- Email: [email protected]
Neurophysiologic assessment of mucopolysaccharidosis III
Clinical Neurophysiology 117 (2006) 2059–2063 www.elsevier.com/locate/clinph
Neurophysiologic assessment of mucopolysaccharidosis III Aatif M. Husain b
a,b,*
, Maria L. Escolar c, Joanne Kurtzberg
d
a Department of Medicine (Neurology), 202 Bell Building, Box 3678, Duke University Medical Center, Durham, NC 27710, USA Neurodiagnostic Center, Veterans Administration Medical Center, Durham, NC, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA c Program for Neurodevelopmental Function in Rare Disorders, Clinical Center for the Study of Development and Learning, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA d Pediatric Blood and Bone Marrow Transplantation Program, Duke University Medical Center, Durham, NC, USA
Accepted 31 May 2006
Abstract Objective: To describe finding of various neurophysiologic tests in patients with mucopolysaccharidosis III (MPS III) early in the disease course. Methods: Patients were evaluated with flash visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), electroencephalography (EEG), and nerve conduction studies (NCS) before they underwent hematopoietic stem cell transplantation (HSCT). Results: Thirteen children underwent at least one neurophysiologic test before HSCT. The mean age at testing was 2.7 years. Ten of 11 (91%) patients had a normal flash VEP, and all 9 who had BAEP had normal central conduction. EEG was normal in 7/13 (54%), with the others showing diffuse slowing. NCS was normal in 10/11 (91%) patients. Conclusions: Despite extensive central nervous system involvement in MPS III, flash VEP and BAEP are almost always normal. EEG is often abnormal early in the disease. Significance: This is the first report of neurophysiologic tests in a large series of MPS III patients. Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Mucopolysaccharidosis III; Flash visual evoked potentials; Brainstem auditory evoked potentials; Electroencephalography; Nerve conduction studies
1. Introduction Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III) is a rare lysosomal storage disorder in which there is impaired degradation of heparan sulfate. This condition was initially described by Sanfilippo et al. (1963) in eight children with cognitive impairment and acid mucopolysacchariduria. Though clinically similar, there are four subtypes of MPS III, A–D, each with a unique enzyme deficiency (Yogalingam and Hopwood, 2001) The incidence of MPS III in the United States is unknown, though Australian and European studies have estimated it to range
*
Corresponding author.Tel.: +1 919 684 8485; fax: +1 919 684 8955. E-mail address: [email protected] (A.M. Husain).
from approximately 1 in 58,000 to 1 in 345,000 live births (Applegarth et al., 2000; Lowry et al., 1990; Nelson, 1997; Nelson et al., 2003) Among the various subtypes, MPS IIIC and MPS IIID appear to be the most rare (Jones et al., 1997; Siciliano et al., 1991). Unlike other mucopolysaccharidosis, patients with MPS III have early and severe involvement of the central nervous system with few somatic manifestations (Muenzer, 2004) Consequently the typical coarse facial features, organomegaly, and dysostosis multiplex seen in other mucopolysaccharidosis are less prominent in these patients. Cognitive deterioration, however, typically begins between 2 and 6 years of age, and by age 10 years many have profound impairment (Neufeld and Muenzer, 2001) Treatment of MPS III with hematopoietic stem cell transplantation (HSCT) remains investigational.
1388-2457/$32.00 Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.05.031
2060
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
Given the severity of involvement of the central nervous system with MPS III, we wanted to describe the neurophysiologic pattern of abnormality early in the disease. To date neurophysiologic findings in MPS III have not been reported beyond isolated case reports and small series. 2. Methods Patients with a variety of inborn errors of metabolism are evaluated and treated at the Division of Pediatric Blood and Marrow Transplantation at Duke University Medical Center (DUMC). Prior to HSCT patients undergo various neurophysiologic tests. Informed consent was obtained by the HSCT team for performing all the studies and data analysis. Charts of all patients with MPS III referred to DUMC between 1996 and 2005 for HSCT were reviewed. In all patients, the diagnosis of MPS III (A–D) was confirmed by enzyme studies and skin biopsy. All patients who had at least a brainstem auditory evoked potential (BAEP) study, visual evoked potential (VEP) study, electroencephalogram (EEG), or nerve conduction study (NCS) prior to HSCT were further analyzed. In some patients all studies were not performed for logistical reasons. Results of these data were entered in a spreadsheet with patient identifiers removed. A descriptive analysis of the data was performed. Patients were administered conscious sedation (chloral hydrate 50 mg/kg) if their ability to cooperate with testing was impaired. BAEP and EEG were performed first followed by flash VEP. NCS were performed without conscious sedation. The protocol used for performing flash VEP and BAEP has been described previously and is summarized here (Aldosari et al., 2004) Flash VEP were obtained with monocular stimulation with light-emitting diode (LED) goggles. Stimulation was at a rate of 1.9/s. Recordings were obtained from a mid-occipital (MO) to mid-frontal (MF) derivation. Two to three trials were performed to establish reproducibility; 200 responses were averaged per trial. Filter settings and other stimulation and recording parameters were as per American Clinical Neurophysiology Society (ACNS) guidelines (ACNS, 1994a,b,c) Flash VEP were considered normal if the P1 response was present and abnormal if the response was absent, as recommended in the ACNS guidelines. BAEP were obtained following independent monaural stimulation with rarefaction clicks delivered at a rate of 51.1/s and an intensity of 70 dBnHL. A total of 4000 responses were averaged per trial, and two trials were conducted for each ear to ensure reproducibility. Filter settings and other stimulation and recording parameters were as per American Clinical Neurophysiology Society guidelines (ACNS, 1994a,b,c) If the wave I–V interpeak latency (IPL) was abnormal, the study was repeated at a stimulation rate of 11.1/s, and condensation clicks were also attempted. If the wave I could not be obtained, the stimulation intensity was increased to 80 dBnHL, and
alternating clicks were used. The I–V IPL was compared to laboratory norms. At DUMC, the upper limit of normal for the I–V IPL at a stimulation rate of 51.1/s is 4.8 ms and 4.6 ms at a stimulation rate of 11.1/s. Responses were considered abnormal if the IPL was prolonged or if one or more of the obligate waveforms (waves I, III or V) was absent. Additionally, the absolute latency of wave I was noted; a prolongation was considered suggestive of peripheral hearing loss. The upper limit of normal of the absolute latency of wave I at DUMC is 1.9 ms; however ear inserts are used to deliver the auditory stimulus, adding 0.9 ms to the latency. Thus, a wave I occurring later than 2.8 ms is considered abnormal. Digital EEG were obtained after electrodes were applied to according to the International 10/20 System. Technical guidelines proposed by the American Clinical Neurophysiology Society were followed. (ACNS, 1994a,b,c) At least 30 min of EEG were obtained. In many patients conscious sedation with chloral hydrate was used; consequently sleep was recorded in many patients. The studies were reviewed in at least three montages: anterior–posterior bipolar, transverse bipolar, and referential to ipsilateral ear. To minimize patient discomfort, NCS of one sural sensory and peroneal motor nerve was conducted. When cold, limbs were warmed to at least 34 ° C. Results were compared to published age-matched normative data (Miller and Kuntz, 1986) If abnormalities were present further testing was performed at the neurophysiologist’s discretion. Patients with abnormal NCS were classified as having an axonal or demyelinating neuropathy depending on whether the predominant abnormality was reduced amplitude or prolonged latency, respectively. 3. Results A total of 15 patients with MPS III were evaluated at DUMC; all were treated with HSCT. Thirteen underwent at least one neurophysiologic test prior to HSCT. Two did not have any pre-HSCT neurophysiologic studies due to logistical reasons. Of the 13 patients, 9 patients had MPS IIIA, whereas 4 had MPS IIIB. There were no patients with MPS IIIC and MPS IIID. There were only 3 girls among the 13 patients. The mean age at the time of neurophysiologic testing was 2.7 years. Twelve patients had mild symptoms, usually consisting of developmental delay, frequent ear infections, hearing loss, and organomegaly. One child was diagnosed prior to symptoms due to presence of the disease in an older sibling. The results of the neurophysiologic tests are presented in Tables 1 and 2. Seven of 9 patients with MPS IIIA had flash VEP; in only 1 (14%) patient the responses were absent. Flash VEP were present (normal) in all 4 patients with MPS IIIB. BAEP were performed in 6 patients with MPS IIIA. Obligate peaks were present in every patient. The I–V IPL was normal in all patients, whereas in 1 (17%) the
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
2061
Table 1 Flash VEP and BAEP data No.
Sex
Diagnosis
Age at testing (yrs.)
Left VEP
Right VEP
Left BAEP Wave I AL (ms)
I–V IPL (ms)
Wave I AL (ms)
I–V IPL (ms)
1 2 3 4 5 6 7 8 9 10 11 12 13
M M M F F F M M M M M M M
MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS
3 4 2 4 2 4 1 2 3 4 1 3 2
Present Absent
Present Absent
2.97 (P)* 2.72 (N)*
4.26 (N)* 4.24 (N)*
3.32 (P)* 2.46 (N)*
4.34 (N)* 4.52 (N)*
Present
Present
2.48 (N)
4.26 (N)
2.22 (N)
4.23 (N)
Present Present Present Present Present Present Present Present
Present Present Present Present Present Present Present Present
2.55 (N)* 2.79 (N) 2.64 (N)
4.38 (N)* 4.71 (N) 4.80 (N)
2.64 (N)* 2.75 (N) 2.60 (N)
4.41 (N)* 4.80 (N) 4.71 (N)
2.64 (N) 4.44 (P)
4.53 (N) 4.56 (N)
2.58 (N) 4.41 (N)
4.68 (N) 4.38 (N)
2.64 (N)
4.58 (N)
2.72 (N)
4.36 (N)
IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIB IIIB IIIB IIIB
Right BAEP
M, male; F, female; MPS, mucopolysaccharidosis; HSCT, hematopoietic stem cell transplantation; VEP, visual evoked potential; BAEP, brainstem auditory evoked potential; AL, absolute latency; IPL, interpeak latency; N, normal; P, prolonged; *study performed at a stimulation rate of 11.1/s (all other performed at a stimulation rate of 51.1/s).
absolute latency of wave I was prolonged after bilateral stimulation. In the MPS IIIB group, all 3 patients who underwent testing had all obligate waveforms and normal I–V IPL, but 1 (33%) had prolongation of the wave I absolute latency. EEG was normal in 6 of 9 (67%) patients with MPS IIIA, whereas the other 3 (33%) had diffuse slowing. None had epileptiform abnormalities. In the MPS IIIB group, 1 of 4 (25%) had a normal EEG, whereas 3 (75%) had diffuse slowing without epileptiform abnormalities. With both groups taken together, EEG was abnormal in 6 of 13 (46%) patients. NCS were normal in 10 of 11 (91%) patients. One patient had reduced amplitude of the sural sensory nerve action potential and peroneal compound muscle action potential with normal conduction velocities, suggestive of an axonal neuropathy. This patient had MPS IIIA.
Table 2 EEG and NCS data No.
EEG Normal
1 2 3 4 5 6 7 8 9 10 11 12 13
NCS Diffuse slowing
Spikes
Sural sensory
Peroneal motor
4 Hz
Normal Normal
Normal Normal
Normal Normal
Normal Normal
6 Hz – –
– – – – – – – –
– 6 Hz 7 Hz 6 Hz –
– – – – –
Normal Decreased amplitude Normal Normal Normal Normal Normal
Normal Decreased amplitude Normal Normal Normal Normal Normal
+ 6 Hz + + + + +
+
EEG, electroencephalogram; NCS, nerve conduction studies.
4. Discussion MPS III, more so than other mucopolysaccharidosis, is characterized by marked neurological deterioration. In addition to delayed development, these children also manifest hyperactivity, aggressive behaviors, impaired speech development, hearing loss, insomnia, and deterioration in social skills. Later in the disease course, seizures, profound cognitive impairment, and uncontrollable hyperactivity are common. It is not possible to reliably differentiate the different types of MPS III on clinical examination (Cleary and Wraith, 1993; Muenzer, 2004; Neufeld and Muenzer, 2001). The neuropathology of the various types of MPS III is similar (Suzuki and Suzuki, 2002) The cerebral cortex is remarkably atrophic but the cerebellum is spared. The leptomeninges are thickened (Ghatak et al., 1977) There are extensive white matter changes, most severe in the occipital region (Ghatak et al., 1977) Microscopically, there is accumulation of membranous cytoplasmic bodies in many regions, including the cerebral cortex, basal ganglia, cerebellum, midbrain, and pons (Jones et al., 1997) Additionally, there is accumulation of connective tissue in perivascular areas giving rise to the characteristic ‘‘cribriform’’ appearance of the white matter on magnetic resonance imaging (MRI) (Barone et al., 1999; Kriel et al., 1978). With thirteen patients, this is the largest study reporting the neurophysiologic evaluation of patients with MPS III. In this study, the neurophysiologic assessment was performed early in the disease course at a mean age of 2.7 years. At the time of this evaluation, most children had a normal flash VEP, BAEP, and NCS. However, EEG were normal in only 54% of children and showed diffuse slowing without epileptiform abnormalities in the rest. The frequency with which the flash VEP and BAEP were normal in this series of MPS III was unexpected. In this
2062
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
disease there is considerable involvement of cerebral white matter, cortical atrophy, and accumulation of membranous cytoplasmic bodies throughout all parts of the central nervous system (Ghatak et al., 1977; Jones et al., 1997) Given the extent of involvement, greater abnormalities in the evoked potentials were expected. The absence of flash VEP seen in two patients could be either due to the extensive white matter changes seen mainly posteriorly or due to ophthalmic pathology. Though the frequency of corneal clouding is not as high in MPS III as other types of mucopolysaccharidosis, other types of ocular pathology, such as accumulation of granular material in the sclera, retinal pigmentary degeneration with ballooning of ganglion cells, and optic atrophy can occur (Cleary and Wraith, 1993; Muenzer, 2004) The latter two changes could result in loss of the flash VEP. An extensive review of the literature did not yield any reports of BAEP in patients with MPS III. The lack of BAEP abnormalities noted in this series suggests relative sparing of at least the auditory pathways in the brainstem. Alternatively, the presence of the cytoplasmic bodies found in many locations throughout the brainstem may not produce functional compromise severe enough to disrupt the evoked potentials. The only abnormality noted in BAEP was a prolongation in the absolute latency of the wave I, suggestive of peripheral hearing loss, in 2 (22%) patients. Similar findings have been reported previously, with one study noting hearing loss in 26% of patients (Cleary and Wraith, 1993). It was not surprising that NCS were normal in most patients in this series. Others have noted lack of peripheral nervous system involvement with MPS III (Cleary and Wraith, 1993; Muenzer, 2004; Neufeld and Muenzer, 2001) However, carpal tunnel syndrome has been reported with mucopolysaccharidosis and is thought to occur due to deposition of glycosaminoglycans in the flexor retinaculum (Gschwind and Tonkin, 1992) In the present series, only sural sensory and peroneal motor nerves were tested to minimize patient discomfort, and consequently presence of median nerve entrapment at the wrist was not evaluated. EEG was abnormal much more frequently than other neurophysiologic tests in this series, with 46% showing diffuse slowing. In many patients with normal EEG, normal sleep architecture was noted. This is in distinction to previous reports which have found absence of normal sleep architecture such as sleep spindles and have noted rapid eye movement (REM) sleep at sleep onset (Hauser et al., 1976; Kriel et al., 1978) One explanation for this difference might have been that in many patients sleep was pharmacologically induced with chloral hydrate in the present series. Though this is the largest series of MPS III to report on neurophysiologic findings, the main shortcoming of this study is the small number of patients included where significant variations are likely to occur. However, MPS III is a very rare condition and accumulating a larger number of patients that are geographically dispersed is difficult. This study also did not address presence of symptoms, clinical
outcomes, or neuroimaging findings in these children. These features and whether HSCT is of benefit will be the focus of a subsequent report. MPS III is a rare lysosomal storage disease which affects the central nervous system more severely than other mucopolysaccharidosis but does not cause peripheral nervous system abnormalities. Surprisingly, flash VEP and BAEP are remarkably preserved but diffuse slowing may be noted in the EEG early in this disorder. Acknowledgment The authors thank Laura Neil, Kristine Ashton, Cindy Mohrhouse, Carolyn Bolles, Alyson Amtman, and Sharon Elliott of the Evoked Potentials Laboratory for performing the neurodiagnostic tests. References ACNS. Guideline nine: guidelines on evoked potentials. American Electroencephalographic Society. J Clin Neurophysiol 1994a;11 :40–73. ACNS. Guideline one: minimum technical requirements for performing clinical electroencephalography. American Electroencephalographic Society. J Clin Neurophysiol 1994b;11:2–5. ACNS. Guideline two: minimum technical standards for pediatric electroencephalography. American Electroencephalographic Society. J Clin Neurophysiol 1994c;11:6–9. Aldosari M, Altuwaijri M, Husain AM. Brain-stem auditory and visual evoked potentials in children with Krabbe disease. Clin Neurophysiol 2004;115:1653–6. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105:e10. Barone R, Nigro F, Triulzi F, Musumeci S, Fiumara A, Pavone L. Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanfilippo syndrome). Neuropediatrics 1999;30:270–4. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child. 1993;69:403–6. Ghatak NR, Fleming DF, Hinman A. Neuropathology of Sanfilippo syndrome. Ann Neurol 1977;2:161–6. Gschwind C, Tonkin MA. Carpal tunnel syndrome in children with mucopolysaccharidosis and related disorders. J Hand Surg [Am] 1992;17:44–7. Hauser WA, Kriel RL, Sung JH. Electroencephalographic findings in San Filippo type A syndrome. Electroen Clin Neuro 1976;40:321. Jones MZ, Alroy J, Rutledge JC, et al.. Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics. J Neuropath Exp Neur 1997;56:1158–67. Kriel RL, Hauser WA, Sung JH, Posalaky Z. Neuroanatomical and electroencephalographic correlations in Sanfilippo syndrome, type A. Arch Neurol 1978;35:838–43. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet 1990;85:389–90. Miller RG, Kuntz NL. Nerve conduction studies in infants and children. J Child Neurol 1986;1:19–26. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144:S27–34. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet 1997;101:355–8. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A 2003;123:310–3.
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beadet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 3421–52. Sanfilippo SJ, Podosin R, Langer L, Good RA. Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type). J Pediatr 1963;63:837–8.
2063
Siciliano L, Fiumara A, Pavone L, et al.. Sanfilippo syndrome type D in two adolescent sisters. J Med Genet 1991;28:402–5. Suzuki K, Suzuki K. Lysosomal diseases. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology. London: Springer; 2002. p. 682–735. Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001;18:264–81.
Neurophysiologic assessment of mucopolysaccharidosis III Aatif M. Husain b
a,b,*
, Maria L. Escolar c, Joanne Kurtzberg
d
a Department of Medicine (Neurology), 202 Bell Building, Box 3678, Duke University Medical Center, Durham, NC 27710, USA Neurodiagnostic Center, Veterans Administration Medical Center, Durham, NC, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA c Program for Neurodevelopmental Function in Rare Disorders, Clinical Center for the Study of Development and Learning, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA d Pediatric Blood and Bone Marrow Transplantation Program, Duke University Medical Center, Durham, NC, USA
Accepted 31 May 2006
Abstract Objective: To describe finding of various neurophysiologic tests in patients with mucopolysaccharidosis III (MPS III) early in the disease course. Methods: Patients were evaluated with flash visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), electroencephalography (EEG), and nerve conduction studies (NCS) before they underwent hematopoietic stem cell transplantation (HSCT). Results: Thirteen children underwent at least one neurophysiologic test before HSCT. The mean age at testing was 2.7 years. Ten of 11 (91%) patients had a normal flash VEP, and all 9 who had BAEP had normal central conduction. EEG was normal in 7/13 (54%), with the others showing diffuse slowing. NCS was normal in 10/11 (91%) patients. Conclusions: Despite extensive central nervous system involvement in MPS III, flash VEP and BAEP are almost always normal. EEG is often abnormal early in the disease. Significance: This is the first report of neurophysiologic tests in a large series of MPS III patients. Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Mucopolysaccharidosis III; Flash visual evoked potentials; Brainstem auditory evoked potentials; Electroencephalography; Nerve conduction studies
1. Introduction Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III) is a rare lysosomal storage disorder in which there is impaired degradation of heparan sulfate. This condition was initially described by Sanfilippo et al. (1963) in eight children with cognitive impairment and acid mucopolysacchariduria. Though clinically similar, there are four subtypes of MPS III, A–D, each with a unique enzyme deficiency (Yogalingam and Hopwood, 2001) The incidence of MPS III in the United States is unknown, though Australian and European studies have estimated it to range
*
Corresponding author.Tel.: +1 919 684 8485; fax: +1 919 684 8955. E-mail address: [email protected] (A.M. Husain).
from approximately 1 in 58,000 to 1 in 345,000 live births (Applegarth et al., 2000; Lowry et al., 1990; Nelson, 1997; Nelson et al., 2003) Among the various subtypes, MPS IIIC and MPS IIID appear to be the most rare (Jones et al., 1997; Siciliano et al., 1991). Unlike other mucopolysaccharidosis, patients with MPS III have early and severe involvement of the central nervous system with few somatic manifestations (Muenzer, 2004) Consequently the typical coarse facial features, organomegaly, and dysostosis multiplex seen in other mucopolysaccharidosis are less prominent in these patients. Cognitive deterioration, however, typically begins between 2 and 6 years of age, and by age 10 years many have profound impairment (Neufeld and Muenzer, 2001) Treatment of MPS III with hematopoietic stem cell transplantation (HSCT) remains investigational.
1388-2457/$32.00 Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.05.031
2060
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
Given the severity of involvement of the central nervous system with MPS III, we wanted to describe the neurophysiologic pattern of abnormality early in the disease. To date neurophysiologic findings in MPS III have not been reported beyond isolated case reports and small series. 2. Methods Patients with a variety of inborn errors of metabolism are evaluated and treated at the Division of Pediatric Blood and Marrow Transplantation at Duke University Medical Center (DUMC). Prior to HSCT patients undergo various neurophysiologic tests. Informed consent was obtained by the HSCT team for performing all the studies and data analysis. Charts of all patients with MPS III referred to DUMC between 1996 and 2005 for HSCT were reviewed. In all patients, the diagnosis of MPS III (A–D) was confirmed by enzyme studies and skin biopsy. All patients who had at least a brainstem auditory evoked potential (BAEP) study, visual evoked potential (VEP) study, electroencephalogram (EEG), or nerve conduction study (NCS) prior to HSCT were further analyzed. In some patients all studies were not performed for logistical reasons. Results of these data were entered in a spreadsheet with patient identifiers removed. A descriptive analysis of the data was performed. Patients were administered conscious sedation (chloral hydrate 50 mg/kg) if their ability to cooperate with testing was impaired. BAEP and EEG were performed first followed by flash VEP. NCS were performed without conscious sedation. The protocol used for performing flash VEP and BAEP has been described previously and is summarized here (Aldosari et al., 2004) Flash VEP were obtained with monocular stimulation with light-emitting diode (LED) goggles. Stimulation was at a rate of 1.9/s. Recordings were obtained from a mid-occipital (MO) to mid-frontal (MF) derivation. Two to three trials were performed to establish reproducibility; 200 responses were averaged per trial. Filter settings and other stimulation and recording parameters were as per American Clinical Neurophysiology Society (ACNS) guidelines (ACNS, 1994a,b,c) Flash VEP were considered normal if the P1 response was present and abnormal if the response was absent, as recommended in the ACNS guidelines. BAEP were obtained following independent monaural stimulation with rarefaction clicks delivered at a rate of 51.1/s and an intensity of 70 dBnHL. A total of 4000 responses were averaged per trial, and two trials were conducted for each ear to ensure reproducibility. Filter settings and other stimulation and recording parameters were as per American Clinical Neurophysiology Society guidelines (ACNS, 1994a,b,c) If the wave I–V interpeak latency (IPL) was abnormal, the study was repeated at a stimulation rate of 11.1/s, and condensation clicks were also attempted. If the wave I could not be obtained, the stimulation intensity was increased to 80 dBnHL, and
alternating clicks were used. The I–V IPL was compared to laboratory norms. At DUMC, the upper limit of normal for the I–V IPL at a stimulation rate of 51.1/s is 4.8 ms and 4.6 ms at a stimulation rate of 11.1/s. Responses were considered abnormal if the IPL was prolonged or if one or more of the obligate waveforms (waves I, III or V) was absent. Additionally, the absolute latency of wave I was noted; a prolongation was considered suggestive of peripheral hearing loss. The upper limit of normal of the absolute latency of wave I at DUMC is 1.9 ms; however ear inserts are used to deliver the auditory stimulus, adding 0.9 ms to the latency. Thus, a wave I occurring later than 2.8 ms is considered abnormal. Digital EEG were obtained after electrodes were applied to according to the International 10/20 System. Technical guidelines proposed by the American Clinical Neurophysiology Society were followed. (ACNS, 1994a,b,c) At least 30 min of EEG were obtained. In many patients conscious sedation with chloral hydrate was used; consequently sleep was recorded in many patients. The studies were reviewed in at least three montages: anterior–posterior bipolar, transverse bipolar, and referential to ipsilateral ear. To minimize patient discomfort, NCS of one sural sensory and peroneal motor nerve was conducted. When cold, limbs were warmed to at least 34 ° C. Results were compared to published age-matched normative data (Miller and Kuntz, 1986) If abnormalities were present further testing was performed at the neurophysiologist’s discretion. Patients with abnormal NCS were classified as having an axonal or demyelinating neuropathy depending on whether the predominant abnormality was reduced amplitude or prolonged latency, respectively. 3. Results A total of 15 patients with MPS III were evaluated at DUMC; all were treated with HSCT. Thirteen underwent at least one neurophysiologic test prior to HSCT. Two did not have any pre-HSCT neurophysiologic studies due to logistical reasons. Of the 13 patients, 9 patients had MPS IIIA, whereas 4 had MPS IIIB. There were no patients with MPS IIIC and MPS IIID. There were only 3 girls among the 13 patients. The mean age at the time of neurophysiologic testing was 2.7 years. Twelve patients had mild symptoms, usually consisting of developmental delay, frequent ear infections, hearing loss, and organomegaly. One child was diagnosed prior to symptoms due to presence of the disease in an older sibling. The results of the neurophysiologic tests are presented in Tables 1 and 2. Seven of 9 patients with MPS IIIA had flash VEP; in only 1 (14%) patient the responses were absent. Flash VEP were present (normal) in all 4 patients with MPS IIIB. BAEP were performed in 6 patients with MPS IIIA. Obligate peaks were present in every patient. The I–V IPL was normal in all patients, whereas in 1 (17%) the
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
2061
Table 1 Flash VEP and BAEP data No.
Sex
Diagnosis
Age at testing (yrs.)
Left VEP
Right VEP
Left BAEP Wave I AL (ms)
I–V IPL (ms)
Wave I AL (ms)
I–V IPL (ms)
1 2 3 4 5 6 7 8 9 10 11 12 13
M M M F F F M M M M M M M
MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS MPS
3 4 2 4 2 4 1 2 3 4 1 3 2
Present Absent
Present Absent
2.97 (P)* 2.72 (N)*
4.26 (N)* 4.24 (N)*
3.32 (P)* 2.46 (N)*
4.34 (N)* 4.52 (N)*
Present
Present
2.48 (N)
4.26 (N)
2.22 (N)
4.23 (N)
Present Present Present Present Present Present Present Present
Present Present Present Present Present Present Present Present
2.55 (N)* 2.79 (N) 2.64 (N)
4.38 (N)* 4.71 (N) 4.80 (N)
2.64 (N)* 2.75 (N) 2.60 (N)
4.41 (N)* 4.80 (N) 4.71 (N)
2.64 (N) 4.44 (P)
4.53 (N) 4.56 (N)
2.58 (N) 4.41 (N)
4.68 (N) 4.38 (N)
2.64 (N)
4.58 (N)
2.72 (N)
4.36 (N)
IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIB IIIB IIIB IIIB
Right BAEP
M, male; F, female; MPS, mucopolysaccharidosis; HSCT, hematopoietic stem cell transplantation; VEP, visual evoked potential; BAEP, brainstem auditory evoked potential; AL, absolute latency; IPL, interpeak latency; N, normal; P, prolonged; *study performed at a stimulation rate of 11.1/s (all other performed at a stimulation rate of 51.1/s).
absolute latency of wave I was prolonged after bilateral stimulation. In the MPS IIIB group, all 3 patients who underwent testing had all obligate waveforms and normal I–V IPL, but 1 (33%) had prolongation of the wave I absolute latency. EEG was normal in 6 of 9 (67%) patients with MPS IIIA, whereas the other 3 (33%) had diffuse slowing. None had epileptiform abnormalities. In the MPS IIIB group, 1 of 4 (25%) had a normal EEG, whereas 3 (75%) had diffuse slowing without epileptiform abnormalities. With both groups taken together, EEG was abnormal in 6 of 13 (46%) patients. NCS were normal in 10 of 11 (91%) patients. One patient had reduced amplitude of the sural sensory nerve action potential and peroneal compound muscle action potential with normal conduction velocities, suggestive of an axonal neuropathy. This patient had MPS IIIA.
Table 2 EEG and NCS data No.
EEG Normal
1 2 3 4 5 6 7 8 9 10 11 12 13
NCS Diffuse slowing
Spikes
Sural sensory
Peroneal motor
4 Hz
Normal Normal
Normal Normal
Normal Normal
Normal Normal
6 Hz – –
– – – – – – – –
– 6 Hz 7 Hz 6 Hz –
– – – – –
Normal Decreased amplitude Normal Normal Normal Normal Normal
Normal Decreased amplitude Normal Normal Normal Normal Normal
+ 6 Hz + + + + +
+
EEG, electroencephalogram; NCS, nerve conduction studies.
4. Discussion MPS III, more so than other mucopolysaccharidosis, is characterized by marked neurological deterioration. In addition to delayed development, these children also manifest hyperactivity, aggressive behaviors, impaired speech development, hearing loss, insomnia, and deterioration in social skills. Later in the disease course, seizures, profound cognitive impairment, and uncontrollable hyperactivity are common. It is not possible to reliably differentiate the different types of MPS III on clinical examination (Cleary and Wraith, 1993; Muenzer, 2004; Neufeld and Muenzer, 2001). The neuropathology of the various types of MPS III is similar (Suzuki and Suzuki, 2002) The cerebral cortex is remarkably atrophic but the cerebellum is spared. The leptomeninges are thickened (Ghatak et al., 1977) There are extensive white matter changes, most severe in the occipital region (Ghatak et al., 1977) Microscopically, there is accumulation of membranous cytoplasmic bodies in many regions, including the cerebral cortex, basal ganglia, cerebellum, midbrain, and pons (Jones et al., 1997) Additionally, there is accumulation of connective tissue in perivascular areas giving rise to the characteristic ‘‘cribriform’’ appearance of the white matter on magnetic resonance imaging (MRI) (Barone et al., 1999; Kriel et al., 1978). With thirteen patients, this is the largest study reporting the neurophysiologic evaluation of patients with MPS III. In this study, the neurophysiologic assessment was performed early in the disease course at a mean age of 2.7 years. At the time of this evaluation, most children had a normal flash VEP, BAEP, and NCS. However, EEG were normal in only 54% of children and showed diffuse slowing without epileptiform abnormalities in the rest. The frequency with which the flash VEP and BAEP were normal in this series of MPS III was unexpected. In this
2062
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063
disease there is considerable involvement of cerebral white matter, cortical atrophy, and accumulation of membranous cytoplasmic bodies throughout all parts of the central nervous system (Ghatak et al., 1977; Jones et al., 1997) Given the extent of involvement, greater abnormalities in the evoked potentials were expected. The absence of flash VEP seen in two patients could be either due to the extensive white matter changes seen mainly posteriorly or due to ophthalmic pathology. Though the frequency of corneal clouding is not as high in MPS III as other types of mucopolysaccharidosis, other types of ocular pathology, such as accumulation of granular material in the sclera, retinal pigmentary degeneration with ballooning of ganglion cells, and optic atrophy can occur (Cleary and Wraith, 1993; Muenzer, 2004) The latter two changes could result in loss of the flash VEP. An extensive review of the literature did not yield any reports of BAEP in patients with MPS III. The lack of BAEP abnormalities noted in this series suggests relative sparing of at least the auditory pathways in the brainstem. Alternatively, the presence of the cytoplasmic bodies found in many locations throughout the brainstem may not produce functional compromise severe enough to disrupt the evoked potentials. The only abnormality noted in BAEP was a prolongation in the absolute latency of the wave I, suggestive of peripheral hearing loss, in 2 (22%) patients. Similar findings have been reported previously, with one study noting hearing loss in 26% of patients (Cleary and Wraith, 1993). It was not surprising that NCS were normal in most patients in this series. Others have noted lack of peripheral nervous system involvement with MPS III (Cleary and Wraith, 1993; Muenzer, 2004; Neufeld and Muenzer, 2001) However, carpal tunnel syndrome has been reported with mucopolysaccharidosis and is thought to occur due to deposition of glycosaminoglycans in the flexor retinaculum (Gschwind and Tonkin, 1992) In the present series, only sural sensory and peroneal motor nerves were tested to minimize patient discomfort, and consequently presence of median nerve entrapment at the wrist was not evaluated. EEG was abnormal much more frequently than other neurophysiologic tests in this series, with 46% showing diffuse slowing. In many patients with normal EEG, normal sleep architecture was noted. This is in distinction to previous reports which have found absence of normal sleep architecture such as sleep spindles and have noted rapid eye movement (REM) sleep at sleep onset (Hauser et al., 1976; Kriel et al., 1978) One explanation for this difference might have been that in many patients sleep was pharmacologically induced with chloral hydrate in the present series. Though this is the largest series of MPS III to report on neurophysiologic findings, the main shortcoming of this study is the small number of patients included where significant variations are likely to occur. However, MPS III is a very rare condition and accumulating a larger number of patients that are geographically dispersed is difficult. This study also did not address presence of symptoms, clinical
outcomes, or neuroimaging findings in these children. These features and whether HSCT is of benefit will be the focus of a subsequent report. MPS III is a rare lysosomal storage disease which affects the central nervous system more severely than other mucopolysaccharidosis but does not cause peripheral nervous system abnormalities. Surprisingly, flash VEP and BAEP are remarkably preserved but diffuse slowing may be noted in the EEG early in this disorder. Acknowledgment The authors thank Laura Neil, Kristine Ashton, Cindy Mohrhouse, Carolyn Bolles, Alyson Amtman, and Sharon Elliott of the Evoked Potentials Laboratory for performing the neurodiagnostic tests. References ACNS. Guideline nine: guidelines on evoked potentials. American Electroencephalographic Society. J Clin Neurophysiol 1994a;11 :40–73. ACNS. Guideline one: minimum technical requirements for performing clinical electroencephalography. American Electroencephalographic Society. J Clin Neurophysiol 1994b;11:2–5. ACNS. Guideline two: minimum technical standards for pediatric electroencephalography. American Electroencephalographic Society. J Clin Neurophysiol 1994c;11:6–9. Aldosari M, Altuwaijri M, Husain AM. Brain-stem auditory and visual evoked potentials in children with Krabbe disease. Clin Neurophysiol 2004;115:1653–6. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105:e10. Barone R, Nigro F, Triulzi F, Musumeci S, Fiumara A, Pavone L. Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanfilippo syndrome). Neuropediatrics 1999;30:270–4. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child. 1993;69:403–6. Ghatak NR, Fleming DF, Hinman A. Neuropathology of Sanfilippo syndrome. Ann Neurol 1977;2:161–6. Gschwind C, Tonkin MA. Carpal tunnel syndrome in children with mucopolysaccharidosis and related disorders. J Hand Surg [Am] 1992;17:44–7. Hauser WA, Kriel RL, Sung JH. Electroencephalographic findings in San Filippo type A syndrome. Electroen Clin Neuro 1976;40:321. Jones MZ, Alroy J, Rutledge JC, et al.. Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics. J Neuropath Exp Neur 1997;56:1158–67. Kriel RL, Hauser WA, Sung JH, Posalaky Z. Neuroanatomical and electroencephalographic correlations in Sanfilippo syndrome, type A. Arch Neurol 1978;35:838–43. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet 1990;85:389–90. Miller RG, Kuntz NL. Nerve conduction studies in infants and children. J Child Neurol 1986;1:19–26. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144:S27–34. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet 1997;101:355–8. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A 2003;123:310–3.
A.M. Husain et al. / Clinical Neurophysiology 117 (2006) 2059–2063 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beadet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 3421–52. Sanfilippo SJ, Podosin R, Langer L, Good RA. Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type). J Pediatr 1963;63:837–8.
2063
Siciliano L, Fiumara A, Pavone L, et al.. Sanfilippo syndrome type D in two adolescent sisters. J Med Genet 1991;28:402–5. Suzuki K, Suzuki K. Lysosomal diseases. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology. London: Springer; 2002. p. 682–735. Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001;18:264–81.