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Evolution and Treatment of Childhood Chronic Inflammatory Polyneuropathy
Evolution and Treatment of Childhood Chronic Inflammatory Polyneuropathy Elsa Rossignol, MD*, Guy D’Anjou, MD*, Normand Lapointe, MD, MSC†, Elie Haddad, MD, PhD*, and Michel Vanasse, MD* Chronic inflammatory demyelinating polyneuropathy is a rare disease in pediatric patients. The disease usually responds well to standard therapies including immunoglobulins, corticosteroids, and plasmapheresis. However, a minority of cases appear refractory to standard treatments. This report presents the evolution of 13 patients with chronic inflammatory demyelinating polyneuropathy monitored in our pediatric neurology clinic between 1975 and 2005, including two recent patients with refractory diseases. The literature regarding treatment of refractory cases in adults and children is also reviewed. © 2007 by Elsevier Inc. All rights reserved. Rossignol E, D’Anjou G, Lapointe N, Haddad E, Vanasse M. Evolution and treatment of childhood chronic inflammatory polyneuropathy. Pediatr Neurol 2007;36:88-94.
Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) represents a group of acquired polyneuropathies characterized by progressive symmetrical proximal weakness and hyporeflexia or areflexia evolving over a minimum of 2 months. Muscle weakness is occasionally associated with paresthesias or ataxia. The presentation may be subacute or insidious, and the evolution monophasic progressive or polyphasic with remissions and recurrences. Electrodiagnostic studies and laboratory investigations reveal evidence of demyelination, inflammation, and proteinorachia. The pathophysiology of chronic inflammatory demyelinating polyneuropathy is not fully understood, but seems to be immune-mediated through a variety of humoral and cellular autoimmune mechanisms [1,2]. In this context, the
From *Services de neurologie et †d’immunologie, Département de pédiatrie, Centre hospitalier universitaire Sainte-Justine, Montréal, Québec, Canada.
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standard treatments recommended are immune-modulators and include intravenous immunoglobulins, prednisone, and plasmapheresis. The initial response is usually satisfactory, but repeated treatments are often required. In addition, many patients have been considered refractory to conventional therapies and require a variety of other immune-suppressant drugs. However, there are no published guidelines to help clinicians in treating refractory cases. Two recent chronic inflammatory demyelinating polyneuropathy cases monitored in our pediatric neurology clinic were refractory to conventional therapies. This prompted us to review the charts of all patients diagnosed with chronic inflammatory demyelinating polyneuropathy since 1975 in the pediatric neurology clinic, in order to evaluate the usual clinical course, treatment response, and outcome. In addition, the current literature regarding treatments in adult and pediatric patients was reviewed, with particular attention to management of refractory cases. Patients and Methods Patients and Diagnostic Criteria The charts of all the patients diagnosed with chronic inflammatory demyelinating polyneuropathy at the neuropediatric clinics of the Centre hospitalier universitaire Ste-Justine (Montreal) between 1975 and 2005 were reviewed retrospectively. Diagnostic criteria for chronic inflammatory demyelinating polyneuropathy have been published by the American Association of Neurology in 1991. These criteria have been revised for the clinical diagnosis of chronic inflammatory demyelinating polyneuropathy in children by the members of the 88th European Neuromuscular Center International Workshop in 2000 [3], as summarized in Appendix 1. With these new criteria, diagnosis is confirmed if both electrodiagnostic studies and lumbar puncture findings are compatible with the disease. Nerve biopsy is no longer considered mandatory for diagnosis in
Communications should be addressed to: Dr. Vanasse; Service de neurologie; 5ème Bloc 4; Centre hospitalier universitaire Ste-Justine; 3175 Côte Ste-Catherine; Montréal, Québec, Canada H3T 1C5. E-mail: [email protected] Received May 28, 2006; accepted September 20, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.09.012 ● 0887-8994/07/$—see front matter
children. The diagnosis of chronic inflammatory demyelinating polyneuropathy was confirmed in all of our patients in accordance with the revised diagnostic criteria of the European Neuromuscular Center. All patients had a clinical history of progressive weakness and hyporeflexia of more than 4 weeks duration, or a protracted course with relapses over more than a year. Diagnosis was supported by evidence of demyelination upon electrophysiologic studies, including general slowing of conduction velocities (⬍75% normal for age), conduction block or dispersion of the compound muscle action potential, prolonged distal latencies, or prolonged or absent F-waves. In addition, when obtained, an increased cerebrospinal fluid protein count ⬎35 mg/dL (with leukocytes ⬍10/mL) or sural nerve biopsy presenting pathologic evidence of segmental demyelination supported the diagnosis. Patients with evidence of hereditary neuropathies or underlying medical conditions (e.g., neoplasias, metabolic diseases) were excluded.
Clinical Evaluation of Outcome The date of diagnosis was defined as the time when the abovementioned diagnostic criteria were fulfilled. The duration of follow-up consisted of the time period between the date of diagnosis and the date of the last medical visit. Patients were monitored in the neurology clinic, and their functional status was evaluated using the modified Rankin score [4]: 0: Asymptomatic. 1: Minimal symptoms, not disabling and not interfering with lifestyle. 2: Minor disability symptoms causing some restriction of lifestyle, but with unimpaired autonomy 3: Moderately disabling symptoms that significantly interfere with lifestyle or prevent totally independent existence. 4: Moderately disabling symptoms that clearly prevent independent existence, without need for constant attention. 5: Severely disabling symptoms that require constant attention day and night. The evolution of patients was classified as either monophasic or relapsing (with at least two separate episodes of deterioration interspaced by a period of partial or complete remission of symptoms). Relapses and significant improvements were considered as sustained modifications of one point on the modified Rankin score. Patients were considered refractory to treatment when they required more than one treatment modality and presented frequent relapses (every 4-6 weeks).
Results Descriptive Data Thirteen patients fulfilling the European Neuromuscular Center criteria for chronic inflammatory demyelinating polyneuropathy were monitored in our pediatric neurology clinic between 1975 and 2005. Of these, 4 were females and 9 were males. Age at diagnosis varied between 3 and 14 years. Descriptive data on each patient are recorded in Table 1. Table 2 summarizes presentation, evolution, and outcome data for the entire cohort. Presentation and Evolution All patients presented with a history of symmetrical muscle weakness, mainly in the lower limbs, with frequent falls or difficulties in climbing stairs. However, one patient presented with asymmetrical upper limb weakness. Globally, symptoms had evolved over a period of 1 week to 1 year at the time of initial presentation, and diagnosis
was confirmed after at least 4 weeks of progressive symptoms or a relapsing course. Sensory symptoms, including hypoesthesia and painful paresthesias, were present in 54% (7/13) of the patients at diagnosis. Two patients had cranial nerve involvement at presentation, manifesting as diplopia. The symptoms were preceded by respiratory tract viral infections in 23% (3/13) in the weeks before diagnosis. The maximal level of disability, as estimated by the modified Rankin score using the data collected in medical charts at the time of diagnosis and during follow-up varied between 2 and 5, with two patients graded as 4 and two graded as 5. The diagnosis of chronic inflammatory demyelinating polyneuropathy was suggested by the clinical history of progression over more than 4 weeks, or a relapsing course in the following months, together with abnormalities compatible with demyelination on nerve conduction velocities studies and elevated protein content in otherwise sterile cerebrospinal fluid. Nerve biopsy was performed in five patients (38%) to confirm the diagnosis. It was considered noncontributory in one patient, but the other biopsies performed demonstrated inflammation and typical myelin abnormalities in the four other patients. The evolution of symptoms was polyphasic in 10 (77%) patients, with 1 to 10 relapses over a follow-up period of 6 months to 5 years.
Treatment As illustrated in Table 1, treatment varied over time. Patients treated before 1983 (Patients 1 to 5) and between 1990 and 2000 (Patients 7 and 8) received prednisone as first-line treatment. Those treated between 1983 and 1990 (Patients 6 and 7) received both prednisone and azathioprine at onset of disease. Since 2000, the initial treatment was intravenous immunoglobulins, at a standard dose of 2 gm/kg over 2 days, with gradual weaning of doses and spacing of treatments as symptoms resolved (Patients 9 to 12). However, Patient 13 was treated with prednisone alone because of parental concerns regarding the side effects of intravenous immunoglobulins. These treatments were combined, and adjuvant treatments were added when required by the clinical condition. Evolution and treatments of all patients are summarized in Table 1. Most patients evolved in a satisfactory manner. However, two patients remained with an elevated Rankin score at follow-up (Patients 2 and 4). Patient 2 responded well to prednisone initially and during her relapse 5 years later, but had persistent foot drops which left her with moderate disability (off treatment) at her last follow-up after 9 years. Patient 4 was known for spastic diplegia secondary to perinatal anoxia. He responded well to prednisone for 6 months and to a second 6-month treatment when he relapsed a year later. He required the addition of azathioprine during his last relapse. He remained off treatment but with moderate disability at his
Rossignol et al: Evolution of Pediatric CIDP 89
Table 1.
Clinical data on individual patients
Patient Dx 1 1975 2 1976 3 1977 4 1982 5 1982 6 1987 7 1990 8 1998 9 2000 10 2001 11 2002 12 2003 13 2005
Sex/Age
Presentation
M3
Weakness LL, pain, falls 1 week Pain, weakness LL, diplopia 1 week Weakness all limbs, paresthesias 3 months Weakness, paresthesias 2 years Weakness LL, paresthesias, diplopia 6 weeks Pain ⫹ weakness all limbs 8 weeks Weakness all limbs 6 weeks Weakness LL⬎UL 4 months Pain ⫹ weakness LL 1 week Weakness LL⬎UL 1½ years Weakness LL⬎UL 5 weeks Weakness, paresthesias. 2 weeks Weakness UL (R⬎L) 6 weeks
F6 F9 M4 F 14 M 13 M8 M 12 M6 M 10 F5 M 13 F 14
Abbreviations: Aza ⫽ Azathioprine Cyclopho ⫽ Cyclophosphamide Dx ⫽ Year of diagnosis IVIG ⫽ Intravenous immunoglobulin LL ⫽ Lower limbs M ⫽ Monophasic MM ⫽ Mycophenolate mofetil
MTX P Pred R tx UL
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Evolution (# events)
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P (3)
Pred
P (1)
Pred
P (3)
Pred, Aza
P (1)
Pred, Aza
M
Pred
P (1)
Pred, Aza
P (4) M
Pred, PE, IVIG Aza, Cyclopho Pred
P (3)
IVIG, Pred
P (10)
Pred, IVIG, Aza, MTX IVIG, Pred
P (4) P (6) M
IVIG, Pred, Aza, PE, MM Pred
Follow-up (Rankin Score) R (2) No tx 7yr R (3) No tx 9yr R (1) No tx 3yr R (3) No tx 3yr R (2) No tx 2yr R (1) No tx 1yr R (1) No tx R (0) No tx 6yr R (0) No tx 2yr R (2) on tx R (0) No tx 1yr R (1) ontx R (1) No tx 15mo
Methotrexate Polyphasic Prednisone Modified Rankin score Treatment Upper limbs
3-year follow-up (modified Rankin 3); this could be partly attributable to his underlying spastic diplegia. Patients 7, 10, and 12 were considered refractory to treatment, but Patient 7 was eventually weaned off medications. He had received prednisone and azathioprine initially to which he responded well, but symptoms recurred on weaning after 6 months. The same regimen was begun again for 6 months, and he relapsed again. He was then treated with plasmapheresis, followed by intravenous immunoglobulin and cyclophosphamide with good response. He eventually required an additional course of prednisone, but is now off medication and doing well. Patient 10 was initially treated with steroids with complete remission, but relapsed during weaning after a 4-month course. He was then treated with three courses of intravenous immunoglobulins without improvement. Prednisone was reinitiated (maximum dose of 70 mg/day) together with azathioprine. The patient developed elevated liver enzymes after 7 months, and azathioprine was discontinued. He was then treated with pulse dexamethasone (4 consecutive days every month) and intravenous immunoglobulins at monthly intervals, but still relapsed every month. Methotrexate was added after another 6 months. Because this patient lives in a remote area, it was not feasible to
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Tx
administer regular intravenous immunoglobulins or plasmapheresis at shorter intervals. It was decided to administer pulse therapy with high-dose prednisone (10 mg/kg/ day) only on weekend days. The patient is now stable with this treatment, with minimal disabilities (modified Rankin 2), but with significant side effects of the steroids, including obesity and hypertension. Patient 12 responded well initially to intravenous immunoglobulins, but required repeated treatments at 2- to 5-week intervals, and eventually required addition of prednisone and azathioprine for frequent relapses. His relapses remained frequent, and his therapy was changed to regular plasmapheresis (once or twice a week) and mycophenolate mofetil, with partial response. Anti-CD20 treatment was then added in exchange for mycophenolate, and the patient remains functional but with recurrent relapses (modified Rankin 1 between episodes). Summary Eleven of the 13 (85%) patients presented with acute or subacute bilateral symmetrical weakness. The majority (77%) had a polyphasic course with 1 to 10 relapses, and 54% initially presented sensory symptoms. Those treated
Table 2. Summarized data on presentation, evolution, and outcome Number of Patients (%) (n ⴝ 13) Demographics Sex Female Male Median age at onset Presentation Acute or subacute (4 months) Weakness legs Sensory symptoms Cranial nerve involvement Preceding viral infection Evolution Polyphasic Median number of relapses Maximal Rankin score Outcome at last follow-up Rankin score
4 (31%) 9 (69%) 9 years
Range
3-14 years
11 (85%) 12 (92%) 7 (54%) 2 (15%) 3 (23%)
10 (77%) 3
1-10
3
2-5
1
0-3
before 2000 were first administered prednisone with good response. Most required reinitiating prednisone when they relapsed, and some required additional medications such as azathioprine or cyclophosphamide. Three of the four patients treated after 2000 were administered intravenous immunoglobulins with an excellent initial response. However, all three required repeat treatment for relapses, and multiple add-on agents were necessary for two of these patients. The other patient responded well to prednisone alone, with no relapse after 18 months of follow-up. Two patients currently monitored in our clinic (Patients 10 and 12) are considered refractory. However, their functional level is quite good between relapses (modified Rankin 1 and 2). Discussion Chronic inflammatory demyelinating polyneuropathy is a rare condition in children; its prevalence has been estimated to be 0.48 in 100,000 children [5] compared with 1-1.9/100 000 adults [6,7]. The clinical presentation and evolution varies considerably between children and adults. In adults, the onset is most often insidious (63-84%) rather than subacute (16-27%). Patients usually present with distal or generalized weakness and sensory symptoms (⬎75%), but pure motor and pure sensory-ataxic forms have been described. Rare cases with central nervous system or cranial nerve involvement have been reported. Evolution is generally monophasic progressive (70-88%) with a minority of cases (12-47%) being polyphasic and recurrent. A subclass of patients has been
recognized as having underlying medical conditions such as paraproteinemias/gammopathies, neoplasias, autoimmune conditions, and chronic infections [8-13]. In contrast, children most often present with subacute symptoms of bilateral symmetrical lower limb weakness. The disease most often takes a polyphasic form with remissions and relapses (60-80%), and only rarely evolves as a chronic progressive condition. Sensory symptoms such as paresthesias are less frequent (30-50% of cases) [3,4,11,14-16]. The atypical forms are quite rare: one patient described in the literature presented with predominant cranial nerve involvement [17]. Another presented with central nervous system demyelinating lesions as well as peripheral demyelination [18]. There are no reported cases of an underlying medical condition in children with chronic inflammatory demyelinating polyneuropathy; however, one patient monitored in our hospital presented a chronic inflammatory demyelinating polyneuropathy–like picture in the context of an underlying lymphoma (not included in this report). The patients described in this series closely resemble the pediatric patients reported in the literature. Most presented with a subacute or acute condition (69%). All had bilateral, symmetrical limb weakness. Sensory symptoms were described in 54% of patients at presentation. Most developed a polyphasic disease (77%) with one to six relapses over a few months up to 5 years. The underlying mechanisms of chronic inflammatory demyelinating polyneuropathy pathogenesis have not been fully explained yet. However, an autoimmune process seems likely, as a number of autoantibodies have been reported in animal models and in chronic inflammatory demyelinating polyneuropathy patients, including antigangliosides, antisulfatides, antiSchwann cells, antibetatubulin, and antiprotein 22 peptide (present in 41% of adult patients with chronic inflammatory demyelinating polyneuropathy) [1]. In addition, cellular autoimmune mechanisms are likely involved as CD4 and CD8 lymphocytes are found in nerve biopsies. This autoimmune hypothesis has influenced treatment modalities for chronic inflammatory demyelinating polyneuropathy. The standard treatments recognized for chronic inflammatory demyelinating polyneuropathy consist of intravenous immunoglobulins, prednisone, and plasmapheresis, used alone or in combination. Corticosteroids are usually administered at 1-2 mg/kg/day daily or on alternate days, with gradual weaning when symptoms have stabilized. Intravenous immunoglobulins are administered at 1-2 mg/kg on a 2- or 5-day treatment, and repeated every 3-6 weeks. Plasmapheresis is performed for 3-5 treatments over 1 to 2 weeks. It is now widely accepted that intravenous immunoglobulins, prednisone, and plasmapheresis have similar efficacy, as documented by a recent Cochrane review in 2002 (CD001797). The response rates in the adult population vary between 65-70% [10-13] compared with 80100% initial response rates in children [3,4,11,15-17]. However, repeated treatments are often required in chil-
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dren as the polyphasic form of chronic inflammatory demyelinating polyneuropathy is more frequently encountered. The initial treatment is often chosen on the basis of its cost, availability, and side effects. Intravenous immunoglobulins have less side effect than corticosteroids and are less invasive and more accessible than plasmapheresis. They are used safely in children with a variety of other autoimmune disorders, including Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, and Kawasaki’s disease. Minor side effects, such as rash, fever, chills, and headaches may be minimized by slowing the infusion rate and using anti-inflammatory premedication. Serious side effects including thromboembolic events, aseptic meningitis, and allergic reactions occur in less than 5% of infusions. A concern remains regarding the potential infectious risks of intravenous immunoglobulins. Furthermore, intravenous immunoglobulins are costly and may not be available worldwide. Side effects of chronic therapy with corticosteroids include weight gain, hypertension, capillary fragility, susceptibility to infections, cataracts, osteopenia, and altered growth. These side effects may be minimized by administering the medication on an alternate day basis or in pulse treatments [19,20]. Improvement was reported in 7 of 10 chronic inflammatory demyelinating polyneuropathy cases treated with high-dose dexamethasone pulse therapy (10 mg/kg/day on four consecutive days every 28 days) [21]. Plasmapheresis is less often used in children because it requires the installation of central catheters, with potential infectious and thrombotic complications, as well as hemodynamic complications of the treatment itself. All of our patients received prednisone at some point in their treatment, and three received intravenous immunoglobulins as initial therapy. All responded well initially, but required retreatment or additional therapies for recurrences. Standard treatments are occasionally insufficient. Reported refractory adult cases have been treated by combining standard treatments with different immune-modulating drugs, including azathioprine, cyclophosphamide, cyclosporin A, mycophenolate mofetil, methotrexate, interferon alpha and beta-1a, rituximab, and tacrolimus. Results have been quite variable as reported by different case series and retrospective studies. A recent Cochrane review (2003; CD003280) stated that evidence published to date is insufficient to preferentially recommend one of these treatments. Mycophenolate mofetil appears to have less side effect than other immunosuppressive drugs, and some authors have advocated its use in chronic inflammatory demyelinating polyneuropathy. However, a recent study reported significant improvement in only 3 of the 13 patients with chronic inflammatory demyelinating polyneuropathy treated with this medication [22]. Anti-CD20 medications such as rituximab seem promising in chronic inflammatory demyelinating polyneuropathy, particularly when associated with paraproteinemia. These medications
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target CD20 membrane antigen expressed on pre-B cells and resting and activated mature B-cells, and induce a deep and long-lasting B-cell depletion. They have been beneficial in two adult cases of refractory chronic inflammatory demyelinating polyneuropathy [23,24]. Only a minority of studies report treatment outcomes with immune-modulating drugs in childhood chronic inflammatory demyelinating polyneuropathy. Treatments used include azathioprine, cyclophosphamide, cyclosporine, and methotrexate. In one pediatric study, corticosteroid-resistant patients were placed on azathioprine and 69% (6/9) had a favorable response [16]. In the present group of patients, 38% (5/13) received azathioprine in the course of their treatment. Four had a favorable response, but one relapsed on the medication after an initial improvement. In one patient, the medication was discontinued owing to elevated liver enzymes. Overall, children seem to evolve more favorably with complete remission or minimal residual weakness in 70-100% cases. In comparison, adults exhibit moderate to severe sequelae in 30-40% of cases. These data are consistent with the ones reported in our series as 85% (11/13) had no or minimal symptoms at last follow-up (modified Rankin 0-2). Two (15%) of the patients in the present study had moderate disabilities (modified Rankin 3), but one had a spastic diplegia attributable to perinatal anoxia, which made assessment of his functional status more difficult. None of our patients had severe disability at the end of follow-up. We are currently treating two refractory cases (Patients 10 and 12), who still require repeated treatments on a regular basis, but their functional status remains good in between relapses (modified Rankin 1-2). The modified Rankin score used in this study to assess clinical outcome at follow-up is a simple graded scale that enabled us to compare global functional status at peak of symptoms and at follow-up. However, prospective studies designed to assess outcome after specific treatments should include a more refined motor scale such as the Medical Research Council scale, as well as functional evaluations including timed tasks (timed six-meter walk or timed four-steps climbing) as was done for other pediatric neuromuscular conditions [25]. Conclusion Chronic inflammatory demyelinating polyneuropathy is a rare condition in the pediatric age-group. It presents somewhat differently in children, with more subacute and acute onset and numerous relapses, compared with the more chronic indolent course of adult chronic inflammatory demyelinating polyneuropathy. Its evolution is usually favorable in children, with 80-100% response to standard treatments—steroids, intravenous immunoglobulins, and plasmapheresis—and excellent outcome with complete functional recovery in most patients. However, cases refractory to intravenous immunoglobulins and cor-
ticosteroids do exist in pediatric patients, and additional treatments must be used. No specific recommendations may be made at this point regarding the choice of an adjunctive immunosuppressive treatment, as safety and efficacy data are still insufficient. We have had good responses to azathioprine and high-dose pulses of corticosteroids, and these treatments could be tried in treatmentresistant cases. We would like to emphasize the importance of initiating treatment as early as possible in order to minimize demyelination and secondary axonal damage. In addition, neurotoxic drugs and infections must be avoided when possible. Appendix 1: European Neuromuscular Center Diagnostic Criteria Revised for Childhood Chronic Inflammatory Demyelinating Polyneuropathy (Data from [3]) Mandatory clinical criteria: 1) Progressive generalized limb weakness over a minimum of 4 weeks OR rapid progression (Guillain-Barré syndrome–like) followed by relapsing or protracted course over more than a year. 2) Areflexia or hyporeflexia. Major laboratory features: A) Major electrophysiological criteria*: 1) Conduction block (drop of 50% of proximal compound muscle action potential amplitude, if duration of proximal compound muscle action potential is ⬍130% of distal compound muscle action potential) or temporal dispersion (duration of proximal compound muscle action potential is ⬎130% of distal compound muscle action potential) in one or more motor nerves (not compression sites). 2) Reduced conduction velocity in 2 or more nerves (⬍75% of the mean – 2 S.D. conduction velocity adjusted for age). 3) Prolonged distal latency in 2 or more nerves (⬎130% of the mean distal latency ⫹ 2 S.D. adjusted for age). 4) Absent F wave or prolonged F wave latency in 2 or more nerves (⬎130% of the mean minimal latency ⫹2 S.D. adjusted for age) with a minimum of 2 trials for F waves. B) Supportive electrophysiologic features when no conduction block is demonstrated: 1) Abnormal median sensory nerve action potential with normal sural sensory nerve action potential 2) Abnormal minimal latency index 3) Difference ⬎10 m/second in motor conduction velocities between upper and lower limbs. *Require 3 of 4 major electrophysiologic criteria or 2 major and 2 supportive criteria.
C) Cerebrospinal fluid 1) Protein count ⬎35 mg/dL 2) Cell count ⬍10 cells/mm3 D) Nerve biopsy features: Predominant features of demyelination Exclusion criteria: 1) No features of hereditary neuropathy, other underlying systemic disease, or exposure to drugs or toxins known to cause peripheral neuropathy. 2) Laboratory features ( nerve biopsy or molecular study) compatible with another diagnosis. 3) Electrophysiologic evidence of abnormal neurotransmission, myopathy, or anterior horn cell disease. Diagnostic criteria: 1) Confirmed chronic inflammatory demyelinating polyneuropathy: mandatory clinical features ⫹ electrodiagnostic and cerebrospinal fluid features. 2) Possible chronic inflammatory demyelinating polyneuropathy: mandatory clinical features ⫹ one of the three laboratory findings. We would like to thank the patients and families that have been monitored in our clinic over the last 20 years, and have provided us with sound knowledge of this particular disease.
References [1] Kieseier BC, Dalakas MC, Hartung H-P. Immune mechanisms in chronic inflammatory demyelinating neuropathy. Neurology 2002;59:S712. [2] Toyka KV, Gold R. The pathogenesis of CIDP: Rationale for treatment with immunomodulatory agents. Neurology 2003;60:S2-7. [3] Nevo Y, Topaloglu H. 88th ENMC International Workshop: Childhood chronic inflammatory demyelinating polyneuropathy (including revised diagnostic criteria), Naarden, The Netherlands, Dec 2000. Neuromusc Disord 2002;12:195-200. [4] Hattori N, Ichimura M, Aoki S, et al. Clinicopathological features of chronic inflammatory demyelinating polyradiculoneuropathy in childhood. J Neurol Sci 1998;154:66-71. [5] Connolly AM. Chronic inflammatory demyelinating polyneuropathy in childhood. Pediatr Neurol 2001;24:177-82. [6] Lunn MP, Manji H, Choudhary PP, Hughes RA, Thomas PK. Chronic inflammatory demyelinating polyradiculoneuropathy: A prevalence study in south east England. J Neurol Neurosurg Psychiatry 1999;66:677-80. [7] McLeod JG, Pollard JD, Macaskill P, Mohamed A, Spring P, Khurana V. Prevalence of chronic inflammatory demyelinating polyneuropathy in New South Wales, Australia. Ann Neurol 1999;46:910-3. [8] Busby M, Donaghy M. Chronic dysimmune neuropathy: A subclassification based upon the clinical features of 102 patients. J Neurol 2003;250:714-24. [9] Bouchard C, Lacroix C, Plante V, et al. Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy. Neurology 1999;52:498-503. [10] Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: Clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 1997;48:321-8.
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[11] Simmons Z, Wald JJ, Albers JW. Chronic inflammatory demyelinating polyradiculoneuropathy in children: II. Long-term follow-up, with comparison to adults. Muscle Nerve 1997;20:1569-75. [12] Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46:878-84. [13] McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain 1987;110:1617-30. [14] Ryan MM, Grattan-Smith PJ, Procopis PG, Morgan G, Ouvrier RA. Childhood chronic inflammatory demyelinating polyneuropathy: Clinical course and long-term outcome. Neuromusc Disord 2000;10:398406. [15] Korinthenberg R. Chronic inflammatory demyelinating polyradiculoneuropathy in children and their response to treatment. Neuropediatrics 1999;30:190-6. [16] Nevo Y, Pestronk A, Kornberg AJ, et al. Childhood chronic inflammatory demyelinating neuropathies: Clinical course and long-term follow-up. Neurology 1996;47:98-102. [17] Costello F, Lee AG, Affifi AK, Kelkar P, Kardon RH, White M. Childhood-onset chronic inflammatory demyelinating polyradiculoneuropathy with cranial nerve involvement. J Child Neurol 2002;17:819-23. [18] Rodriguez-Casero MV, Shield LK, Coleman LT, Kornberg AJ. Childhood chronic inflammatory demyelinating polyneuropathy with
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central nervous system demyelination resembling multiple sclerosis. Neuromusc Disord 2003;13:158-61. [19] Connolly AM, Schierbecker J, Renna R, Florence J. High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Neuromusc Disord 2002;12:917-25. [20] Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6:153-9. [21] Molenaar DS, van Doom PA, Vermeulen M. Pulsed high-dose dexamethasone treatment in chronic inflammatory demyelinating polyneuropathy: A pilot study. J Neurol Neurosurg Psychiatry 1997;62:38890. [22] Gorson KC, Amato AA, Ropper AH. Efficacy of mycophenolate mofetil in patients with chronic immune demyelinating polyneuropathy. Neurology 2004;63:715-7. [23] Briani C, Zara G, Zambello R, Trentin L, Rana M, Zaja F. Rituximab-responsive CIDP. Eur J Neurol 2004;11:788. [24] Knecht H, Baumerberger M, Tobon A, Streck A. Sustained remission of CIDP associated with Evans syndrome. Neurology 2004; 63:730-2. [25] Bonifati MD, Ruzza G, Bonometto P, et al. A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 2000;23:1344-7.
Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) represents a group of acquired polyneuropathies characterized by progressive symmetrical proximal weakness and hyporeflexia or areflexia evolving over a minimum of 2 months. Muscle weakness is occasionally associated with paresthesias or ataxia. The presentation may be subacute or insidious, and the evolution monophasic progressive or polyphasic with remissions and recurrences. Electrodiagnostic studies and laboratory investigations reveal evidence of demyelination, inflammation, and proteinorachia. The pathophysiology of chronic inflammatory demyelinating polyneuropathy is not fully understood, but seems to be immune-mediated through a variety of humoral and cellular autoimmune mechanisms [1,2]. In this context, the
From *Services de neurologie et †d’immunologie, Département de pédiatrie, Centre hospitalier universitaire Sainte-Justine, Montréal, Québec, Canada.
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standard treatments recommended are immune-modulators and include intravenous immunoglobulins, prednisone, and plasmapheresis. The initial response is usually satisfactory, but repeated treatments are often required. In addition, many patients have been considered refractory to conventional therapies and require a variety of other immune-suppressant drugs. However, there are no published guidelines to help clinicians in treating refractory cases. Two recent chronic inflammatory demyelinating polyneuropathy cases monitored in our pediatric neurology clinic were refractory to conventional therapies. This prompted us to review the charts of all patients diagnosed with chronic inflammatory demyelinating polyneuropathy since 1975 in the pediatric neurology clinic, in order to evaluate the usual clinical course, treatment response, and outcome. In addition, the current literature regarding treatments in adult and pediatric patients was reviewed, with particular attention to management of refractory cases. Patients and Methods Patients and Diagnostic Criteria The charts of all the patients diagnosed with chronic inflammatory demyelinating polyneuropathy at the neuropediatric clinics of the Centre hospitalier universitaire Ste-Justine (Montreal) between 1975 and 2005 were reviewed retrospectively. Diagnostic criteria for chronic inflammatory demyelinating polyneuropathy have been published by the American Association of Neurology in 1991. These criteria have been revised for the clinical diagnosis of chronic inflammatory demyelinating polyneuropathy in children by the members of the 88th European Neuromuscular Center International Workshop in 2000 [3], as summarized in Appendix 1. With these new criteria, diagnosis is confirmed if both electrodiagnostic studies and lumbar puncture findings are compatible with the disease. Nerve biopsy is no longer considered mandatory for diagnosis in
Communications should be addressed to: Dr. Vanasse; Service de neurologie; 5ème Bloc 4; Centre hospitalier universitaire Ste-Justine; 3175 Côte Ste-Catherine; Montréal, Québec, Canada H3T 1C5. E-mail: [email protected] Received May 28, 2006; accepted September 20, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.09.012 ● 0887-8994/07/$—see front matter
children. The diagnosis of chronic inflammatory demyelinating polyneuropathy was confirmed in all of our patients in accordance with the revised diagnostic criteria of the European Neuromuscular Center. All patients had a clinical history of progressive weakness and hyporeflexia of more than 4 weeks duration, or a protracted course with relapses over more than a year. Diagnosis was supported by evidence of demyelination upon electrophysiologic studies, including general slowing of conduction velocities (⬍75% normal for age), conduction block or dispersion of the compound muscle action potential, prolonged distal latencies, or prolonged or absent F-waves. In addition, when obtained, an increased cerebrospinal fluid protein count ⬎35 mg/dL (with leukocytes ⬍10/mL) or sural nerve biopsy presenting pathologic evidence of segmental demyelination supported the diagnosis. Patients with evidence of hereditary neuropathies or underlying medical conditions (e.g., neoplasias, metabolic diseases) were excluded.
Clinical Evaluation of Outcome The date of diagnosis was defined as the time when the abovementioned diagnostic criteria were fulfilled. The duration of follow-up consisted of the time period between the date of diagnosis and the date of the last medical visit. Patients were monitored in the neurology clinic, and their functional status was evaluated using the modified Rankin score [4]: 0: Asymptomatic. 1: Minimal symptoms, not disabling and not interfering with lifestyle. 2: Minor disability symptoms causing some restriction of lifestyle, but with unimpaired autonomy 3: Moderately disabling symptoms that significantly interfere with lifestyle or prevent totally independent existence. 4: Moderately disabling symptoms that clearly prevent independent existence, without need for constant attention. 5: Severely disabling symptoms that require constant attention day and night. The evolution of patients was classified as either monophasic or relapsing (with at least two separate episodes of deterioration interspaced by a period of partial or complete remission of symptoms). Relapses and significant improvements were considered as sustained modifications of one point on the modified Rankin score. Patients were considered refractory to treatment when they required more than one treatment modality and presented frequent relapses (every 4-6 weeks).
Results Descriptive Data Thirteen patients fulfilling the European Neuromuscular Center criteria for chronic inflammatory demyelinating polyneuropathy were monitored in our pediatric neurology clinic between 1975 and 2005. Of these, 4 were females and 9 were males. Age at diagnosis varied between 3 and 14 years. Descriptive data on each patient are recorded in Table 1. Table 2 summarizes presentation, evolution, and outcome data for the entire cohort. Presentation and Evolution All patients presented with a history of symmetrical muscle weakness, mainly in the lower limbs, with frequent falls or difficulties in climbing stairs. However, one patient presented with asymmetrical upper limb weakness. Globally, symptoms had evolved over a period of 1 week to 1 year at the time of initial presentation, and diagnosis
was confirmed after at least 4 weeks of progressive symptoms or a relapsing course. Sensory symptoms, including hypoesthesia and painful paresthesias, were present in 54% (7/13) of the patients at diagnosis. Two patients had cranial nerve involvement at presentation, manifesting as diplopia. The symptoms were preceded by respiratory tract viral infections in 23% (3/13) in the weeks before diagnosis. The maximal level of disability, as estimated by the modified Rankin score using the data collected in medical charts at the time of diagnosis and during follow-up varied between 2 and 5, with two patients graded as 4 and two graded as 5. The diagnosis of chronic inflammatory demyelinating polyneuropathy was suggested by the clinical history of progression over more than 4 weeks, or a relapsing course in the following months, together with abnormalities compatible with demyelination on nerve conduction velocities studies and elevated protein content in otherwise sterile cerebrospinal fluid. Nerve biopsy was performed in five patients (38%) to confirm the diagnosis. It was considered noncontributory in one patient, but the other biopsies performed demonstrated inflammation and typical myelin abnormalities in the four other patients. The evolution of symptoms was polyphasic in 10 (77%) patients, with 1 to 10 relapses over a follow-up period of 6 months to 5 years.
Treatment As illustrated in Table 1, treatment varied over time. Patients treated before 1983 (Patients 1 to 5) and between 1990 and 2000 (Patients 7 and 8) received prednisone as first-line treatment. Those treated between 1983 and 1990 (Patients 6 and 7) received both prednisone and azathioprine at onset of disease. Since 2000, the initial treatment was intravenous immunoglobulins, at a standard dose of 2 gm/kg over 2 days, with gradual weaning of doses and spacing of treatments as symptoms resolved (Patients 9 to 12). However, Patient 13 was treated with prednisone alone because of parental concerns regarding the side effects of intravenous immunoglobulins. These treatments were combined, and adjuvant treatments were added when required by the clinical condition. Evolution and treatments of all patients are summarized in Table 1. Most patients evolved in a satisfactory manner. However, two patients remained with an elevated Rankin score at follow-up (Patients 2 and 4). Patient 2 responded well to prednisone initially and during her relapse 5 years later, but had persistent foot drops which left her with moderate disability (off treatment) at her last follow-up after 9 years. Patient 4 was known for spastic diplegia secondary to perinatal anoxia. He responded well to prednisone for 6 months and to a second 6-month treatment when he relapsed a year later. He required the addition of azathioprine during his last relapse. He remained off treatment but with moderate disability at his
Rossignol et al: Evolution of Pediatric CIDP 89
Table 1.
Clinical data on individual patients
Patient Dx 1 1975 2 1976 3 1977 4 1982 5 1982 6 1987 7 1990 8 1998 9 2000 10 2001 11 2002 12 2003 13 2005
Sex/Age
Presentation
M3
Weakness LL, pain, falls 1 week Pain, weakness LL, diplopia 1 week Weakness all limbs, paresthesias 3 months Weakness, paresthesias 2 years Weakness LL, paresthesias, diplopia 6 weeks Pain ⫹ weakness all limbs 8 weeks Weakness all limbs 6 weeks Weakness LL⬎UL 4 months Pain ⫹ weakness LL 1 week Weakness LL⬎UL 1½ years Weakness LL⬎UL 5 weeks Weakness, paresthesias. 2 weeks Weakness UL (R⬎L) 6 weeks
F6 F9 M4 F 14 M 13 M8 M 12 M6 M 10 F5 M 13 F 14
Abbreviations: Aza ⫽ Azathioprine Cyclopho ⫽ Cyclophosphamide Dx ⫽ Year of diagnosis IVIG ⫽ Intravenous immunoglobulin LL ⫽ Lower limbs M ⫽ Monophasic MM ⫽ Mycophenolate mofetil
MTX P Pred R tx UL
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Evolution (# events)
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P (3)
Pred
P (1)
Pred
P (3)
Pred, Aza
P (1)
Pred, Aza
M
Pred
P (1)
Pred, Aza
P (4) M
Pred, PE, IVIG Aza, Cyclopho Pred
P (3)
IVIG, Pred
P (10)
Pred, IVIG, Aza, MTX IVIG, Pred
P (4) P (6) M
IVIG, Pred, Aza, PE, MM Pred
Follow-up (Rankin Score) R (2) No tx 7yr R (3) No tx 9yr R (1) No tx 3yr R (3) No tx 3yr R (2) No tx 2yr R (1) No tx 1yr R (1) No tx R (0) No tx 6yr R (0) No tx 2yr R (2) on tx R (0) No tx 1yr R (1) ontx R (1) No tx 15mo
Methotrexate Polyphasic Prednisone Modified Rankin score Treatment Upper limbs
3-year follow-up (modified Rankin 3); this could be partly attributable to his underlying spastic diplegia. Patients 7, 10, and 12 were considered refractory to treatment, but Patient 7 was eventually weaned off medications. He had received prednisone and azathioprine initially to which he responded well, but symptoms recurred on weaning after 6 months. The same regimen was begun again for 6 months, and he relapsed again. He was then treated with plasmapheresis, followed by intravenous immunoglobulin and cyclophosphamide with good response. He eventually required an additional course of prednisone, but is now off medication and doing well. Patient 10 was initially treated with steroids with complete remission, but relapsed during weaning after a 4-month course. He was then treated with three courses of intravenous immunoglobulins without improvement. Prednisone was reinitiated (maximum dose of 70 mg/day) together with azathioprine. The patient developed elevated liver enzymes after 7 months, and azathioprine was discontinued. He was then treated with pulse dexamethasone (4 consecutive days every month) and intravenous immunoglobulins at monthly intervals, but still relapsed every month. Methotrexate was added after another 6 months. Because this patient lives in a remote area, it was not feasible to
90
Tx
administer regular intravenous immunoglobulins or plasmapheresis at shorter intervals. It was decided to administer pulse therapy with high-dose prednisone (10 mg/kg/ day) only on weekend days. The patient is now stable with this treatment, with minimal disabilities (modified Rankin 2), but with significant side effects of the steroids, including obesity and hypertension. Patient 12 responded well initially to intravenous immunoglobulins, but required repeated treatments at 2- to 5-week intervals, and eventually required addition of prednisone and azathioprine for frequent relapses. His relapses remained frequent, and his therapy was changed to regular plasmapheresis (once or twice a week) and mycophenolate mofetil, with partial response. Anti-CD20 treatment was then added in exchange for mycophenolate, and the patient remains functional but with recurrent relapses (modified Rankin 1 between episodes). Summary Eleven of the 13 (85%) patients presented with acute or subacute bilateral symmetrical weakness. The majority (77%) had a polyphasic course with 1 to 10 relapses, and 54% initially presented sensory symptoms. Those treated
Table 2. Summarized data on presentation, evolution, and outcome Number of Patients (%) (n ⴝ 13) Demographics Sex Female Male Median age at onset Presentation Acute or subacute (4 months) Weakness legs Sensory symptoms Cranial nerve involvement Preceding viral infection Evolution Polyphasic Median number of relapses Maximal Rankin score Outcome at last follow-up Rankin score
4 (31%) 9 (69%) 9 years
Range
3-14 years
11 (85%) 12 (92%) 7 (54%) 2 (15%) 3 (23%)
10 (77%) 3
1-10
3
2-5
1
0-3
before 2000 were first administered prednisone with good response. Most required reinitiating prednisone when they relapsed, and some required additional medications such as azathioprine or cyclophosphamide. Three of the four patients treated after 2000 were administered intravenous immunoglobulins with an excellent initial response. However, all three required repeat treatment for relapses, and multiple add-on agents were necessary for two of these patients. The other patient responded well to prednisone alone, with no relapse after 18 months of follow-up. Two patients currently monitored in our clinic (Patients 10 and 12) are considered refractory. However, their functional level is quite good between relapses (modified Rankin 1 and 2). Discussion Chronic inflammatory demyelinating polyneuropathy is a rare condition in children; its prevalence has been estimated to be 0.48 in 100,000 children [5] compared with 1-1.9/100 000 adults [6,7]. The clinical presentation and evolution varies considerably between children and adults. In adults, the onset is most often insidious (63-84%) rather than subacute (16-27%). Patients usually present with distal or generalized weakness and sensory symptoms (⬎75%), but pure motor and pure sensory-ataxic forms have been described. Rare cases with central nervous system or cranial nerve involvement have been reported. Evolution is generally monophasic progressive (70-88%) with a minority of cases (12-47%) being polyphasic and recurrent. A subclass of patients has been
recognized as having underlying medical conditions such as paraproteinemias/gammopathies, neoplasias, autoimmune conditions, and chronic infections [8-13]. In contrast, children most often present with subacute symptoms of bilateral symmetrical lower limb weakness. The disease most often takes a polyphasic form with remissions and relapses (60-80%), and only rarely evolves as a chronic progressive condition. Sensory symptoms such as paresthesias are less frequent (30-50% of cases) [3,4,11,14-16]. The atypical forms are quite rare: one patient described in the literature presented with predominant cranial nerve involvement [17]. Another presented with central nervous system demyelinating lesions as well as peripheral demyelination [18]. There are no reported cases of an underlying medical condition in children with chronic inflammatory demyelinating polyneuropathy; however, one patient monitored in our hospital presented a chronic inflammatory demyelinating polyneuropathy–like picture in the context of an underlying lymphoma (not included in this report). The patients described in this series closely resemble the pediatric patients reported in the literature. Most presented with a subacute or acute condition (69%). All had bilateral, symmetrical limb weakness. Sensory symptoms were described in 54% of patients at presentation. Most developed a polyphasic disease (77%) with one to six relapses over a few months up to 5 years. The underlying mechanisms of chronic inflammatory demyelinating polyneuropathy pathogenesis have not been fully explained yet. However, an autoimmune process seems likely, as a number of autoantibodies have been reported in animal models and in chronic inflammatory demyelinating polyneuropathy patients, including antigangliosides, antisulfatides, antiSchwann cells, antibetatubulin, and antiprotein 22 peptide (present in 41% of adult patients with chronic inflammatory demyelinating polyneuropathy) [1]. In addition, cellular autoimmune mechanisms are likely involved as CD4 and CD8 lymphocytes are found in nerve biopsies. This autoimmune hypothesis has influenced treatment modalities for chronic inflammatory demyelinating polyneuropathy. The standard treatments recognized for chronic inflammatory demyelinating polyneuropathy consist of intravenous immunoglobulins, prednisone, and plasmapheresis, used alone or in combination. Corticosteroids are usually administered at 1-2 mg/kg/day daily or on alternate days, with gradual weaning when symptoms have stabilized. Intravenous immunoglobulins are administered at 1-2 mg/kg on a 2- or 5-day treatment, and repeated every 3-6 weeks. Plasmapheresis is performed for 3-5 treatments over 1 to 2 weeks. It is now widely accepted that intravenous immunoglobulins, prednisone, and plasmapheresis have similar efficacy, as documented by a recent Cochrane review in 2002 (CD001797). The response rates in the adult population vary between 65-70% [10-13] compared with 80100% initial response rates in children [3,4,11,15-17]. However, repeated treatments are often required in chil-
Rossignol et al: Evolution of Pediatric CIDP 91
dren as the polyphasic form of chronic inflammatory demyelinating polyneuropathy is more frequently encountered. The initial treatment is often chosen on the basis of its cost, availability, and side effects. Intravenous immunoglobulins have less side effect than corticosteroids and are less invasive and more accessible than plasmapheresis. They are used safely in children with a variety of other autoimmune disorders, including Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, and Kawasaki’s disease. Minor side effects, such as rash, fever, chills, and headaches may be minimized by slowing the infusion rate and using anti-inflammatory premedication. Serious side effects including thromboembolic events, aseptic meningitis, and allergic reactions occur in less than 5% of infusions. A concern remains regarding the potential infectious risks of intravenous immunoglobulins. Furthermore, intravenous immunoglobulins are costly and may not be available worldwide. Side effects of chronic therapy with corticosteroids include weight gain, hypertension, capillary fragility, susceptibility to infections, cataracts, osteopenia, and altered growth. These side effects may be minimized by administering the medication on an alternate day basis or in pulse treatments [19,20]. Improvement was reported in 7 of 10 chronic inflammatory demyelinating polyneuropathy cases treated with high-dose dexamethasone pulse therapy (10 mg/kg/day on four consecutive days every 28 days) [21]. Plasmapheresis is less often used in children because it requires the installation of central catheters, with potential infectious and thrombotic complications, as well as hemodynamic complications of the treatment itself. All of our patients received prednisone at some point in their treatment, and three received intravenous immunoglobulins as initial therapy. All responded well initially, but required retreatment or additional therapies for recurrences. Standard treatments are occasionally insufficient. Reported refractory adult cases have been treated by combining standard treatments with different immune-modulating drugs, including azathioprine, cyclophosphamide, cyclosporin A, mycophenolate mofetil, methotrexate, interferon alpha and beta-1a, rituximab, and tacrolimus. Results have been quite variable as reported by different case series and retrospective studies. A recent Cochrane review (2003; CD003280) stated that evidence published to date is insufficient to preferentially recommend one of these treatments. Mycophenolate mofetil appears to have less side effect than other immunosuppressive drugs, and some authors have advocated its use in chronic inflammatory demyelinating polyneuropathy. However, a recent study reported significant improvement in only 3 of the 13 patients with chronic inflammatory demyelinating polyneuropathy treated with this medication [22]. Anti-CD20 medications such as rituximab seem promising in chronic inflammatory demyelinating polyneuropathy, particularly when associated with paraproteinemia. These medications
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target CD20 membrane antigen expressed on pre-B cells and resting and activated mature B-cells, and induce a deep and long-lasting B-cell depletion. They have been beneficial in two adult cases of refractory chronic inflammatory demyelinating polyneuropathy [23,24]. Only a minority of studies report treatment outcomes with immune-modulating drugs in childhood chronic inflammatory demyelinating polyneuropathy. Treatments used include azathioprine, cyclophosphamide, cyclosporine, and methotrexate. In one pediatric study, corticosteroid-resistant patients were placed on azathioprine and 69% (6/9) had a favorable response [16]. In the present group of patients, 38% (5/13) received azathioprine in the course of their treatment. Four had a favorable response, but one relapsed on the medication after an initial improvement. In one patient, the medication was discontinued owing to elevated liver enzymes. Overall, children seem to evolve more favorably with complete remission or minimal residual weakness in 70-100% cases. In comparison, adults exhibit moderate to severe sequelae in 30-40% of cases. These data are consistent with the ones reported in our series as 85% (11/13) had no or minimal symptoms at last follow-up (modified Rankin 0-2). Two (15%) of the patients in the present study had moderate disabilities (modified Rankin 3), but one had a spastic diplegia attributable to perinatal anoxia, which made assessment of his functional status more difficult. None of our patients had severe disability at the end of follow-up. We are currently treating two refractory cases (Patients 10 and 12), who still require repeated treatments on a regular basis, but their functional status remains good in between relapses (modified Rankin 1-2). The modified Rankin score used in this study to assess clinical outcome at follow-up is a simple graded scale that enabled us to compare global functional status at peak of symptoms and at follow-up. However, prospective studies designed to assess outcome after specific treatments should include a more refined motor scale such as the Medical Research Council scale, as well as functional evaluations including timed tasks (timed six-meter walk or timed four-steps climbing) as was done for other pediatric neuromuscular conditions [25]. Conclusion Chronic inflammatory demyelinating polyneuropathy is a rare condition in the pediatric age-group. It presents somewhat differently in children, with more subacute and acute onset and numerous relapses, compared with the more chronic indolent course of adult chronic inflammatory demyelinating polyneuropathy. Its evolution is usually favorable in children, with 80-100% response to standard treatments—steroids, intravenous immunoglobulins, and plasmapheresis—and excellent outcome with complete functional recovery in most patients. However, cases refractory to intravenous immunoglobulins and cor-
ticosteroids do exist in pediatric patients, and additional treatments must be used. No specific recommendations may be made at this point regarding the choice of an adjunctive immunosuppressive treatment, as safety and efficacy data are still insufficient. We have had good responses to azathioprine and high-dose pulses of corticosteroids, and these treatments could be tried in treatmentresistant cases. We would like to emphasize the importance of initiating treatment as early as possible in order to minimize demyelination and secondary axonal damage. In addition, neurotoxic drugs and infections must be avoided when possible. Appendix 1: European Neuromuscular Center Diagnostic Criteria Revised for Childhood Chronic Inflammatory Demyelinating Polyneuropathy (Data from [3]) Mandatory clinical criteria: 1) Progressive generalized limb weakness over a minimum of 4 weeks OR rapid progression (Guillain-Barré syndrome–like) followed by relapsing or protracted course over more than a year. 2) Areflexia or hyporeflexia. Major laboratory features: A) Major electrophysiological criteria*: 1) Conduction block (drop of 50% of proximal compound muscle action potential amplitude, if duration of proximal compound muscle action potential is ⬍130% of distal compound muscle action potential) or temporal dispersion (duration of proximal compound muscle action potential is ⬎130% of distal compound muscle action potential) in one or more motor nerves (not compression sites). 2) Reduced conduction velocity in 2 or more nerves (⬍75% of the mean – 2 S.D. conduction velocity adjusted for age). 3) Prolonged distal latency in 2 or more nerves (⬎130% of the mean distal latency ⫹ 2 S.D. adjusted for age). 4) Absent F wave or prolonged F wave latency in 2 or more nerves (⬎130% of the mean minimal latency ⫹2 S.D. adjusted for age) with a minimum of 2 trials for F waves. B) Supportive electrophysiologic features when no conduction block is demonstrated: 1) Abnormal median sensory nerve action potential with normal sural sensory nerve action potential 2) Abnormal minimal latency index 3) Difference ⬎10 m/second in motor conduction velocities between upper and lower limbs. *Require 3 of 4 major electrophysiologic criteria or 2 major and 2 supportive criteria.
C) Cerebrospinal fluid 1) Protein count ⬎35 mg/dL 2) Cell count ⬍10 cells/mm3 D) Nerve biopsy features: Predominant features of demyelination Exclusion criteria: 1) No features of hereditary neuropathy, other underlying systemic disease, or exposure to drugs or toxins known to cause peripheral neuropathy. 2) Laboratory features ( nerve biopsy or molecular study) compatible with another diagnosis. 3) Electrophysiologic evidence of abnormal neurotransmission, myopathy, or anterior horn cell disease. Diagnostic criteria: 1) Confirmed chronic inflammatory demyelinating polyneuropathy: mandatory clinical features ⫹ electrodiagnostic and cerebrospinal fluid features. 2) Possible chronic inflammatory demyelinating polyneuropathy: mandatory clinical features ⫹ one of the three laboratory findings. We would like to thank the patients and families that have been monitored in our clinic over the last 20 years, and have provided us with sound knowledge of this particular disease.
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