| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Department of Neurology, Children’s Hospital Boston and Harvard Medical School, Boston, MA.
Address correspondence and reprint requests to Dr. Jennifer A. Markowitz, Department of Neurology, Fegan 11, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 jennifer.markowitz{at}childrens.harvard.edu
 |
Abstract. |
|---|
 Top. Abstract. CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
|
CLINICAL CASE, PART I |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
Differential diagnosis. In the evaluation of gait difficulty, as with other neurologic complaints, localization based on history and physical examination is the first step. The decreased tendon reflexes, flexor plantar responses, and Gowers maneuver ("walking" the hands up the thighs to arise from a squat) all suggest a lower motor neuron localization. Within this broad category, diseases of the motor neuron and spinal cord, nerve, neuromuscular junction, and muscle should be considered. Among motor neuron and spinal cord etiologies, tethered spinal cord and spinal muscular atrophy type III can both present with depressed or absent reflexes and should be considered. Intrinsic spinal cord processes such as neoplastic, vascular, and demyelinating lesions are also in the differential, although these are less likely to present with hyporeflexia. Inherited and acquired neuropathies are possibilities, and are discussed in more detail below. The lack of fluctuation in his symptoms makes a neuromuscular junction disorder such as myasthenia gravis less likely, although this does not exclude it completely. Inherited and acquired myopathies are also possible, although the patient does not have some of the classic associated symptoms or signs of these disorders, such as the calf hypertrophy of muscular dystrophy, myalgias of infectious myositis, or heliotrope rash of dermatomyositis.
Among polyneuropathies, two key distinctions that assist with the differential diagnosis are inherited vs acquired etiologies and demyelinating vs axonal physiology. The subacute onset suggests that this is more likely to be acquired. The physiology cannot be determined until electrophysiologic testing is performed. Another important distinction is between large and small fiber neuropathies. In this case, the lack of prominent sensory symptoms makes a small fiber neuropathy less likely.
An important class of acquired neuropathy is the autoimmune neuropathies. Among these, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), or Guillain-Barré syndrome, is less likely due to the subacute presentation. This patient’s clinical course is more consistent with CIDP. CIDP is an autoimmune disorder characterized by proximal and distal weakness that develops over a period of at least 1 month, with a monophasic progressive or relapsing-remitting course. Deep tendon reflexes are diminished or absent. Pathologically, there is patchy demyelination of nerve roots and distal nerves. Although this disease is rare in children, it is important to recognize since children with CIDP often respond favorably to immunomodulatory therapy.1,10
Other acquired neuropathies should also be considered in children who present with a subacute to chronic peripheral neuropathy. These include those resulting from infectious causes such as HIV and Lyme disease; metabolic derangements such as uremia, hypothyroidism, or vitamin B12 deficiency; inflammatory causes such as vasculitis; or exposure to toxins, such as lead or heavy metals.1
If this patient’s course had been more chronic, inherited neuropathies would be more prominent in the differential diagnosis, especially since the onset is typically in childhood. Charcot-Marie-Tooth disease is the most common inherited neuropathy. Other considerations include the neuropathies of more generalized inherited disorders, such as Krabbe disease and metachromatic leukodystrophy. Inherited neuropathies tend to present with uniform rather than patchy involvement of nerves on electrophysiologic testing, with some notable exceptions.1 Sensory loss may be more prominent than in CIDP. The time course of inherited neuropathies tends to be chronic, rather than subacute or relapsing, so that findings such as pes cavus or contractures are more commonly observed.1,2
|
CLINICAL CASE, PART II |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
44 m/s], right tibial 28.7 m/s, left tibial 17.9 m/s [normal 41 m/s]) with temporal dispersion, and low amplitude bilateral tibial and right peroneal compound motor action potentials (figures 1 and 2). Further laboratory workup for infectious, metabolic, toxic, and inflammatory causes of neuropathy was normal. Based on the electrophysiologic findings, cytoalbuminologic dissociation, and nerve root enhancement on MRI, he was diagnosed with CIDP.
|
|
|
DISCUSSION |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
Clinical characteristics. The most common complaint that brings children with CIDP to medical attention is gait disturbance and falling. This results from symmetric, predominantly motor involvement of the proximal and distal lower extremities. Upper extremity weakness, hand tremor, and ataxia are also present in some cases. Deep tendon reflexes are always reduced or absent.1,4,9 Some studies indicate that at least one-third of pediatric patients experience sensory symptoms, characterized by paresthesias, dysesthesias, and large fiber sensory loss.2,4,7,9 Cranial nerve involvement, respiratory muscle weakness, and autonomic dysfunction are all uncommon in childhood CIDP.9
Prodromal events, most often upper respiratory infections, have been described in 33–57% of children with CIDP in various series.3,4,6,8,9 In contrast, as many as 60–80% of children with AIDP (or Guillain-Barré syndrome) have a history of a prodromal event.9
The onset of this disease may be insidious over a period of months, or there may be a more acute presentation of symptoms with recurrent episodes.2 Compared with adults, children present earlier in the course of the disease, exhibit a more rapid progression of neurologic dysfunction, and are more likely to have a relapsing-remitting course.4,7,9
It may sometimes be difficult to distinguish CIDP from AIDP initially, especially since patients with both conditions can reach maximal motor disability within 4 weeks.9 A history of antecedent illness, weakness of facial and respiratory muscles, pain, and autonomic dysfunction are all more common in AIDP.1,9
Pathogenesis. CIDP is an autoimmune disorder in which the inflammatory process is mediated by both the cellular and humoral immune systems.1,2 Demyelination is segmental and occurs anywhere from the nerve roots to the distal portion of nerves. In addition to demyelination, sural nerve biopsy reveals inflammatory infiltrates and subperineural edema. Chronic disease may be associated with "onion bulb" formation, due to concentric proliferation of Schwann cells in the course of repeated demyelination and remyelination.1,2,6,11 Axonal loss is variably observed, and may correlate with a more severe prognosis.2
Diagnostic studies. There are three basic diagnostic studies that help support the diagnosis of CIDP. NCS/EMG provide the most data, and can also provide information about the severity of the disease. Lumbar puncture and spine MRI can provide supportive evidence. Laboratory studies can help exclude other causes of neuropathy.
NCS/EMG in patients with CIDP show evidence of a predominantly demyelinating polyneuropathy, typically in a segmental, or nonuniform pattern (figure 1). Some axonal loss may be present. Demyelinating features include diminished motor and sensory conduction velocities, prolonged distal latencies, and prolonged or absent F waves. Nonuniform features include abnormal temporal dispersion, conduction block, and disparities in nerve conduction slowing between nerves or within a nerve.1,2,6,9
CSF analysis in children with CIDP commonly reveals albuminocytologic dissociation, defined as a protein greater than 35 mg/dL and white blood cell count less than 10 per mm3, similar to that seen in AIDP.1,2 If there is a significant pleocytosis in the CSF, other conditions should be considered. In two recent case series the mean CSF protein ranged from 194–197 mg/dL.8,9 However, not all children with CIDP have an elevated CSF protein, and albuminocytologic dissociation is not specific to AIDP or CIDP, although it provides important supportive information.1
As observed in AIDP, patients with CIDP may demonstrate enhancement of nerve roots on spine MRI. This enhancement likely relates to disruption of the blood–brain barrier due to the inflammatory process.1,8
Adults with CIDP may have identifiable serum autoantibodies (e.g., anti-GM1, anti-MAG, anti-sulfatide), but these have not been observed in children and are thus not commonly tested.2 Sural nerve biopsy is also no longer routinely performed for the diagnosis of CIDP in children.1
|
CLINICAL CASE, PART III |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
Four months later he had the first of two relapses of his symptoms. He was again treated with IVIg 2 g/kg over 2 days. He had no improvement in his symptoms, so 1 month later he began oral prednisone 1 mg/kg/day and monthly IVIg infusions of 2 g/kg, with full recovery after 3 weeks. He later relapsed in the setting of adenoviral pneumonia, and this was treated successfully with an increase in his prednisone dose and IVIg. After recovery the prednisone was weaned to an every other day regimen, and he continues on monthly IVIg. He has no residual symptoms and is back to playing soccer.
Treatment. Immunomodulatory therapy is the mainstay of treatment for CIDP. Our approach to therapy is derived from 1) large adult studies, 2) small case series in children, and 3) our own personal experience with a number of such pediatric CIDP patients. One difference in our approach to pediatric CIDP compared to adults is a higher threshold for the use of steroids.
IVIg is more of a first-line therapy for CIDP in children compared to adults. While there have been no randomized controlled trials in children, several case series have indicated that a large proportion of pediatric patients with CIDP show clinical improvement after treatment with IVIg.8,10,11 Our personal experience with several patients correlates with these findings. The initial dose is 2 g/kg divided over 2 to 5 days, and most patients require maintenance therapy of 1 g/kg/day for 1 to 2 days every 1 to 6 weeks.11 Drawbacks to the use of IVIg include cost; the need for IV placement; infusion-related side effects such as headache, nausea, rash, fever, chills, and hypotension; risk of infectious exposure; aseptic meningitis; anaphylaxis in IgA deficient individuals when non-IgA depleted IVIg is used; hemolytic anemia; and thromboembolism.
Plasmapheresis is a reasonable alternative in older children, especially those whose peripheral veins are accessible for large-bore IV lines. In adults, plasmapheresis appears to be of equivalent efficacy to IVIg.2,6 Plasmapheresis may need to be administered more frequently than IVIg, although this has not been clearly established across series.4 Risks of the treatment include coagulopathy, electrolyte abnormalities, hypotension, and anemia in those treated chronically.
Prednisone was the first agent identified as an effective treatment for CIDP in adults.1,10 A large proportion of children in several case series responded favorably to prednisone, usually within several weeks.2–4,6,8,10 Recent studies in children have recommended initiating treatment with prednisone at a dose of 1–2 mg/kg daily or on alternate days, followed by a gradual wean as symptoms improve.7,10 The side effects of steroids in children must be taken into consideration, such as weight gain, hypertension, hyperglycemia, cataracts, osteopenia, poor wound healing, infection, and growth suppression. The medical and cosmetic complications of steroid therapy have more substantial long-term consequences in children than in adults, thus we prefer not to use them unless the alternatives are not efficacious or tolerated.
There are little data regarding other options for treatment of children with refractory CIDP. Other immunomodulatory agents such as azathioprine, methotrexate, cyclosporine, cyclophosphamide, and interferon have been used, but at present there are no clear data favoring one of these treatments over another.4,6,8
Prognosis. Children with CIDP have a more favorable outcome than adults, with complete remission or minimal residual weakness seen in the majority of patients.3,4,7,8,10 In adults, the relapsing form has a better prognosis than the monophasic form of CIDP, and children are more likely to present with the relapsing form of the disease.7,10 In children, the number of relapses does not seem to be associated with the severity of prognosis. However, few studies have followed children to adulthood. In one series most children required treatment for at least 1 to 2 years, although in many cases treatment could ultimately be discontinued.10 Relapses often occur in the setting of intercurrent illness or weaning of immunomodulatory medication.4,8,10 Most of these relapses occur within the first 2 years after diagnosis, although patients have relapsed after 7–10 years.8,10
|
FUTURE PERSPECTIVES |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
Further research is needed to evaluate the efficacy of different therapies in the pediatric CIDP population, including randomized controlled trials with a sufficient number of patients. The formation of a multicenter consortium could help to pool the experience of different hospitals and enable a large group of patients to be followed over time.
Disclosure: The authors report no disclosures.
|
REFERENCES |
|---|
|
Top.Abstract.CLINICAL CASE, PART ICLINICAL CASE, PART IIDISCUSSIONCLINICAL CASE, PART IIIFUTURE PERSPECTIVESREFERENCES |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
