proximal nerve segments or spinal roots. Conduction block and temporal dispersion of proximally evoked compound motor action potentials are also features of multifocal segmental demyelination in peripheral nerves and are indicative of an acquired inflammatory demyelinating neuropathy. Box 90-2 includes the somewhat dated but useful consensus criteria of electrodiagnostic features considered supportive of the diagnosis of Guillain-Barré syndrome [Asbury and Cornblath, 1990]. Application of a modified version of these criteria resulted in 60 percent of adult patients with Guillain-Barré syndrome fulfilling the criteria for polyneuropathy at the first examination (mean time interval, 6 days since disease onset) [Meulstee and van der Meche, 1995].

Pathogenesis

The pathologic findings of Guillain-Barré syndrome are confined predominantly to spinal nerve roots and peripheral nerves [Asbury et al., 1969]. The pathogenesis of the disorder is immune-orchestrated, with macrophage-mediated injury to sensory and motor axons within the peripheral nervous system [Hafer-Macko et al., 1996b; Hartung et al., 1996; Hughes et al., 1999]. In contradistinction to the traditional notion that Schwann cell/myelin-related constituents are the primary targets of the autoimmune process and that associated axonal damage is a nonspecific “bystander effect” of the inflammatory reaction, there is evidence that epitopes expressed exclusively on axolemma may also be singled out for immune attack and result in concomitant axonal degeneration [Hafer-Macko et al., 1996b; Hartung and Kieseier, 1999; Hughes et al., 1999; Asbury, 2000; Hughes and Cornblath, 2005; Jones, 2000; van Doorn, 2009; van Doorn et al., 2008]. It is likely that myelin/Schwann cell and axonal surface epitopes are immunologically targeted to variable degrees during the active phase of Guillain-Barré syndrome, resulting in the spectrum of clinical manifestations that are features of the syndrome. The typical pathogenic mechanism in Guillain-Barré syndrome involves macrophages insinuating themselves under the myelin sheath at the node of Ranvier or between myelin lamellae, stripping myelin from the underlying axon [Hafer-Macko et al., 1996b; Hartung et al., 1996, 2002; Hughes et al., 1992, 1999; Kiefer et al., 2001; Steck et al., 1998; Vucic et al., 2009; Willison et al., 2002, 2008; Willison, 2005b]. Documenting the early events in the immune-mediated attack on the peripheral nervous system is, for obvious reasons, difficult in humans. The early pathologic changes have been characterized in a laboratory model, experimental allergic neuritis (EAN), a disorder nearly homologous to acute inflammatory demyelinating polyneuropathy. Experimental allergic neuritis can be induced in laboratory rodents immunized with constituents of peripheral nerve myelin, or with transfer of activated T cells from animals with the disease (Figure 90-1) [Rostami, 1997]. A different pattern of injury has been described (Figure 90-2) in acute motor axonal neuropathy related to Campylobacter infection in children from northern China. In these patients, macrophages have been found to interrupt axoglial tight junctions at nodes of Ranvier and attack and destroy the motor axon, sparing the circumferential myelin, which then secondarily breaks down [Griffin et al., 1995, 1996a, b; Hafer-Macko et al., 1996a; McKhann et al., 1993]. This process results in a relatively pure motor syndrome without evidence of primary demyelination on histopathologic examination or electrophysiologic testing [Griffin et al., 1995, 1996a, b; Hafer-Macko et al., 1996a; McKhann et al., 1993; Hughes and Cornblath, 2005; Kuwabara et al., 2001; Lu et al., 2000; Vucic et al., 2009; Willison et al., 2002, 2008; Willison, 2005b].

It is clear that, early in the immunological cascade that ultimately results in neurological disease, an exquisitely precise targeting mechanism is activated, which directs subsequent downstream events, resulting in focal tissue or cellular damage. Previous hypotheses that these disorders are directed principally at myelin-related antigens and that the extensive axonal injury that frequently occurs is a nonspecific “bystander effect” have been questioned by empirical observations, especially among variants within the Guillain-Barré syndrome family of diseases. These are among the best-studied disorders in which firm evidence exists that antibodies elicited against antigenic components found on the membrane surfaces of an infectious organism play a significant role in the pathogenesis of human disease.

In the most directly relevant examples, there are recognizable homologies between the infectious agent and constituents of the nervous system that reinforce the notion of cross-reactivity underpinning immune-mediated neurological injury, a process that has been termed “molecular mimicry.” This case can best be made with C. jejuni, where epidemiological studies confirm a significant relation between antecedent Campylobacter enteritis and subsequent peripheral neuropathy [Hadden and Gregson, 2001; Kuwabara et al., 2004; Liu et al., 2003; Nachamkin et al., 2007; Takahashi et al., 2005; Wu et al., 1999]. Investigators also have established that infection with a relatively small group of specific C. jejuni serotypes accounts for the majority of cases of Guillain-Barré syndrome-like illness worldwide. The precise relation among serotypes, specific antibodies, and clinical phenotypes requires further study. There are compositional identities between oligosaccharides expressed on the lipo-oligosaccharide membrane of the bacterium and neural membrane gangliosides from which oligosaccharide moieties protrude, where they are recognizable by immune surveillance mechanisms. Antibodies directed toward these surface epitopes can be demonstrated in many patients and almost certainly play a role in disease pathogenesis [Hughes and Cornblath, 2005; van Doorn et al., 2008; Willison, 2005b; Willison and Plomp, 2008]. There are even stronger correlations between some phenotypical subtypes in which discrete populations of peripheral axons and Schwann cells are attacked by antibodies directed against specific gangliosides, as has been persuasively demonstrated with anti-GQ1b antibody expression in patients with the Miller Fisher syndrome variant [Akinci et al., 2007; Koga et al., 2001; Nagashima et al., 2004; Nagashima, 2007; Nishimoto et al., 2004; Takahashi et al., 2005]. Similarly, in the acute motor axonal variant of Guillain-Barré syndrome, acute motor axonal neuropathy, anti-GM1 or GD1a, ganglioside antibodies specifically target motor nerve axolemmal membranes.

The sequence of events that engenders autoimmune neuromuscular disorders such as Guillain-Barré syndrome is incompletely understood. Dalakas [1995] emphasized that several sequential steps are required to orchestrate autoimmune-mediated tissue injury:

The presence of proinflammatory and anti-inflammatory cytokines acts to modulate the intensity of the autoimmune attack on endoneurial contents through multiple pathways. Nerve fibers in peripheral nerves are relatively protected from systemic immune responses and inflammatory reactions by the specialized endoneurial, endothelial, and perineural barriers [Dalakas, 1995; Hartung et al., 2001, 2002; Hughes et al., 1999]. Compared with peripheral nerve trunks, there are more macrophage-like cells and more permeable blood vessels in the dorsal root ganglia and spinal roots that are preferred sites for the inflammatory response in experimental allergic neuritis. As noted earlier, experimental allergic neuritis can be induced by immunization with myelin proteins or fragments of the proteins. P0 and P2 proteins have been most consistently used to induce this model; a similar but less inflammatory, more chronic demyelinating neuropathy can be induced in rabbits with the glycolipid, galactocerebroside [Harvey et al., 1987; Ang et al., 2001b, 2002a, b; Willison, 2005b; Willison and O’Hanlon, 1999; Willison and Plomp, 2008

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