Epidemiology

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) comprises a small but important subset of chronic childhood polyneuropathies. One series identified childhood CIDP in 11/125 (9%) of all children with a chronic polyneuropathy confirmed by sural nerve biopsy. A second series reported CIDP in 35/249 (14%) of all children diagnosed with a sensorimotor polyneuropathy.

CIDP can present from infancy to late adulthood. The mean age of childhood CIDP onset is 8 to 9 years, but it can appear at any age. No gender predilection is observed. The overall annual incidence of CIDP (all ages) is estimated to be 0.15 per 100,000 per year. By comparison the annual incidence of acute inflammatory demyelinating polyradiculoneuropathy, or Guillain-Barré syndrome, has been estimated to be 1.3 per 100,000 per year (range 0.4 to 4.0) reflecting a 10-fold higher annual incidence of the acute form of the disease. The overall prevalence of CIDP is estimated at 1–2 per 100,000 with disease prevalence increasing with advancing age. An Australian study reported the prevalence of childhood CIDP to be 0.5 per 100,000, increasing more than 12-fold to 6.7 per 100,000 among 70- to 79-year-old adults.

Pathogenesis

CIDP is an autoimmune disease resulting from a loss of immunologic self-tolerance. Cellular and humoral factors both contribute to autoimmune attack as autoreactive T and B lymphocytes, antibodies, and complement target myelinated peripheral nerves. Molecular mimicry is believed to be the mechanism underlying the autoimmune attack in CIDP. Molecular mimicry occurs when an individual is exposed to a new exogenous antigen (i.e. viral or bacterial infection) or when a normal endogenous intracellular protein becomes exposed to the immune system as a result of trauma, cancer, or a degenerative disease. The antigenic determinant known as the epitope is identified as foreign by the host’s immune system and targeted for cellular and humoral immune attack. While this process is essential for normal immune functioning, in circumstances where the foreign epitope resembles normal host tissue it can lead to an ongoing autoimmune attack redirected toward the host’s own tissue. In CIDP, the autoimmune attack is directed toward peripheral nerves and nerve roots. Only about one-third of children with CIDP can point to an inciting or antecedent event in the months prior to disease onset. Even among children with an acute inflammatory neuropathy such as Guillain-Barré syndrome, where less time has passed between potential preceding infection and disease onset, only two-thirds of patients recall prior infectious symptoms. Nevertheless, there are multiple levels of evidence to support an autoimmune basis for CIDP regardless of the initiating event.

Animal models of experimental allergic neuritis show a strong clinical and pathological resemblance to human CIDP. By injecting components of peripheral nerve myelin such as myelin protein zero (MPZ) or peripheral myelin protein 22 (PMP22) into the blood of healthy animals, a syndrome of chronic neuritis can be induced that is clinically and pathologically analogous to human CIDP. Affected animals show chronic inflammatory changes in their endoneurium as well as onion bulb formation similar to that seen in sural nerves of humans with CIDP. Such experiments were important in confirming an autoimmune basis for CIDP, redirecting attention away from a potential infectious cause. Later studies confirmed that passive transfer of serum or purified IgG from human CIDP patients to healthy rats can induce conduction block and demyelination. Antibody-mediated disease offers an explanation for specific types of inflammatory nerve disease such as Miller Fisher syndrome (MFS). This subtype of Guillain-Barré syndrome is characterized by ataxia, areflexia, and ophthalmoplegia and shows a very strong association with anti-GQ1b antibodies, which opsonize the GQ1b protein that is highly expressed on motor nerves innervating extraocular muscles. Unlike MFS, there has been no convincing antibody link to CIDP. Fewer than 10% of all CIDP patients have anti-ganglioside, anti-sulfatide, or other autoantibodies. Although an antibody-mediated attack does not appear to be the main immune process in patients with CIDP, the link with an autoimmune process is clear. T-lymphocytes remain important in the pathophysiology of CIDP. Sural nerve biopsies of adult CIDP patients show a correlation between the abundance of T lymphocytes in the endoneurium and the severity of demyelination.

Finally, support for autoimmunity in CIDP is supported by response of patients to immunomodulating therapies such as intravenous immunogloblins (IVIg), plasma exchange (PLEX), and corticosteroids, which will be described in greater detail later in this chapter.

Clinical Features

Three main areas must be considered by the clinician evaluating a child with possible chronic inflammatory demyelinating polyradiculoneuropathy. The first is to determine if the child exhibits the necessary clinical features to meet diagnostic criteria for CIDP. The second is to confirm the duration of symptoms that are reported. Finally, it is important to ascertain if the child demonstrates any clinical features potentially consistent with one of the many CIDP mimics, raising clinical suspicion of an alternative diagnosis and possibly excluding CIDP.

Children with CIDP demonstrate clinical signs and symptoms consistent with a sensorimotor polyneuropathy. Generalized muscle weakness and reduced or absent deep tendon reflexes are the two mandatory clinical criteria required for diagnosis of CIDP ( Box 21.1 ). Children will often have evidence of both proximal and distal muscle weakness, owing to the patchy immune attack along the entire length of the peripheral nerves. Weakness in CIDP patients is typically symmetrical; significant asymmetry should raise suspicion for alternative diagnoses. Hyporeflexia or areflexia is an early clinical feature of an inflammatory polyneuropathy and reflects involvement of both sensory afferents and—to a lesser degree—motor efferent fibers in this disease.

Gait impairment and/or clumsiness are the most common presenting features of CIDP, particularly in younger children. Parents will often become concerned about their child’s increasing clumsiness, frequent falls, and inability to run or get up from the floor without assistance. Our recently published cohort of childhood CIDP noted gait difficulty as an initial symptom in 29/30 (97%) of patients. All 30 patients demonstrated some degree of muscle weakness, but the severity of weakness was typically moderate, with only 23% being nonambulatory. Gait ataxia results from a combination of muscle weakness and sensory loss due to involvement of large myelinated sensory afferents conveying proprioceptive input. Decreased or absent deep tendon reflexes in an ataxic child provide a valuable clinical clue directing attention toward a peripheral nerve disorder, and away from central nervous system disorders such as a posterior fossa tumor or a central demyelinating disease.

Sensory symptoms such as paresthesia and hypesthesia are seen in about 65–90% of children with CIDP, reflecting involvement of small fiber sensory afferents. Since sensory symptoms are subjective, they can be challenging to evaluate in some young children, and they are not included in the diagnostic criteria. There are also rare reports of childhood CIDP presenting with isolated motor nerve involvement. While clinical and electrodiagnostic evidence of sensory nerve involvement reassures clinicians that the lesion localizes best to the peripheral nerve, this evidence is not required for diagnosis of CIDP.

Back pain and limb pain are less common but are reported in <30% of children with CIDP. In adults, CIDP has been reported to cause nerve root inflammation causing nonspecific backache, massive nerve root enlargement has caused radiculopathy-like symptoms, and leg pain with walking has been has been attributed to a spinal cord stenosis-like syndrome related to massive enlargement of the cauda equina. Awareness that these symptoms can be associated with CIDP is important for correct diagnosis, institution of immunomodulatory therapy, and avoidance of unnecessary surgical interventions. Magnetic resonance imaging in CIDP is discussed in detail below.

Cranial nerve involvement, manifesting as facial or oculobulbar weakness, is seen in only 10–15% of children with CIDP. Dysautonomia and respiratory failure is exceedingly rare in children and adult CIDP patients.

Temporal progression of CIDP symptoms provides additional clinical information that can help differentiate this chronic inflammatory polyneuropathy from its acute counterpart, Guillain-Barré syndrome (GBS). Diagnostic criteria stipulate that the progression of muscle weakness (i.e. time from initial symptom onset until time of maximal clinical deficit) in CIDP must be over at least 4 weeks. In situations where patients demonstrate initial rapid symptom onset (i.e. a GBS-like presentation), this must be followed by a relapsing or protracted disease course lasting at least 12 months ( Box 21.1 ). Accurate differentiation of CIDP from GBS is important to ensure correct management with regard to the choice and duration of immunomodulatory therapy.

Most children with CIDP present with an initial insidious or chronic symptom-onset. We recently reported a large cohort of children with CIDP, in which 60% of patients demonstrated at least an 8 week period between their initial symptoms and the time of maximal clinical deficit. The mean time between symptom onset and maximal clinical deficit was 7.9 months for this group. A smaller group (20%) of patients demonstrated subacute onset of disease, which was defined as between 4 and 8 weeks between initial symptom onset and maximal clinical deficit. Subacute onset of CIDP has been well described in prior studies. Combining the subacute and chronic subgroups, 80% of childhood CIDP patients demonstrate at least a 4 week period between their initial symptoms and the time of maximal clinical deficit.

A third group of children with CIDP (20% patients) initially presented with acute-onset disease, where less than 4 weeks elapsed between initial symptom and maximal clinical deficit. One of these children presented with rapidly progressive weakness over several days, becoming quadriplegic and requiring intubation and mechanical ventilation. The proportion of our acute-onset group was similar to that of a prior group of pediatric and adult CIDP patients, wherein 16% of individuals eventually found to have CIDP presented with an initial acute onset of disease. CIDP patients with acute-onset disease (A-CIDP) are initially difficult to distinguish from patients with demyelinating Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy, AIDP). However, unlike AIDP patients, children who eventually go on to be diagnosed with CIDP must demonstrate persistent and/or relapsing disease with symptoms persisting for longer than 12 months.

Adult studies have looked for features distinguishing the 16–20% of acute-onset CIDP patients from the 10% of GBS patients who may show transient weakness or treatment-related fluctuations after treatment with intravenous immunoglobulin (IVIg) or plasma exchange (PLEX). Adults with AIDP show less prominent sensory symptoms and a higher incidence of autonomic dysregulation, facial weakness, preceding infection, and need for mechanical ventilation compared to the acute-onset CIDP group. Another study found that adults with AIDP generally showed a more rapid time to maximal clinical deficit (mean=8.5 days) compared to the acute-onset CIDP group (mean=16.5 days), as well as a shorter time to symptom exacerbation and a higher likelihood of needing mechanical ventilation.

Childhood CIDP has a relapsing-remitting or polyphasic course in 60–70% patients, with the remaining 30–40% of children demonstrating a protracted monophasic disease.

The final area of inquiry is to ensure that the child does not demonstrate any clinical features that could be consistent with one of the many CIDP mimics which will be discussed in the next section.

Differential Diagnosis

There are numerous features on clinical history and/or physical examination that should raise concern for a potential diagnosis other than CIDP. These include: (1) sensory level or unequivocal sphincter disturbance; (2) self-mutilation; (3) marked asymmetry of symptoms; (4) early or predominant oculobulbar symptoms; (5) drug or toxin exposure; (6) central nervous system involvement; and/or (7) early onset and/or family history of polyneuropathy ( Table 21.1 ).

Sensory findings in CIDP are typically length-dependent. A clear sensory level should raise suspicion of a lesion within the spinal cord. Another diagnostic clue may be brisk reflexes or extensor plantar responses, indicating corticospinal tract involvement. Caution is required, however, in the patient who shows an abrupt clinical deterioration (i.e. an acute upon chronic decline) since deep tendon reflexes may be temporarily depressed in a patient with spinal shock. The extensor plantar response should point toward a central or spinal lesion in such cases. Similarly, while children with CIDP may exhibit urinary or fecal incontinence due to an inability to reach the toilet in time, this typically occurs later in the disease course. Incontinence is not an early or predominant feature in CIDP, and should raise concern about a potential spinal cord lesion.

Self-mutilation can be seen with some hereditary sensory neuropathies (e.g. hereditary sensory and autonomic neuropathy (HSAN)). Patients with spinal cord lesions (i.e. syrinx or hydromyelia) may also develop painless burns, ulcerations, lacerations, or even fractures. While patients with CIDP may demonstrate decreased pain sensation, particularly in the feet, this again should not be an isolated or predominant finding.

Marked asymmetry of symptoms should raise suspicion of motor neuron diseases such as Hirayama disease, poliomyelitis, Hopkins syndrome, or other polio-like illnesses, as well as other forms of inflammatory nerve disease including vasculitic neuropathies. CIDP is generally a symmetrical disease of peripheral nerves. While mild side-to-side differences can be seen in clinical and electrodiagnostic abnormalities, marked asymmetry is atypical.

Although cranial nerve involvement is seen in 10–15% of children with CIDP, early or predominant oculobulbar symptoms are less typical of this disease. Early ocular weakness (i.e. ophthalmoplegia, ptosis) is common with disorders of neuromuscular transmission such as congenital myasthenic syndrome or juvenile myasthenia gravis, but can also be seen with mitochondrial diseases and congenital myopathies.

Prior or concomitant drug or toxin exposure should raise suspicion for a potential CIDP mimic. Glue or gasoline inhalation can give rise to a sensorimotor polyneuropathy with demyelinating features.

Central nervous system involvement raises suspicion of metabolic conditions such as globoid cell leukodystrophy (Krabbe disease) or metachromatic leukodystrophy, rare diseases inherited in an autosomal recessive manner. Due to their inheritance patterns, there may be no family history of these conditions. Affected children demonstrate progressive irritability as well as cognitive and language delay or regression due to central and peripheral nerve demyelination. Symptoms of neuropathy may predate central nervous system involvement in some patients with leukodystrophies. Peroxisomal diseases such as Refsum disease or adrenoleukodystrophy may also be associated with central and peripheral nerve demyelination. Peroxisomal diseases can present from infancy to early adulthood and can show progressive patterns of abnormality on electrodiagnostic testing, that could be mistaken for CIDP. Cockayne syndrome may show a resemblance to CIDP on electrodiagnostic grounds; however, the distinctive clinical phenotype—distinctive facial features (deep set eyes, progerioid appearance), microcephaly, developmental delay and failure to thrive—should alert the clinician to this genetic disorder. Mitochondrial disease can show clinical and electrodiagnostic overlap with CIDP.

Lastly, in very young children, or those with a family history of neuropathy, hereditary neuropathies such as Charcot-Marie-Tooth (CMT) disease should be considered. Both CMT and CIDP cause chronically progressive motor and sensory deficits. Although hereditary neuropathies such as CMT1A typically show uniform conduction slowing, occasional patients with CMT1B or CMTX demonstrate features of nonuniform slowing, including temporal dispersion and conduction block ( Table 21.2 ). Similar findings are also seen occasionally in children with metachromatic or globoid cell dystrophies. Hereditary neuropathy with liability to pressure palsies (HNPP) is most commonly associated with a 1.5 Mb deletion at chromosome 17p11, a region that contains the PMP22 gene. The gene deletion results in inadequate peripheral myelin protein expression, rendering peripheral nerves more susceptible to injury after minor trauma or compression. HNPP patients typically present in early adulthood with a painless mononeuropathy usually involving the peroneal or ulnar nerve. Less commonly patients develop a painless brachial plexopathy or a progressive polyneuropathy. Electrodiagnostic testing demonstrates evidence of both generalized and segmental demyelination in all symptomatic and most asymptomatic HNPP patients over 15 years old. Although the clinical phenotype infrequently overlaps CIDP, the electrodiagnostic findings can show similarities between these two disorders. CMTX can also show significant clinical and neurophysiologic overlap with CIDP. Reports of CMT and CIDP coexisting in the same patient raise concern that some CIDP patients who demonstrate only a transient response to immunosuppressant therapy could be affected by two overlapping or concomitant diseases ( Figure 21.1 ). One such report is of a 26-year-old man who walked at 26 months of age and had progressive weakness from early childhood, necessitating wheelchair use by age 13 years. At 22 years old he suffered a left femoral fracture. Around that time he developed severe, progressive weakness of his left upper extremity, clinically mimicking an inflammatory neuropathy, which left his hand functionally useless within 2 years. He was found to have compound heterozygous mutations in FIG4 consistent with the diagnosis of CMT type 2J.

There can be significant clinical overlap between chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth (CMT) disease. A small subset of genetic neuropathies has been clearly associated with a predisposition to CIDP (*).

Another report is of a woman with normal early neurodevelopmental milestones, who was diagnosed with kyphoscoliosis at 4 years old and from age 14 developed progressive muscle weakness and sensory loss. She was found to have CMT due to SH3TC2 gene mutations (CMT type 4C). She was diagnosed with ulcerative colitis at age 24 years old and treated with corticosteroids. Upon withdrawal of corticosteroid therapy she developed marked progressive muscle weakness. She had an acellular CSF with a markedly elevated CSF protein (1.06 g/L, normal <0.45 g/L). Her sural nerve biopsy revealed classic onion bulb formations, with CD4 cell staining showing T-lymphocyte infiltration supporting a superimposed inflammatory disease. She was diagnosed with CIDP superimposed upon CMT. She initially showed a partial response to IVIG which later became ineffective, and failed to respond to corticosteroids and azathioprine. These examples are important for clinicians caring for CIDP patients who demonstrate a transient or inadequate clinical response to multiple immunomodulatory therapies. There are other cases of patients with inherited neuropathies due to GJB1 , SPTLC1 and SIMPLE gene mutations who were initially diagnosed with an inflammatory polyneuropathy.

Molecular mimicry has been discussed as the most accepted etiology of inflammatory neuropathy. Patients with inherited polyneuropathy are particularly susceptible to this process as their chronic axonal degeneration, with accumulation of myelin and cellular debris, can presumably act as a focus to sensitize the immune system to further autoimmune attack.

Laboratory Studies

An elevated CSF protein (>35 mg/dL or >0.35 g/L) without pleocytosis (<10 leukocytes per mm ³ ) is known as albuminocytologic dissociation. This finding is observed in 87–100% of childhood CIDP patients (see Case Example 21.1 ). Elevated CSF protein is certainly not specific to CIDP and can be seen in children with congenital hypomyelinating neuropathy, Charcot-Marie-Tooth disease or leukodystrophies such as Krabbe disease. Infrequently children with CIDP have a normal CSF protein, as seen in Case Example 21.2 . In such circumstances clinicians must look to other tests to ensure that diagnostic criteria are met. A CSF leukocyte count greater than 10 cells/mm ³ is atypical of childhood CIDP, and should prompt consideration of alternative diagnoses such as demyelinating disorders or infectious myelitis (i.e. human immunodeficiency virus or Lyme disease).

Case Example 21.1

A 14-year-old boy presented with a 5-month history of gait difficulty and clumsiness. He described increased difficulty walking in snow and on ice and reported falling more frequently. He remained able to climb stairs and rise from the floor without difficulty. He had bilateral foot paresthesia below the ankles. His upper extremities were unaffected, and he had no symptoms of bowel or bladder dysfunction. His symptoms had improved slightly by the time he was evaluated by a neurologist. On examination his muscle bulk and strength were normal. He had decreased sensation to pin-prick and fine touch below the ankles and decreased vibration to his great toes, and was areflexic. No pes cavus was apparent. Nerve conduction studies identified a moderate sensorimotor polyneuropathy with demyelinating features. Based upon the clinical and electrodiagnostic testing, he was diagnosed with a resolving Guillain-Barré syndrome due to his normal strength. Over the ensuing months, his symptoms remained stable but he did not return to baseline. He was unable to use a skateboard over the summer months. Twelve months after initial symptom onset, he had an upper respiratory tract infection, followed within two weeks by a marked deterioration in strength. He could no longer run or jump. He began falling more frequently, although he remained independent with dressing and walking, could climb stairs, grasp a pen, and write normally. His lower limb paresthesia returned, and he described numbness extending up to both knees. His past medical history was significant only for stable scoliosis, and the family history was noncontributory. His physical examination revealed normal growth parameters and normal cranial nerve examination. Muscle strength testing (MRC scale) revealed mild distal upper limb weakness: abductor pollicus brevis 4+, first dorsal interosseous 4+ as well as lower extremity weakness: tibialis anterior 4+, extensor hallicus longus 4. Proximal muscle strength remained full. The deep tendon reflexes were absent. Sensory testing revealed decreased sensation below the mid-thigh and absent below the ankles, with decreased pin-prick sensation in all fingers. Vibration sensation was absent at the toes, ankles, and knees. Proprioception was absent in the toes. Cold sensation was intact. No dysmetria or tremor was apparent. Repeat nerve conduction studies (12 months after symptom onset) revealed a severe sensorimotor polyneuropathy with demyelinating features. Sensory responses were absent at his bilateral median, ulnar, peroneal, and sural nerves. His right radial sensory nerve amplitude was low at 2.3 mcV (normal >11 mcV). Motor nerve studies revealed prolonged distal latencies, slowed conduction velocity, and absent late responses, although these findings did not meet criteria for conduction block or temporal dispersion. Concentric needle electromyography (EMG) of his left medial gastrocnemius revealed mild (1+) fibrillation potentials and positive sharp waves as well as an increase in polyphasic and long duration motor units. His left tibialis anterior revealed an increase in polyphasic and long duration units. Spinal fluid analysis revealed a marked elevation of cerebrospinal fluid (CSF) protein 1.33 g/L (normal 0.15 to 0.60 g/L), with normal CSF leukocytes (3 cells/mm ³ ), erythrocytes (1 cells/mm ³ ), and glucose (2.7 mmol/L). A spinal MRI with gadolinium 12 months after symptom onset revealed diffuse hypertrophy and enhancement of the nerve roots in the cervical and lumbar spine bilaterally ( Figure 21.2 ). The nerve root thickening was symmetric with no nodular appearance noted. There was enhancement of cranial nerves VII and VIII in the internal auditory canal. Based upon the findings of weakness and areflexia persisting >12 months, the nerve condition studies and CSF results, he was diagnosed with CIDP ( Table 21.3 ). Nerve biopsy was not performed. He was treated with IVIg (1 g/kg)×2 days followed by maintenance dosing of IVIg 1g/kg once per month. He demonstrated progressive improvement in the first few months of IVIg therapy. After 3 months of IVIg his distal muscle strength returned to normal, although he remained areflexic and reported decreased sensation distally. After 6 months of IVIg, knee and ankle reflexes could be elicited (1+), and sensation was almost normal. The interval between IVIG treatments was gradually increased. After 12 months, therapy was discontinued, subsequent to which he has remained well and has returned to all activities including trampoline, snowboarding, and skating.

MR imaging of the spine in a 14-year-old boy ( Case Example 21.1 ) with CIDP, performed 12 months after initial symptom-onset. ( A ) Axial T1-weighted image with gadolinium contrast illustrates nerve root thickening and enhancement. ( B ) Coronal STIR images reveal smooth thickening of nerve roots in the cervical spine. Thickening and enhancement was also noted in cranial nerves VII and VIII and lumbar nerve roots (not shown). Image ( B ) is previously published.

Table 21.3

Motor Nerve Conduction Studies of a 14-year-old Boy ( Case Example 21.1 ) with CIDP

Site	NR	Distal Onset Latency (ms)	Amplitude (mV)	Conduction Velocity (m/sec)	F-Response
Left Median Motor (at abductor pollicis brevis; APB)
Wrist		7.7	7.7	26	NR
Elbow		16.9	4.5
Right Median Motor (at abductor pollicis brevis; APB)
Wrist		8.5	6.8	26	NR
Elbow		18.2	5.2
Left Ulnar Motor (at adductor digiti minimi; ADM)
Wrist		5.9	2.6	30	NR
B. Elbow		12.9	2.4	28
A. Elbow		17.2	2.4
Right Ulnar Motor (at adductor digiti minimi; ADM)
Wrist		6.0	4.2	25	NR
B. Elbow		14.6	3.1	29
A. Elbow		18.8	3.2
Left Peroneal Motor (at extensor digitorum brevis; EDB)
Ankle	NR
B. Fib
Poplt
Right Peroneal Motor (at extensor digitorum brevis; EDB)
Ankle		13.9	0.2	18
B. Fib		33.8	0.2	11
Poplt		39.5	0.2
Left Tibial Motor (at abductor hallucis; AH)
Ankle	NR
Knee
Right Tibial Motor (at abductor hallucis; AH)
Ankle		28.8	0.1	23
Knee		47.5	0.1

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