| Article Access Statistics|
| Viewed||6336 |
| Printed||139 |
| Emailed||6 |
| PDF Downloaded||184 |
| Comments ||[Add] |
| Cited by others ||4 |
Click on image for details.
|Year : 2014 | Volume
| Issue : 2 | Page : 153-158
Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease
Satyabrata Pulai1, Atanu Biswas1, Arijit Roy1, Deb Sankar Guin1, Alak Pandit1, Goutam Gangopadhyay1, Prabhat Kumar Ghorai2, Sujit Sarkhel3, Asit Kumar Senapati1
1 Department of Neurology, Bangur Institute of Neurosciences, Kolkata, India
2 Department of Radiology, Bangur Institute of Neurosciences, Kolkata, India
3 Institute of Psychiatry, Institute of Post-Graduate Medical Education and Research, Kolkata, West Bengal, India
|Date of Submission||01-Oct-2013|
|Date of Decision||08-Oct-2013|
|Date of Acceptance||31-Mar-2014|
|Date of Web Publication||14-May-2014|
Department of Neurology, Bangur Institute of Neurosciences, 52/1A, S. N. Pandit Street, Kolkata - 700 025, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Magnetic resonance imaging (MRI) helps in the diagnosis of neurologic Wilson's disease (WD). The literature regarding MR spectroscopy (MRS) and diffusion-weighted imaging (DWI) in WD is limited. Objectives: To evaluate the clinical features and neuroimaging findings in drug-naοve neurologic WD and to find correlation between clinical stage and disease duration with different imaging findings. Materials and Methods: The study subjects included consecutive and follow-up neurologic WD patients attending movement disorder clinic. The initial clinical and MRI features before commencement of chelation therapy were noted. Of 78 patients, 34 underwent DWI study and MRS was done in 38 patients and in 32 control subjects. Results: Dystonia, dysarthria, tremor, and behavioral abnormality were common presenting features. All patients had MRI abnormality with major affection of basal ganglia. The clinical severity and anatomical extent of MRI abnormalities were positively correlated (P < 0.001; r s = 0.709). Presence of diffusion restriction was inversely related to duration of disease (P < 0.001; r s = 0.760). WD patients had reduced N-acetylaspartate/creatine (Cr) and choline (Cho)/Cr ratio (P < 0.001) as compared with control subjects in MRS study. Conclusion: Dystonia, dysarthria and tremor are common neurological features of WD. In this study, MRI abnormalities were positively correlated with disease severity; diffusion restriction was inversely correlated with the duration of the disease process. MRS was also a sensitive tool for diagnosing patient of neurologic WD.
Keywords: Clinical features, diffusion-weighted imaging, magnetic resonance spectroscopy, Wilson′s disease
|How to cite this article:|
Pulai S, Biswas A, Roy A, Guin DS, Pandit A, Gangopadhyay G, Ghorai PK, Sarkhel S, Senapati AK. Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease. Neurol India 2014;62:153-8
|How to cite this URL:|
Pulai S, Biswas A, Roy A, Guin DS, Pandit A, Gangopadhyay G, Ghorai PK, Sarkhel S, Senapati AK. Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease. Neurol India [serial online] 2014 [cited 2021 May 9];62:153-8. Available from: https://www.neurologyindia.com/text.asp?2014/62/2/153/132349
| » Introduction|| |
Of the Wilson's disease (WD), neurologic presentation accounts for 40-60%. , Diagnosis of WD is based on a combination of clinical and diagnostic tests including presence of Kayser-Fleisher (K-F) ring in the cornea, low serum ceruloplasmin, and increased 24 h urinary copper excretion. , Magnetic resonance imaging (MRI) of brain in WD shows symmetrical putaminal high signal intensity on T 2 -weighted (T2W) images.  These MRI features are caused by edema, gliosis, demyelination, neuronal necrosis, or cystic degeneration. ,, Reversibility of the high signal changes considered to be due to focal gliosis or edema occurring after chelation therapy.  Rarely T2W hypointensity is seen in the basal ganglia regions as a result of iron deposition in exchange for copper and this occurs after chelation therapy.  Diffusion-weighted image (DWI) evaluates the mobility of water molecules, more precisely the proton in H 2 O in the cells. In WD, copper toxicity causes inflammation and cell swelling leading to diffusion restriction.  There are limited studies on DWI in WD patients. MR-spectroscopy (MRS) denotes chemical microenvironment of brain. N-alanine aspartate (NAA)/Cr ratio may be reduced in patients of WD due to copper-induced cell injury; however, this decrease may be partially reversible with chelation therapy. ,, Choline (Cho) is a marker of Cho-containing compounds that forms a pool involved in the membrane synthesis and degradation. Cho: Cr ratio may be decreased, normal, or high in WD.  There are only few studies done on MRS changes in WD with contradictory findings, and the clinical significance is yet to be fully defined. ,,
The present study was aimed to evaluate the clinical profile and to elucidate the MRI and MRS changes in drug-naïve patients of WD. Furthermore, we planned to correlate these imaging changes with clinical stage of the disease.
| » Materials and Methods|| |
The study subjects included consecutive newly diagnosed and old follow-up patients of WD attending movement disorder clinic of the institute between January 2011 and September 2012. The diagnosis of WD was based on the following: (1) neurologic features with or without hepatic involvement, (2) K-F ring in the cornea, and (3) low serum ceruloplasmin (<20 mg/dl) and high 24-h urinary copper excretion (>100 μg). Patients fulfilling all three criteria were included for study. Patients of WD suffering from other systemic diseases like hematological diseases, encephalitis, infective hepatitis, and renal failure were excluded. Old patients of WD who were not having requisite documents specially MR images at drug-naïve stage were excluded from the study.
After inclusion, all patients were assessed clinically. Detailed history was taken from the family members. Patients underwent thorough clinical examination, and the findings were verified by a group of senior neurologists at the clinic. The MRI and MRS findings were independently evaluated by both an experienced radiologist and senior neurologists. For follow-up patients of WD, the documents kept in the clinic were reassessed. History and clinical features documented in the record were rechecked after detailed history taking from the patients and their family members. The biochemical reports and report regarding K-F ring were particularly checked. Their initial MRI plates before chelating therapy were reassessed by an experienced radiologist and a senior neurologist. Patients with damaged or missing MRI plates were excluded from the study. A total of 22 follow-up patients of WD were excluded because of damaged or missing MRI plates.
We correlated the clinical severity of both new and follow-up patients at presentation with their initial MRI findings (before chelation therapy). The clinical severity was assessed using Chu staging.  Stage I: Hand tremors, slurred speech, or tendency to fall with minimal or no functional impairment; Stage II: Moderate rigidity or involuntary movements, usteady gait, dysarthria, psychiatric symptoms, or any combination of these; and Stage III: Confined to bed or wheel chair with severe generalized rigidity or spasticity, gross ataxia, or marked involuntary movements.
MRI and MRS methodology
MRI and MRS were performed at the same time by using a whole body unit operating at 1.5 T (GE SIGNA) with standard quadrature head coil. The MRI protocol was the following: Axial and sagittal spin-echo, T 1 -weighted (T1W) sequences, an axial fast spin-echo T2W sequence, an axial fluid-attenuated inversion recovery sequence, and a coronal spin-echo T2W sequence. To locate the MRS volume of interest (VOI), an axial fast spin-echo T2W sequence was performed having following parameters: TR/TE/NEX = 4000/100/2, echo train length = 22, 5-mm section thickness with 3 mm of intersection gap, a 240-mm FOV, and a 256/192 matrix. We applied the point resolved spectroscopy mode (PRESS) MRS technique using the following parameters: TR/TE = 9999/123, mixing time = 15 ms, eight-phase cycle steps, and 160 acquisitions in the basal ganglia. Spectra were obtained the same way for patients and control subjects in basal ganglia region.
MRI abnormalities were graded by extent of the abnormalities observed in different anatomical sites. The extent of disease was graded from 0 to 8 according to the total number of areas involved. A score of 1 was given for an abnormality in each of the following eight areas: Lentiform nuclei, caudate nuclei, thalamus, midbrain, pons, cerebellum, cortical white matter, and cortical atrophy.  The Chu clinical staging was correlated with the MRI grading.
Statistical analysis was done, International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) by V 19. The correlation between presences of DWI restriction with duration of disease was done by Spearman's correlation method. Metabolic ratios between patients and controls were compared using independent samples 't' test. This study had the institutional ethics committee approval.
| » Results|| |
The study included 78 (male = 52, female = 26) patients of WD, 38 newly diagnosed and 40 follow-up cases. The mean age of onset of disease of our patients was 14.71 years. The mean duration of the disease from the symptom onset to the time of presentation was 2.2 years. The mean period of disease duration was 2.63 years in males and 1.55 years in females.
Limb dystonia was the most common (44%) initial clinical presentation followed by dysarthia (35%), hand tremor (19%), drooling (17%), and behavioral abnormality (15%) [Table 1]. Atypical features included hematuria and renal calculi in a girl due to renal tubular acidosis, bony deformity of extremities like rickets in another girl due to renal tubular acidosis, and chronic bleeding diathesis in a patient due to thrombocytopenia.
|Table 1: The initial presenting feature of Wilson's disease patients (N=78)|
Click here to view
MRIs of all 78 patients were available, MRS in 38 and DWI in 34 patients. All patients had MRI abnormalities: 76 (97%) patients had basal ganglia mainly puramen in 66 (97%) and globus pallidus in 73 (94%) patients [Table 2], [Figure 1]. 'Giant Panda Sign' was present in six patients. We correlated Chu clinical staging with MRI score depending on the number of anatomical sites involved and found a positive correlation between them (P < 0.001; r s = 0.709).
|Figure 1: T2 FLAIR image showing hyperintensity in bilateral basal ganglia and thalamus with diffuse cortical atrophy. FLAIR = Fluid-attenuated inversion recovery|
Click here to view
|Table 2: MRI abnormalities in our study and comparison with other studies|
Click here to view
Of the 34 patients who had DWI, 23 (68%) patients had diffusion restriction [Figure 2]. The mean disease duration in patients with diffusion restriction was 0.89 (±0.64) years, whereas it was 4.04 (±2.58) years in patients with no diffuse restriction. The presence of DWI restriction was inversely correlated with the duration of the disease (P < 0.001; r s = 0.760).
|Figure 2: DWI showing restricted diffusion in bilateral basal ganglia. DWI = Diffusion-weighted image|
Click here to view
Multivoxel MRS at basal ganglia was done in 38 patients and in 32 control subjects. The mean NAA/Cr ratio was 0.91(±0.19) and Cho/Cr ratio was 0.72 (±0.13) in the patients (N = 38), whereas the mean NAA/Cr ratio was 1.27 (±0.13) and Cho/Cr ratio was 0.85 (±0.09) in the control subjects [Table 3], [Figure 3]. The mean metabolic ratios were significantly reduced in the cohort of WD patients compared with the controls (P < 0.001).
|Figure 3: MRS showing reduced NAA/Cr ratio as compared to control in putamen. MRS = Magnetic resonance spectroscopy, NAA = N-alanine aspartate|
Click here to view
| » Discussion|| |
The mean age of onset neurologic WD was younger, similar to the other Indian studies. , The age of onset in the United Kingdom was 18.3 years.  The reasons for early onset of WD in Indian patients are not clear. One of the proposed hypotheses was abundant use of copper utensils in cooking. Predominant male gender was seen in our as well as other Indian studies. ,,,,, Dystonia was the most common (44%) presenting symptom in this study, whereas Prashnath et al., found tremor as the most common presenting feature,  Starosta-Rubinstein et al.,  found bulbar symptom as the most common presenting feature in their study.
This is probably the first study of MRI in a large cohort of drug-naïve neurologic WD patients. The frequency of MRI abnormalities was high in this study compared with other studies. This could be due to the difference in the mean age of onset and the mean duration of the illness and effect of chelating therapy.  This study studied exclusively drug-naïve patients of WD, whereas other studies involved predominantly patients of WD on chelating therapy.
We graded MRI abnormalities in a 0-8 scale by extent of the abnormalities observed in different anatomical sites.  We correlated Chu staging  of the disease with MRI score, there was a positive correlation between Chu staging and MRI score (P < 0.001; r s = 0.709). MRI score was higher in severe stage of disease. There is a controversy concerning the correlation between MRI findings and the severity of clinical picture. While some studies have shown this correlation, ,,,,, others could not find any correlation ,, [Table 4]. In the study by Thuomas et al., a correlation was found between MRI and clinical findings in all the five patients examined.  Other study by Kim et al.,  showed good correlation between changes observed on follow-up MRI and clinical response to treatment in 15 patients. Sinha et al.,  found significant correlation between severity of the disease with MRI changes. These authors also studied sequential MRI changes in 50 patients on chelating therapy and found that an extensive MRI changes were associated with poor prognosis.  Prashnath et al.,  correlated clinical severity with MRI changes in 21 patients who were on chelating therapy. In another study, certain anatomical abnormalities correlated with pseudo Parkinsonism More Details or cerebellar signs. 
|Table 4: Studies on correlation between MRI abnormalities and clinical features in WD patients|
Click here to view
In this study, there was inverse correlation between diffusion restriction and duration of disease (P < 0.001; r s = 0.760). There were only two earlier such studies involving small number of subjects. Sener reported one patient of WD with diffusion restriction in the initial MRI, which reversed after 1.5 years.  In the study involving four patients of WD, Kishibayashi et al., reported diffusion restriction in all the four patients  [Table 5]. Diffusion-weighted MRI usually shows variable findings depending on the age of the cerebral lesions. Recent lesions give restricted diffusion likely due to cytotoxic edema associated with neurotoxicity of copper accumulation. A persistent chronic MRI lesion shows resolution of diffusion restriction in course of time, and this is likely to be due to evolution of lesions to necrosis and spongiform degeneration.  Thus, resolution or reversal of diffusion restriction might be the reflection of the histopathogical stages of WD.  Although our observation substantiates this hypothesis, more studies are needed involving more number of patients to validate this.
In this study, the mean NAA/Cr ratio was 0.91 in the patients and 1.27 in the controls. The mean of Cho/Cr ratio was 0.72 in the patients and 0.85 in the control group. This alteration of the metabolic ratio in the cohort of WD was statistically significant (P < 0.001). Leandro T-Lucato et al., observed significant decrease in NAA/Cr ratio and an increase in Ml/Cr ratio in patients, but Cho/Cr and Gl X/Cr did not significantly differ between patients and control subjects.  In regard to NAA/Cr ratio, our observations corroborate with the observations of Leandro and colleagues.  Our observation of Cho/Cr ratio was not similar to the observation of Leandro and colleagues.  This discrepancy in the results of Cho/Cr ratio can be explained by the balance between gliosis and degeneration of neural tissue and this ratio may be normal, high, or low depending on the balance or preponderance of either of the pathological processes as mentioned.
In addition to conventional MRI, MRS has been studied in WD patients. But there are only few studies done and the results are controversial. Some studies showed remarkable alteration, ,, whereas other study did not demonstrate any alteration  [Table 6]. The main drawback of these studies is the small sample size. MRS is a noninvasive method for depicting biochemical alteration of central nervous system, and it provides metabolic information in patients with WD. Proton MR spectra can be affected by accumulation of paramagnetic copper. Another interesting issue is that biochemical changes may cause functional alteration in the brain before morphological changes occur. Leandro et al., had found reduced NAA/Cr ratio in areas, particularly frontal white matter and parieto-occipital cortex, despite normal MRI.  This signifies that the biochemical alterations seen in WD may not correspond to structural alteration visible on MRI. They also found increase Myoinositol (mI)/Cr ratio suggestive of gliosis. 
Limitation of the study
This study included both old (N = 42) and new patients (N = 34). For old patients, although we took elaborate history from patients and family members and corroborated with our recorded documents, a possible recall bias cannot be ruled out. In our multivoxel MRS study, ml peak was not optimum, so we could not measure the mI/Cr ratio.
| » References|| |
|1.||Walshe JM, Yealland M. Wilson′s disease: The problem of delayed diagnosis. J Neurol Neurosurg Psychiatry 1992;55:692-6. |
|2.||Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore) 1992;71:139-64. |
|3.||Pfeiffer RF. Wilson′s disease. In: Watts RL, Koller WC, editors. Movement Disorders. Neurologic Principles and Practice. New York: McGraw-Hill Medical Publishers; 2004. p. 779-97. |
|4.||Sternlieb I. Perspective on Wilson′s disease. Hepatology 1990;12:1234-9. |
|5.||Nazer H, Brismar J, al-kawi MZ, Gunasekaran TS, Jorulf KH. Magnetic resonance imaging of the brain in Wilson′s disease. Neuroradiology 1993;35:130-3. |
|6.||Sener RN. Wilson disease: MRI demonstration of cavitations in basal ganglia and thalami. Pediatr Radiol 1993;23:157. |
|7.||Huang CC, Chu NS. Wilson′s disease: Resolution of MRI lesions following long-term oral zinc therapy. Acta Neurol Scand 1996;93:215-8. |
|8.||Starosta-Rubinstein S, Young AB, Kluin K, Hill G, Aisen AM, Gabrielsen T, et al. Clinical assessment of 31 patients with Wilson′s disease. Correlations with structural changes on magnetic resonance imaging. Arch Neurol 1987;44:365-70. |
|9.||Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, et al. MR Imaging of the brain in Wilson disease of childhood: Findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol 2006;27:1373-8. |
|10.||Das SK, Roy K. Wilson′s disease: An update. Nat Clin Pract Neurol 2006;2:482-93. |
|11.||Senner RN. Diffusion MR imaging changes associated with Wilson disease. AJNR Am J Neuroradiol 2003;24:965-7. |
|12.||Wang ZJ, Zimmerman RA. Proton MR Spectroscopy of pediatric brain metabolic disorders. Neuroimaging Clin N Am 1998;8:781-807. |
|13.||De Stefano N, Mathews PM, Antel JP, Preul M, Francis G, Arnold DL. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 1995;38:901-9. |
|14.||De Stefano N, Mathews PM, Arnold DL. Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 1995;34:721-7. |
|15.||Lucato LT, Otaduy MC, Barbosa ER, Machado AA, McKinney A, Bacheschi LA, et al. Proton MR spectroscopy in Wilson′s disease: Analysis of 36 cases. AJNR Am J Neuroradiol 2005;26:1066-71. |
|16.||Van Den Heuvel AG, Van der Grond J, Van Rooij LG, Van Wassenaer-van Hall HN, Hoogenraad TU, Mali WP. Differentiation between portal-systemic encephalopathy and neurodegenerative disorders in patients with Wilson disease: H1 MR Spectroscopy. Radiology 1997;203:539-43. |
|17.||Alanen A, Komu M, Penttinen M, Leino R. Magnetic resonance imaging and proton MR spectroscopy in Wilson′s disease. Br J Radiol 1999;72:749-56. |
|18.||Jayasundar R, Sahani AK, Gaikwad S, Singh S, Behari M. Proton MR Spectroscopy of basal ganglia in Wilson′s disease: Case report and review of literature. Magn Reson Imaging 2002;20:131-5. |
|19.||Chu NS. Sensory evoked potentials in Wilson′s disease. Brain 1986;109:491-501. |
|20.||King AD, Walshe JM, Kendall BE, Chinn RJ, Paley MN, Wilkinson ID, et al. Cranial MR imaging in Wilsons disease. AJR Am J Roentgenol 1996;167:1579-84. |
|21.||Raiamani K, Sharma RN, John G, Raju JM, Ganesh A, John L. Wilson′s disease in India: Clinical and laboratory manifestation in thirty patients. J Assoc Physicians India 1987;35:438-41. |
|22.||Prashnath LK, Taly AB, Sinha S, Rabishankar S, Arunodaya GR, Vasudev MK, et al. Prognostic factors in patients presenting with severe neurological forms of Wilson′s disease. QJM 2005;98:557-63. |
|23.||Dastur DK, Manghani DK, Wadia NH. Wilson diseases in India. I. Geographic, genetic, and clinical aspects in 16 families. Neurology 1968;18:21-31. |
|24.||Murthy BS, Murthy JM, Krishnaveni A, Reddy MV, Das SM. Wilson disease in south India and experience with Zinc therapy. J Assoc Physicians India 1988;36:417-9. |
|25.||Strickland GT, Leu ML. Wilson′s disease. Clinical and laboratory manifestations in 40 patients. Medicine (Baltimore) 1975;54:113-37. |
|26.||Sinha S, Jha DK, Sinha KK. Wilson′s disease in Eastern India. J Assoc Physicians India 2001;49:881-4. |
|27.||Singh DS, Bisht DB, Sharma RN, Ranganathan P, Ramakrishnan S. Wilson′s disease in South India. J Assoc Physicians India 1978;26:217-22. |
|28.||Jha SK, Behari M, Ahuja GK. Wilson′s disease: Clinical and radiological features. J Assoc Physicians India 1998;46:602-5. |
|29.||Prashnath LK, Taly AB, Sinha S, Arunadaya GR, Swamy HS. Wilson′s disease: Diagnostic errors and clinical implication. J Neurol Neurosurg Psychiatry 2004;75:907-9. |
|30.||Sinha S, Taly AB, Prashanth LK, Rabishankar S, Arunodaya GR, Vasudev MK. Sequential MRI changes in Wilson′s disease with de-coppering therapy: A study of 50 patients. Br J Radiol 2007;80:744-9. |
|31.||Magalhaes AC, Caramelli P, Menezes JR, Lo LS, Bacheschi LA, Barbosa ER, et al. Wilson′s disease: MRI with clinical correlation. Neuroradiology 1994;36:97-100. |
|32.||Thuomas KA, Aquilonius SM, Bergstorm K, Westermark K. Magnetic resonance imaging of the brain in Wilson′s disease. Neuroradiology 1993;35:134-41. |
|33.||Sinha S, Taly AB, Ravishankar S, Prashanth LK, Venugopal KS, Arunodaya GR, et al. Wilson′s disease: Cranial MRI observation and clinical correlation. Neuroradiology 2006;48:613-21. |
|34.||Prayer L, Wimberger D, Kramer J, Grimm G, Oder W, Imhof H. Cranial MRI in Wilson′s disease. Neuroradiology 1990;32:211-4. |
|35.||van Wassenaer-van Hall HN, van den Heuvel AG, Algra A, Hoogenraad TU, Mali WP. Wilson disease: Findings at MR imaging and CT of the brain with clinical correlation. Radiology 1996;198:531-6. |
|36.||Kishibayashi J, Segawa F, Kamada K, Sunohara N. Study of diffusion weighted magnetic resonance imaging in Wilson′s disease. Rinsho Shinkeigaku 1993;33:1086-9. |
|37.||Kraft E, Trenkwalder C, Then Bergh F, Auer DP. Magnetic resonance proton spectroscopy of the brain in Wilson′s disease. J Neurol 1999;246:693-9. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
|This article has been cited by|
||Diagnostik des Morbus Wilson
| ||W. Hermann,D. Huster |
| ||Der Nervenarzt. 2018; 89(2): 115 |
|[Pubmed] | [DOI]|
||Study on Lesion Assessment of Cerebello-Thalamo-Cortical Network in Wilson’s Disease with Diffusion Tensor Imaging
| ||Anqin Wang,Hongli Wu,Chunsheng Xu,Lanfeng Tang,Jaeyoun Lee,Min Wang,Man Jiang,Chuanfu Li,Qi Lu,Chunyun Zhang |
| ||Neural Plasticity. 2017; 2017: 1 |
|[Pubmed] | [DOI]|
||Social cognition in Wilson’s disease: A new phenotype?
| ||Elodie Peyroux,Nelly Santaella,Emmanuel Broussolle,Caroline Rigard,Emilie Favre,Anne-Sophie Brunet,Muriel Bost,Alain Lachaux,Caroline Demily,Marina A. Pavlova |
| ||PLOS ONE. 2017; 12(4): e0173467 |
|[Pubmed] | [DOI]|
||Tableau encéphalitique révélant une maladie de Wilson chez un garçon de 12 ans
| ||H. Benrhouma,S. Nagi,I. Kraoua,C. Drissi,I. Turki,M. Ben Hammouda |
| ||Archives de Pédiatrie. 2015; 22(8): 892 |
|[Pubmed] | [DOI]|