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Long-term follow-up of children with chronic relapsing polyneuropathy
Long-Term Follow-up of Children With Chronic Relapsing Polyneuropathy Nina Barisˇic´, MD, PhD*, Stefano Regis, PhD†, and Leo Paz˘anin, MD, BSc‡ Long-term follow-up of three children with early-onset chronic inflammatory demyelinating polyneuropathy is presented. A 3-year-old male (Patient 1) manifested initially progressive muscle weakness during 6 months with spontaneous regression, followed by two severe relapses at 5 and 6 years of age. Decreased arylsulfatase A activity was present in Patient 1 (17.6) and his family members (24.1-40 nmol/mg/hour). Arterial hypertension up to 20/12 kPa was present in two patients in the initial phase associated with muscle stiffness, occasional meningism, and left ventricular hypertrophy in one of them (Patient 3). Subsequently, they both developed two mild relapses at 3.5 and 6 years of age. Clinical outcome was excellent in all three cases, although clinical course, therapy response, and electrophysiologic outcome was quite different in the only patient with low arylsulfatase A activity. The significance of this difference is discussed. © 2002 by Elsevier Science Inc. All rights reserved. Barisˇic´ N, Regis S, Paz˘anin L. Long-term follow-up of children with chronic relapsing polyneuropathy. Pediatr Neurol 2002;26:293-297.
Introduction Chronic inflammatory demyelinating polyneuropathy is a relatively rare disorder in childhood. Chronic inflammatory demyelinating polyneuropathy and acute inflammatory demyelinating polyneuropathy most likely represent parts of a continuum, arbitrarily separated by their time course [1]. The pathogenesis of both acute and chronic inflammatory demyelinating polyneuropathies has not been elucidated as yet, although involvement of the immune system has been firmly established [1]. Serum antibodies against several gangliosides, mostly GM1, have been detected in chronic inflammatory demyelinating
From the *Department of Pediatrics; University Medical School Zagreb; Kisˇpatic´eva 12; 10000 Zagreb, Croatia; †Laboratorio di Diagnosi Pre e Postnatale di Malattie Metaboliche; Gaslini 5; 16147 Genova, Italy; and the ‡Department of Neuropathology; University Medical School Zagreb; Kisˇpatic´eva 12; 10000 Zagreb, Croatia.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00401-5 ● 0887-8994/02/$—see front matter
polyneuropathy [2]. GM1 ganglioside is a constituent of the neuronal plasma membrane predominantly in nodes of Ranvier. Chronic inflammatory demyelinating polyneuropathy in children presents more precipitously and with more severe clinical features than in adults [3]. We present a different clinical course, electromyoneurographic findings, and therapeutic response during longterm follow-up of three children with early-onset relapsing chronic inflammatory demyelinating polyneuropathy and low arylsulfatase A activity in one of them. To our knowledge, only one patient with chronic inflammatory demyelinating polyneuropathy with low arylsulfatase A activity has been reported in the literature [4].
Methods Chronic inflammatory demyelinating polyneuropathy was diagnosed according to established diagnostic criteria [5]. Motor fibers were studied with surface electrode stimulation. Sensory fibers were studied by orthodromic recording from the wrist and ankle. Distal latencies and “peak to peak” amplitude of sensory nerve and compound muscle action potential on distal stimulation were measured. The children’s surface body temperature was 36.9-37°C. Immunoglobulin isotypes IgM, IgG, and IgA of serum antibodies against GM1, GQ1b, and myelin-associated glycoprotein were determined using enzyme-linked immunoabsorbent assay. The activity of arylsulfatase A in leukocytes was determined according to the method of Lee-Vaupel and Conzelmann [6]. Genomic DNA was extracted from peripheral blood lymphocytes. The CMT1A duplication was detected using restriction fragment length polymorphic and short tandem repeat markers: pVAW409R3a and respiratory movement11-GT (D17S122), pEW401HE (D17S61), Mfd41 (D17S261), and AFM191xh12 (D17S192). Fragment analysis and genotyping were performed with the automated ABI377 DNA sequencer (Applied Biosystems Inc.) provided with the ABI GENESCAN and GENOTYPER (ABI, Foster City, CA) software [7]. The genomic regions surrounding the N350S mutation and the PolyA-mutation were amplified using specific oligonucleotides, and the obtained polymerase chain reaction products were digested with restriction enzymes that cut only the products carrying the pseudodeficiency mutations (BsrI for the N350S mutation, MaeIII for the PolyA-mutation).
Communications should be addressed to: Dr. Barisˇic´, Department of Pediatrics, Zagreb University Hospital, Kisˇpatic´eva 12, 10000 Zagreb, Croatia. Received July 18, 2001; accepted November 12, 2001.
Barisˇic´ et al: Chronic Relapsing Polyneuropathy 293
Table 1.
Electromyoneurographical findings and leukocyte arylsulfatase A activity in Patient 1 (initial phase) and his family members EMNG
Patient
Mother
Father
Brother 1
Brother 2
Sister
MNCV (m/s) SNCV (m/s) Conduction block CMAP ASA activity (nmol/mg/hour)
7-13.6 0 75% ph 17.6
40-45 0 50% ph 26.5
45-50 35-40 40% ph 24.1
Normal 40 40% tp 40.5
Normal Normal 0 Normal 40.1
Normal Normal 0 Normal 39.8
Abbreviations: ASA ⫽ Arylsulfatase A CMAP ⫽ Compound muscle action potential EMNG ⫽ Electromyoneurography MNCV ⫽ Motor nerve conduction velocity
ph ⫽ Polyphasic SNCV ⫽ Sensory nerve conduction velocity tp ⫽ Triphasic
Case Reports Patient 1 A 3-year-old male manifested progressive muscle weakness during 6 months with spontaneous improvement. Areflexia, hypotonia, and peroneal gait were registered at the onset of disease. Electromyoneurography revealed severe generalized slowing of motor conduction velocities of 7 and 13.6 m/s (normal, 39.4-51.5 m/s) with absent nerve potentials and conduction block of 75%, as well as signs of demyelination (Table 1). Cerebrospinal fluid examination revealed a high protein content, 1.16 gm/L (normal range ⫽ 0.17-0.37 gm/L). Results of brain and spinal magnetic resonance imaging were normal. Phytanic acid and sulfatide excretion levels during 24 hours were also normal. Increased IgG (0.25) and IgM (0.23) anti-GM1 antibody titers were detected (normal range ⫽ 0.08-0.15). Decreased arylsulfatase A activity was present in the patient (17.6), his father (24.1), and mother (26.5), whereas in other family members activity reached the value of 40 (normal arylsulfatase A activity range ⫽ 60-360 nmol/mg/hour) (Table 1). There was no consanguinity in the patient’s family. Neurologic examination of his mother and father, as well as of his younger brother, revealed only slight clumsiness in fine motor performance. Electromyoneurographic studies in some of his family members revealed a slight decrease in motor nerve conduction velocities being around the lower normal limits, with polyphasic compound muscle action potentials and absent nerve potentials on lower extremities (Table 1). The presence of the CMT1 A duplication or HNPP deletion in 17p11.2 and arylsulfatase A pseudodeficiency gene mutations N350S and PolyA-mutation were excluded in the patient and his family members. During the first relapse at 5 years of age, accompanied with intercurrent infection, he was treated with fluocortolone and azathioprine. He became tetraplegic during the second relapse at 6 years of age, after an acute respiratory infection and was treated with plasmapheresis, followed
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by cyclosporine A treatment. Significant improvement occurred after the 4-week course of cyclosporine A. Afterwards he was maintained on fluocortolone treatment for 3 years without relapse. Since 9 years of age, he has been without any treatment for the last 5 years. Bilateral foot drop is still present (Medical Research Council scale ⫽ 3). Mild improvement of peroneal motor conduction velocities (14-27.5 m/s) but lower polyphasic compound muscle action potential (0.5 mV) and prolonged distal latency quotient (4.1 cm/12 ms) were registered in the convalescent period (Table 2). Sensory nerve potentials or F waves remained inelicitable.
Patient 2 A male, 17 months old, presented with symmetric progressive weakness lasting for 2 months, which gradually developed after mild respiratory infection. Electromyoneurography revealed demyelinating polyneuropathy with conduction block of 80%. Cerebrospinal fluid analysis revealed increased protein content of 0.48 gm/L (normal range ⫽ 0.17-0.37 gm/L). Results of brain and spinal magnetic resonance imaging were normal. Phytanic acid, antinuclear factor, B12, and arylsulfatase A activities were normal. Increased IgM (0.20) anti-GM1 antibody titer was detected (normal range ⫽ 0.08-0.15). Arterial hypertension up to 20/12 kPa was registered in the early course of the disease. Vanillyl-mandelic acid level in 24-hour urine and the result of abdominal ultrasound were normal. He was successfully treated with high-dose intravenous immunoglobulin (2 gm/kg/5 days) during the initial phase. Mild relapses occurred at 3.5 and 4.5 years of age (Table 2). Clinical improvement was registered on steroid course (2 mg/kg/day for 3 weeks). No relapses occurred without any treatment after 4.5 years of age. Slight weakness remained in peroneal muscles (Medical Research Council ⫽ 4). Convalescent electromyoneurography was not performed because parents did not give consent for the examination.
Table 2. Assessment of neurographic abnormalities during long-term follow-up in children with chronic inflammatory demyelinating polyneuropathy
Age
Nerve
CMAP d/p (mV)
DLQ (cm/ms)
MNCV (m/s)
Spont. Activity
Fwave (ms)
SNAP ()
4 yr 4.6 yr 5 yr 6 yr 9 yr 14 yr
Ulnar Peroneal Ulnar Peroneal Peroneal Peroneal Median
5/2.5 1/0.5 2/1 0.5/0.25 0.5/0.1 0.5/0.25 2/1
3.9/3.2 4.1/12 5/6.39 7/13 9/8.74 9/9.75 10/12
13.6 20 20 9 14 27.5 24.5
⫹/– – – ⫹/– – –
0 0 0 0 0 0
0 0 0 0 0 0
Patient 2 Initial 2. Relapse
1.5 yr 5 yr
Peroneal Peroneal Median
2/1 2/1.5 3/2.5
5/10 7/9.2 5/5
25 37 38
⫹ –
0 0
0 0
Patient 3 Initial
4 yr
Peroneal Median Peroneal Median Peroneal Median Peroneal Median Peroneal
0/0 0.21/0.1 0.25/0.1 0/6/0.25 3/2.5 1/0.5 1.5/1 3/2 3/2
– 5/39 5/35 5/22 6/5.9 6/4.5 6/5.9 5/3 6/4.5
– 4.5 99
⫹⫹* ⫹⫹ ⫹/– ⫹/– – – –
0 0 0
0 0 0
0
0
0
0
–
0
0
Patient 1 Initial 1. Follow up 1. Relapse 2. Relapse 2. Follow up 3. Follow up
1. Relapse
5.5 yr
1. Follow up
6.5 yr
2. Follow up
7 yr
3. Follow up
9 yr
31 21 50 44 50
* Continuous motor unit activity. Abbreviations: CMAP ⫽ Compound muscle action potential DLQ ⫽ Distal latency quotient MNCV ⫽ Motor nerve conduction velocity SNAP ⫽ Sensory nerve action potential
Patient 3 A male at 4 years of age developed progressive symmetrical flaccid tetraparesis 3 months after DTP vaccination. He manifested clinical muscle stiffness and occasional meningism, areflexia, arterial hypertension (24/12 kPa), left ventricular hypertrophy, and excessive sweating. Cerebrospinal fluid demonstrated a high protein content (3 gm/L; normal range ⫽ 0.17-0.37 gm/L). Electromyoneurography revealed absent compound muscle action potentials on lower extremities and a pronounced decrease of motor conduction velocities on upper extremities (4.5-9 m/s) (normal range ⫽ 39.4-51.5 m/s) and fibrillations and continuous motor unit activity. Results of brain and spinal scans and renal and abdominal ultrasound and vanillyl-mandelic acid in 24-hour urine were normal. Increased IgM (0.32) and IgG (0.32) titers of anti-GM1 antibodies were detected (normal range ⫽ 0.080.15). Phytanic acid level, antinuclear factor, arylsulfatase A activity, and B12 findings were normal. Clinical improvement and arterial normotension occurred on intravenous immunoglobulin (2 gm/kg/5 days), as well as regression of left ventricle hypertrophy and blood pressure normalization. Mild relapses were registered at 5.5 and 6 years of age during respiratory infections. Each time,
improvement occurred on steroid treatment lasting 2 months. No relapses have been registered without any treatment for the last 3 years. On examination, with the exception of decreased tendon jerks on lower extremities, he was otherwise clinically normal. Convalescent electromyoneurography at 6.5, 7, and 9 years of age demonstrated clear improvement of motor conduction velocities (21-50 m/s), compound muscle action potential (1-3 mV), and distal latencies (6 cm/4.5 ms). Sensory nerve potentials and F waves remained inelicitable.
Discussion All three children fulfilled diagnostic criteria for chronic inflammatory demyelinating polyneuropathy [5]. Clinical outcome was excellent in all three cases, although clinical course, treatment response, and electrophysiologic outcome were quite different in the patient with low arylsulfatase A activity (Patient 1) compared with the other two patients. Bilateral foot drop with moderate distal muscle weakness (Medical Research Council ⫽ 3) in the patient with low arylsulfatase A activity, mild muscle weakness (Medical Research Council ⫽ 4), and decreased
Barisˇic´ et al: Chronic Relapsing Polyneuropathy 295
tendon jerks on lower extremities in the other two patients are the only persistent signs of disease. The neurophysiologic follow-up during 5-10 years demonstrated improvement of P/D compound muscle action potential ratio, partial conduction block, motor conduction velocities, and distal latency in Patients 2 and 3, whereas only slight improvement of motor nerve abnormalities occurred in the male with low arylsulfatase A activity (Patient 1) (Table 2). Low arylsulfatase A activity can be related to arylsulfatase A pseudodeficiency, compound heterozygosity for arylsulfatase A pseudodeficiency, and metachromatic leukodystrophy mutations. High arylsulfatase A pseudodeficiency gene frequency in central Europe increases the chance of an association between arylsulfatase A pseudodeficiency and other diseases of the nervous system [8,9]. However, in our patient the presence of the arylsulfatase A pseudodeficiency gene mutations N350S and PolyA- was excluded in Patient 1 and his family members. In any case the complete sequence analysis of the arylsulfatase A gene has not been performed. Therefore the presence of other mutations related to the detected arylsulfatase A deficiency cannot be excluded. In metachromatic leukodystrophy, arylsulfatase A activity is lower than in our patient (Patient 1) and his family members. Subtle clinical symptoms observed in his family members could be related to low arylsulfatase A activity. The possibility that low arylsulfatase A activity may act as the cofactor or subclinical underlying abnormality modifying in an unknown way the pathogenesis of chronic inflammatory demyelinating polyneuropathy (Patient 1) cannot be excluded. Hereditary neuropathies increase susceptibility for development of chronic inflammatory demyelinating polyneuropathy [10]. Secondary, immunemediated, demyelination occurring on hereditary-altered myelin sheaths might be responsible for development and severe course of chronic inflammatory demyelinating polyneuropathy in our patient with low arylsulfatase A activity [11]. On the other hand, the low arylsulfatase A activity detected in Patient 1 might be only a coincidental finding, completely unrelated to the described clinical phenotype. IgG and IgM anti-GM1 antibodies were present in all patients studied. The role of these antibodies in the pathogenesis of chronic inflammatory demyelinating polyneuropathy is unknown [10]. Gangliosides may act as target antigens in the immunopathogenesis of neuronal/ myelin damage. GM1 gangliosides are mostly detected in motor nerve myelin/Schwann cell membrane in nodes of Ranvier causing conduction block and demyelination [13]. Decrease in anti-GM1 antibody titer has been observed in correlation with clinical improvement and with decrease of conduction block degree in chronic inflammatory demyelinating polyneuropathy [2]. Which factors exactly determine the course and the outcome of chronic inflammatory demyelinating polyneuropathy is not known. The loss of axons and spinal motor
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neurons is common in chronic inflammatory demyelinating polyneuropathy, and it may influence the functional prognosis in chronic inflammatory demyelinating polyneuropathy [13]. Despite pronounced axonal damage especially on lower extremities (Patient 3), clinical outcome was excellent. Certainly long-lasting follow-up studies are necessary to analyze the incidence of children who reach complete remission or develop relapses later as adults [10].
Conclusions 1. Chronic inflammatory demyelinating polyneuropathy in children presents with heterogeneous clinical symptoms and course. 2. A positive correlation between the severity of electrophysiologic abnormalities and neurologic dysfunction is observed in the initial phase of relapsing chronic inflammatory demyelinating polyneuropathy in children. 3. Low arylsulfatase A activity might be a risk factor for development and severe course of chronic inflammatory demyelinating polyneuropathy . 4. Clinical outcome and response to treatment are excellent in children with chronic inflammatory demyelinating polyneuropathy, although electrodiagnostic parameters of pronounced demyelination or axonal damage might remain unchanged during long-term follow-up.
We would like to thank Hanns Bernheimer, Professor, Department of Neurology, Algemeine Krankenhaus Wien, Austria for estimation of antiganglioside antibody titer and Vincent Timmerman, PhD, Born Bunge Laboratory, Antwerpen, Belgium for CMT 1 A gene analysis.
References [1] van der Meche FGA, van Doorn PA. Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Immune mechanisms and update on current therapies. Ann Neurol 1995;37 (Suppl 1):S14-S31. [2] Ilyas AA, Mithen FA, Dalakas MC, Zi-Wei, Cook SD. Antibodies to acidic glycolipids in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 1992;107:111-21. [3] Simmons Z, Wald JJ, Albers JW. Chronic inflammatory demyelinating polyradiculoneuropathy in children: I. Presentation, electrodiagnostic studies, and initial clinical course, with comparison to adults. Muscle Nerve 1997;20:1008-15. [4] Hagberg B. Polyneuropathies in pediatrics. Eur J Pediatr 1990; 149:296-305. [5] Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991; 41:617-8. [6] Lee-Vaupel M, Conzelmann E. A simple chromogenic assay for arylsulphatase A. Clin Chem Acta 1987;164:171-80. [7] Navon R, Timmerman V, Lo¨ fgren A, et al. Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) using molecular genetic techniques. Prenatal Diagn 1995;15:633-40.
[8] Hohenschutz C, Eich P, Friedl W, Waheed A, Conzelmann EM, Propping P. Pseudodeficiency of arylsulphatase A: A common genetic polymorphism with possible disease implications. Hum Genet 1989;82: 45-8. [9] Thomas PK, Waker RWH, Rudge P. Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Brain 1987;110:53-76. [10] Connolly AM. Chronic inflammatory demyelinating polyneuropathy in childhood. Pediatr Neurol 2001;24:177-83.
[11] Hays AP, Lee SS, Latov N. Immune reactive C3d on the surface of myelin sheaths in neuropathy. J Neuroimmunol 1988;18:231-44. [12] Santoro M, Thomas FP, Fink ME, et al. IgM deposits at the nodes of Ranvier in a patient with amyotrophic lateral sclerosis, antiGM1 antibodies and multifocal conduction block. Ann Neurol 1990;28: 373-7. [13] Nagamatsu M, Terao S, Misu K, et al. Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 1999;66:727-33.
Barisˇic´ et al: Chronic Relapsing Polyneuropathy 297
Introduction Chronic inflammatory demyelinating polyneuropathy is a relatively rare disorder in childhood. Chronic inflammatory demyelinating polyneuropathy and acute inflammatory demyelinating polyneuropathy most likely represent parts of a continuum, arbitrarily separated by their time course [1]. The pathogenesis of both acute and chronic inflammatory demyelinating polyneuropathies has not been elucidated as yet, although involvement of the immune system has been firmly established [1]. Serum antibodies against several gangliosides, mostly GM1, have been detected in chronic inflammatory demyelinating
From the *Department of Pediatrics; University Medical School Zagreb; Kisˇpatic´eva 12; 10000 Zagreb, Croatia; †Laboratorio di Diagnosi Pre e Postnatale di Malattie Metaboliche; Gaslini 5; 16147 Genova, Italy; and the ‡Department of Neuropathology; University Medical School Zagreb; Kisˇpatic´eva 12; 10000 Zagreb, Croatia.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00401-5 ● 0887-8994/02/$—see front matter
polyneuropathy [2]. GM1 ganglioside is a constituent of the neuronal plasma membrane predominantly in nodes of Ranvier. Chronic inflammatory demyelinating polyneuropathy in children presents more precipitously and with more severe clinical features than in adults [3]. We present a different clinical course, electromyoneurographic findings, and therapeutic response during longterm follow-up of three children with early-onset relapsing chronic inflammatory demyelinating polyneuropathy and low arylsulfatase A activity in one of them. To our knowledge, only one patient with chronic inflammatory demyelinating polyneuropathy with low arylsulfatase A activity has been reported in the literature [4].
Methods Chronic inflammatory demyelinating polyneuropathy was diagnosed according to established diagnostic criteria [5]. Motor fibers were studied with surface electrode stimulation. Sensory fibers were studied by orthodromic recording from the wrist and ankle. Distal latencies and “peak to peak” amplitude of sensory nerve and compound muscle action potential on distal stimulation were measured. The children’s surface body temperature was 36.9-37°C. Immunoglobulin isotypes IgM, IgG, and IgA of serum antibodies against GM1, GQ1b, and myelin-associated glycoprotein were determined using enzyme-linked immunoabsorbent assay. The activity of arylsulfatase A in leukocytes was determined according to the method of Lee-Vaupel and Conzelmann [6]. Genomic DNA was extracted from peripheral blood lymphocytes. The CMT1A duplication was detected using restriction fragment length polymorphic and short tandem repeat markers: pVAW409R3a and respiratory movement11-GT (D17S122), pEW401HE (D17S61), Mfd41 (D17S261), and AFM191xh12 (D17S192). Fragment analysis and genotyping were performed with the automated ABI377 DNA sequencer (Applied Biosystems Inc.) provided with the ABI GENESCAN and GENOTYPER (ABI, Foster City, CA) software [7]. The genomic regions surrounding the N350S mutation and the PolyA-mutation were amplified using specific oligonucleotides, and the obtained polymerase chain reaction products were digested with restriction enzymes that cut only the products carrying the pseudodeficiency mutations (BsrI for the N350S mutation, MaeIII for the PolyA-mutation).
Communications should be addressed to: Dr. Barisˇic´, Department of Pediatrics, Zagreb University Hospital, Kisˇpatic´eva 12, 10000 Zagreb, Croatia. Received July 18, 2001; accepted November 12, 2001.
Barisˇic´ et al: Chronic Relapsing Polyneuropathy 293
Table 1.
Electromyoneurographical findings and leukocyte arylsulfatase A activity in Patient 1 (initial phase) and his family members EMNG
Patient
Mother
Father
Brother 1
Brother 2
Sister
MNCV (m/s) SNCV (m/s) Conduction block CMAP ASA activity (nmol/mg/hour)
7-13.6 0 75% ph 17.6
40-45 0 50% ph 26.5
45-50 35-40 40% ph 24.1
Normal 40 40% tp 40.5
Normal Normal 0 Normal 40.1
Normal Normal 0 Normal 39.8
Abbreviations: ASA ⫽ Arylsulfatase A CMAP ⫽ Compound muscle action potential EMNG ⫽ Electromyoneurography MNCV ⫽ Motor nerve conduction velocity
ph ⫽ Polyphasic SNCV ⫽ Sensory nerve conduction velocity tp ⫽ Triphasic
Case Reports Patient 1 A 3-year-old male manifested progressive muscle weakness during 6 months with spontaneous improvement. Areflexia, hypotonia, and peroneal gait were registered at the onset of disease. Electromyoneurography revealed severe generalized slowing of motor conduction velocities of 7 and 13.6 m/s (normal, 39.4-51.5 m/s) with absent nerve potentials and conduction block of 75%, as well as signs of demyelination (Table 1). Cerebrospinal fluid examination revealed a high protein content, 1.16 gm/L (normal range ⫽ 0.17-0.37 gm/L). Results of brain and spinal magnetic resonance imaging were normal. Phytanic acid and sulfatide excretion levels during 24 hours were also normal. Increased IgG (0.25) and IgM (0.23) anti-GM1 antibody titers were detected (normal range ⫽ 0.08-0.15). Decreased arylsulfatase A activity was present in the patient (17.6), his father (24.1), and mother (26.5), whereas in other family members activity reached the value of 40 (normal arylsulfatase A activity range ⫽ 60-360 nmol/mg/hour) (Table 1). There was no consanguinity in the patient’s family. Neurologic examination of his mother and father, as well as of his younger brother, revealed only slight clumsiness in fine motor performance. Electromyoneurographic studies in some of his family members revealed a slight decrease in motor nerve conduction velocities being around the lower normal limits, with polyphasic compound muscle action potentials and absent nerve potentials on lower extremities (Table 1). The presence of the CMT1 A duplication or HNPP deletion in 17p11.2 and arylsulfatase A pseudodeficiency gene mutations N350S and PolyA-mutation were excluded in the patient and his family members. During the first relapse at 5 years of age, accompanied with intercurrent infection, he was treated with fluocortolone and azathioprine. He became tetraplegic during the second relapse at 6 years of age, after an acute respiratory infection and was treated with plasmapheresis, followed
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by cyclosporine A treatment. Significant improvement occurred after the 4-week course of cyclosporine A. Afterwards he was maintained on fluocortolone treatment for 3 years without relapse. Since 9 years of age, he has been without any treatment for the last 5 years. Bilateral foot drop is still present (Medical Research Council scale ⫽ 3). Mild improvement of peroneal motor conduction velocities (14-27.5 m/s) but lower polyphasic compound muscle action potential (0.5 mV) and prolonged distal latency quotient (4.1 cm/12 ms) were registered in the convalescent period (Table 2). Sensory nerve potentials or F waves remained inelicitable.
Patient 2 A male, 17 months old, presented with symmetric progressive weakness lasting for 2 months, which gradually developed after mild respiratory infection. Electromyoneurography revealed demyelinating polyneuropathy with conduction block of 80%. Cerebrospinal fluid analysis revealed increased protein content of 0.48 gm/L (normal range ⫽ 0.17-0.37 gm/L). Results of brain and spinal magnetic resonance imaging were normal. Phytanic acid, antinuclear factor, B12, and arylsulfatase A activities were normal. Increased IgM (0.20) anti-GM1 antibody titer was detected (normal range ⫽ 0.08-0.15). Arterial hypertension up to 20/12 kPa was registered in the early course of the disease. Vanillyl-mandelic acid level in 24-hour urine and the result of abdominal ultrasound were normal. He was successfully treated with high-dose intravenous immunoglobulin (2 gm/kg/5 days) during the initial phase. Mild relapses occurred at 3.5 and 4.5 years of age (Table 2). Clinical improvement was registered on steroid course (2 mg/kg/day for 3 weeks). No relapses occurred without any treatment after 4.5 years of age. Slight weakness remained in peroneal muscles (Medical Research Council ⫽ 4). Convalescent electromyoneurography was not performed because parents did not give consent for the examination.
Table 2. Assessment of neurographic abnormalities during long-term follow-up in children with chronic inflammatory demyelinating polyneuropathy
Age
Nerve
CMAP d/p (mV)
DLQ (cm/ms)
MNCV (m/s)
Spont. Activity
Fwave (ms)
SNAP ()
4 yr 4.6 yr 5 yr 6 yr 9 yr 14 yr
Ulnar Peroneal Ulnar Peroneal Peroneal Peroneal Median
5/2.5 1/0.5 2/1 0.5/0.25 0.5/0.1 0.5/0.25 2/1
3.9/3.2 4.1/12 5/6.39 7/13 9/8.74 9/9.75 10/12
13.6 20 20 9 14 27.5 24.5
⫹/– – – ⫹/– – –
0 0 0 0 0 0
0 0 0 0 0 0
Patient 2 Initial 2. Relapse
1.5 yr 5 yr
Peroneal Peroneal Median
2/1 2/1.5 3/2.5
5/10 7/9.2 5/5
25 37 38
⫹ –
0 0
0 0
Patient 3 Initial
4 yr
Peroneal Median Peroneal Median Peroneal Median Peroneal Median Peroneal
0/0 0.21/0.1 0.25/0.1 0/6/0.25 3/2.5 1/0.5 1.5/1 3/2 3/2
– 5/39 5/35 5/22 6/5.9 6/4.5 6/5.9 5/3 6/4.5
– 4.5 99
⫹⫹* ⫹⫹ ⫹/– ⫹/– – – –
0 0 0
0 0 0
0
0
0
0
–
0
0
Patient 1 Initial 1. Follow up 1. Relapse 2. Relapse 2. Follow up 3. Follow up
1. Relapse
5.5 yr
1. Follow up
6.5 yr
2. Follow up
7 yr
3. Follow up
9 yr
31 21 50 44 50
* Continuous motor unit activity. Abbreviations: CMAP ⫽ Compound muscle action potential DLQ ⫽ Distal latency quotient MNCV ⫽ Motor nerve conduction velocity SNAP ⫽ Sensory nerve action potential
Patient 3 A male at 4 years of age developed progressive symmetrical flaccid tetraparesis 3 months after DTP vaccination. He manifested clinical muscle stiffness and occasional meningism, areflexia, arterial hypertension (24/12 kPa), left ventricular hypertrophy, and excessive sweating. Cerebrospinal fluid demonstrated a high protein content (3 gm/L; normal range ⫽ 0.17-0.37 gm/L). Electromyoneurography revealed absent compound muscle action potentials on lower extremities and a pronounced decrease of motor conduction velocities on upper extremities (4.5-9 m/s) (normal range ⫽ 39.4-51.5 m/s) and fibrillations and continuous motor unit activity. Results of brain and spinal scans and renal and abdominal ultrasound and vanillyl-mandelic acid in 24-hour urine were normal. Increased IgM (0.32) and IgG (0.32) titers of anti-GM1 antibodies were detected (normal range ⫽ 0.080.15). Phytanic acid level, antinuclear factor, arylsulfatase A activity, and B12 findings were normal. Clinical improvement and arterial normotension occurred on intravenous immunoglobulin (2 gm/kg/5 days), as well as regression of left ventricle hypertrophy and blood pressure normalization. Mild relapses were registered at 5.5 and 6 years of age during respiratory infections. Each time,
improvement occurred on steroid treatment lasting 2 months. No relapses have been registered without any treatment for the last 3 years. On examination, with the exception of decreased tendon jerks on lower extremities, he was otherwise clinically normal. Convalescent electromyoneurography at 6.5, 7, and 9 years of age demonstrated clear improvement of motor conduction velocities (21-50 m/s), compound muscle action potential (1-3 mV), and distal latencies (6 cm/4.5 ms). Sensory nerve potentials and F waves remained inelicitable.
Discussion All three children fulfilled diagnostic criteria for chronic inflammatory demyelinating polyneuropathy [5]. Clinical outcome was excellent in all three cases, although clinical course, treatment response, and electrophysiologic outcome were quite different in the patient with low arylsulfatase A activity (Patient 1) compared with the other two patients. Bilateral foot drop with moderate distal muscle weakness (Medical Research Council ⫽ 3) in the patient with low arylsulfatase A activity, mild muscle weakness (Medical Research Council ⫽ 4), and decreased
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tendon jerks on lower extremities in the other two patients are the only persistent signs of disease. The neurophysiologic follow-up during 5-10 years demonstrated improvement of P/D compound muscle action potential ratio, partial conduction block, motor conduction velocities, and distal latency in Patients 2 and 3, whereas only slight improvement of motor nerve abnormalities occurred in the male with low arylsulfatase A activity (Patient 1) (Table 2). Low arylsulfatase A activity can be related to arylsulfatase A pseudodeficiency, compound heterozygosity for arylsulfatase A pseudodeficiency, and metachromatic leukodystrophy mutations. High arylsulfatase A pseudodeficiency gene frequency in central Europe increases the chance of an association between arylsulfatase A pseudodeficiency and other diseases of the nervous system [8,9]. However, in our patient the presence of the arylsulfatase A pseudodeficiency gene mutations N350S and PolyA- was excluded in Patient 1 and his family members. In any case the complete sequence analysis of the arylsulfatase A gene has not been performed. Therefore the presence of other mutations related to the detected arylsulfatase A deficiency cannot be excluded. In metachromatic leukodystrophy, arylsulfatase A activity is lower than in our patient (Patient 1) and his family members. Subtle clinical symptoms observed in his family members could be related to low arylsulfatase A activity. The possibility that low arylsulfatase A activity may act as the cofactor or subclinical underlying abnormality modifying in an unknown way the pathogenesis of chronic inflammatory demyelinating polyneuropathy (Patient 1) cannot be excluded. Hereditary neuropathies increase susceptibility for development of chronic inflammatory demyelinating polyneuropathy [10]. Secondary, immunemediated, demyelination occurring on hereditary-altered myelin sheaths might be responsible for development and severe course of chronic inflammatory demyelinating polyneuropathy in our patient with low arylsulfatase A activity [11]. On the other hand, the low arylsulfatase A activity detected in Patient 1 might be only a coincidental finding, completely unrelated to the described clinical phenotype. IgG and IgM anti-GM1 antibodies were present in all patients studied. The role of these antibodies in the pathogenesis of chronic inflammatory demyelinating polyneuropathy is unknown [10]. Gangliosides may act as target antigens in the immunopathogenesis of neuronal/ myelin damage. GM1 gangliosides are mostly detected in motor nerve myelin/Schwann cell membrane in nodes of Ranvier causing conduction block and demyelination [13]. Decrease in anti-GM1 antibody titer has been observed in correlation with clinical improvement and with decrease of conduction block degree in chronic inflammatory demyelinating polyneuropathy [2]. Which factors exactly determine the course and the outcome of chronic inflammatory demyelinating polyneuropathy is not known. The loss of axons and spinal motor
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neurons is common in chronic inflammatory demyelinating polyneuropathy, and it may influence the functional prognosis in chronic inflammatory demyelinating polyneuropathy [13]. Despite pronounced axonal damage especially on lower extremities (Patient 3), clinical outcome was excellent. Certainly long-lasting follow-up studies are necessary to analyze the incidence of children who reach complete remission or develop relapses later as adults [10].
Conclusions 1. Chronic inflammatory demyelinating polyneuropathy in children presents with heterogeneous clinical symptoms and course. 2. A positive correlation between the severity of electrophysiologic abnormalities and neurologic dysfunction is observed in the initial phase of relapsing chronic inflammatory demyelinating polyneuropathy in children. 3. Low arylsulfatase A activity might be a risk factor for development and severe course of chronic inflammatory demyelinating polyneuropathy . 4. Clinical outcome and response to treatment are excellent in children with chronic inflammatory demyelinating polyneuropathy, although electrodiagnostic parameters of pronounced demyelination or axonal damage might remain unchanged during long-term follow-up.
We would like to thank Hanns Bernheimer, Professor, Department of Neurology, Algemeine Krankenhaus Wien, Austria for estimation of antiganglioside antibody titer and Vincent Timmerman, PhD, Born Bunge Laboratory, Antwerpen, Belgium for CMT 1 A gene analysis.
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