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Adult-onset Krabbe disease presenting as acute hemiparesis and progressive demyelination detected by diffusion-weighted imaging
Journal of the Neurological Sciences 367 (2016) 326–328
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Adult-onset Krabbe disease presenting as acute hemiparesis and progressive demyelination detected by diffusionweighted imaging Keywords: Krabbe disease Globoid cell leukodystrophy Adult onset Acute progression Diffusion-weighted imaging
1. Introduction Krabbe disease, or globoid cell leukodystrophy, is a rare autosomal recessive hereditary disease caused by a deficiency of lysosomal galactocerebrosidase (GALC) activity [1]. GALC deficiency causes the accumulation of the intermediate metabolites galactosylceramide and cytotoxic galactosylsphingosine (psychosine), which results in the demyelination of both the central and peripheral nervous system [1]. Although most cases are diagnosed in infancy, recently, there has been increased reporting of cases of late-onset Krabbe disease first exhibiting symptoms at 7 months or older [2]. Although the clinical manifestation of adult-form Krabbe disease is heterogeneous and varied, typical symptoms are slowly progressive spastic paraplegia/quadriplegia and sensorimotor neuropathy. Acute progression is very rare [3]. Here, we report a case of adult-onset Krabbe disease that initially presented with acute hemiplegia followed by repetitive remission and exacerbation. As the MRI findings during the acute phase were quite distinctive, we considered that MRI would be useful in evaluating the progression of Krabbe disease. 2. Case report A 24-year-old Japanese woman, who had suddenly developed difficulty writing with her right hand when she was 20 years old, had gradually developed right-sided hemiparesis. Initially, she was diagnosed with acute brain infarction based on the abnormality of her brain MRI. However, because of her age and atypical manifestation, she visited our hospital for further investigation of her illness. She had no family history of neurological diseases, and her parents were not consanguineous. Neurological examination revealed mild right-sided hemiparesis with markedly decreased deep tendon reflexes, right Babinski and Chaddock signs, bilateral pes cavus, and decreased vibratory sensation in distal limbs. Right-sided hemiparesis was temporarily exacerbated by warming, which is similar to Uhthoff's phenomenon as seen in multiple sclerosis (MS). Brain MRI disclosed high signal intensity lesions in the left precentral cortex and along the left pyramidal tract on T2-weighted images (T2WI) and fluid-attenuated inversion recovery (FLAIR) images. No gadolinium
http://dx.doi.org/10.1016/j.jns.2016.06.026 0022-510X/© 2016 Elsevier B.V. All rights reserved.
enhancement was observed in the lesion. The pyramidal tract showed restricted water diffusion at the level of the cortex on Diffusion-weighted image (DWI) with correlation on apparent diffusion coefficient (ADC) maps (Fig. 1A). Routine laboratory tests and cerebrospinal fluid analysis, including the oligoclonal band and myelin basic protein, were normal. Nerve conduction studies showed decreased motor and sensory conduction velocity in all tested nerves, and a sural nerve biopsy revealed the loss of small fiber and thin myelin sheaths, which were consistent with a demyelinating polyneuropathy. After hospitalization, the patient's condition gradually improved with only conservative management, and the patient was discharged after approximately 1 month. One year later, when the patient was 21 years old, the patient's left upper and lower limbs suddenly weakened. According to a brain MRI at that time, the restricted diffusion seen previously in the left pyramidal tract had disappeared, and a new hyperintense area on T2WI images with a partial diffusion restriction was found in the right pyramidal tract (Fig. 1B). Again, the patient's condition gradually improved, and she was discharged without any treatment. Thereafter, her muscle weakness gradually advanced, showing repeated remission and exacerbation. Neurological examination showed mild spastic tetraparesis with bilateral Babinski's sign and increased muscle tone on bilateral limbs. Further, she experienced gradual mental deterioration. A nerve conduction study indicated that her demyelinating polyneuropathy did not worsen significantly. A follow-up MRI performed at age 24 revealed that the hyperintensity on T2WI and FLAIR images along bilateral corticospinal tracts was slightly enlarged and extended across the corpus callosum. High signal areas on DWI disappeared (Fig. 1C). Progressive bilateral pyramidal tract lesions with a demyelinating polyneuropathy raised the possibility of metabolic diseases, and enzymatic studies were performed. It revealed decreased GALC activity in the leucocytes (0.1–0.2 nmol/h/mg; normal range N 1) and in the skin fibroblasts (0.2–0.2 nmol/h/mg), confirming the diagnosis of Krabbe disease. The GALC activity in the leucocytes of her parents was also low; therefore, the parents were considered to be genetic carriers. Results of other tests, including very long chain fatty acids and arylsulfatase A, were normal.
3. Discussion The MRI findings of the present case include changes in the posterior predominant white matter, a lesion of the corpus callosum, and hyperintense lesions along the pyramidal tract on T2WI and FLAIR images. These findings are consistent with previous reports of MRI findings in adult-onset Krabbe disease [3–5]. The incidence of lesions along the pyramidal tract, as observed in the present case, was as high as 82–94% in late-onset Krabbe disease patients. This observation is important in differentiating Krabbe disease from MS [3,5]. Meanwhile, the present case exhibited increased signal intensity on DWI and decreased ADC, which indicate restricted diffusion. No previous reports have mentioned a case of Krabbe disease with restricted diffusion corresponding to the exacerbation of the condition. In other
Letter to the Editor
327
Fig. 1. Brain MRI findings. A: MRI at 20 years of age: Hyperintensity on T2WI (TR 3000 ms, TE 100 ms) in the subcortical white matter of the motor area (arrow) extending along the corticospinal tract. The lesion with high DWI (TR 3768.7 ms, TE 88.0 ms) signals and low ADC, which represent restricted diffusion, was observed in the area of T2WI signal abnormalities. B: At 21 years of age: A brain MRI was taken due to the patient's weakness of the left upper and lower limbs. A hyperintense area appeared along the right upper corticospinal tract on T2WI (arrow). The lesion with restricted diffusion previously seen in the left pyramidal tract disappeared, and high signal intensity on DWI was observed within the T2WI signal abnormalities of the right subcortical lesion. C: At 24 years of age: High intensity lesions on T2WI in the bilateral pyramidal tract have slightly extended (arrow). High DWI signal lesions have disappeared. T2WI: T2-weighted images; DWI: Diffusion-weighted image; ADC: apparent diffusion coefficient.
lysosomal diseases, restricted diffusion, similar to the present case, has been observed, reflecting progressive demyelination [6]. Meanwhile, some MS cases have shown restricted diffusion consistent with acute demyelinating lesions [7]. As for the mechanism of demyelinating lesions that manifest with restricted diffusion, Inal et al. mentioned cellular infiltration induced by the process of inflammation, cytotoxic edema, demyelination, and remyelination [7]. The possible cause of demyelination in Krabbe disease is the involvement of inflammatory conditions induced by the activation of microglia or astrocytes [8]. If localized, inflammation may have induced demyelination. The progression of demyelination in the present case could then be detected by the restricted diffusion. In general, the clinical course of late-onset Krabbe disease, particularly the adult form, is considered to be mostly chronic and slowly progressive. There have been only two reported cases of acute exacerbation similar to the present one. Tomás reported a case of adolescent-onset Krabbe disease, initially diagnosed as MS due to subacute hemiplegia [9]. Arenson reported a case of late-onset Krabbe disease, initially diagnosed as acute disseminated encephalomyelitis; the patient experienced rapid deterioration after infection, becoming bedridden in less than three months [10]. The present report is significant in that it shows the possibility of using MRI to obtain data that reflects the progressive demyelinating process, even though the clinical course of adult-form Krabbe disease
from acute onset to acute exacerbation is very rare. It has the important implication that diffusion-weighted MR imaging is helpful in assessing the progression of Krabbe disease during the follow-up period. Disclosure The authors report no conflicts of interest. Acknowledgments This study was funded by a Scientific Research Grant (C) (No. 26460901) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Dr. A. Ishii (Department of Neurology, Faculty of Medicine, University of Tsukuba), for the findings of nerve biopsy of the patient. References [1] K. Suzuki, Globoid cell leukodystrophy (Krabbe's disease): update, J. Child Neurol. 18 (2003) 595–603. [2] M.A. Hossain, T. Otomo, S. Saito, K. Ohno, H. Sakuraba, Y. Hamada, et al., Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form, Gene 534 (2014) 144–154. [3] R. Debs, R. Froissart, P. Aubourg, C. Papeix, C. Douillard, B. Degos, et al., Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review, J. Inherit. Metab. Dis. 36 (2013) 859–868.
328
Letter to the Editor
[4] L. Farina, A. Bizzi, G. Finocchiaro, D. Pareyson, A. Sghirlanzoni, B. Bertagnolio, et al., MR imaging and proton MR spectroscopy in adult krabbe disease, AJNR Am. J. Neuroradiol. 21 (2000) 1478–1482. [5] A.N. Abdelhalim, R.A. Alberico, A.L. Barczykowski, P.K. Duffner, Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype, Pediatr. Neurol. 50 (2014) 127–134. [6] Z. Seidl, M. Vaneckova, T. Vitak, Metachromatic leukodystrophy: magnetic resonance imaging (diffusion weighted image–DWI), Neuro Endocrinol. Lett. 29 (2008) 428–430. [7] M. Inal, B. Unal, I. Kala, Y. Turkel, Y.K. Bilgili, ADC evaluation of the corticospinal tract in multiple sclerosis, Acta Neurol. Belg. 115 (2015) 105–109. [8] I. Mohri, M. Taniike, H. Taniguchi, T. Kanekiyo, K. Aritake, T. Inui, et al., Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher, J. Neurosci. 26 (2006) 4383–4393. [9] J. Tomás, J. Durães, L. Lacerda, M.C. Macário, Adolescent-onset Krabbe disease with an initial diagnosis of multiple sclerosis and a novel mutation, BMJ Case Rep. (2015)http://dx.doi.org/10.1136/bcr-2015-210625. [10] N.E. Arenson, P.T. Heydemann, Late-onset Krabbe's disease mimicking acute disseminated encephalomyelitis, Pediatr. Neurol. 33 (2005) 208–210.
Naomi Mamada Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Kiyotaka Nakamagoe Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Corresponding author. E-mail address: [email protected]
Ayako Shioya Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Junichi Furuta Department of Dermatology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Norio Sakai Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Suita, Japan Akiko Ishii Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Akira Tamaoka Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan 16 March 2016
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Adult-onset Krabbe disease presenting as acute hemiparesis and progressive demyelination detected by diffusionweighted imaging Keywords: Krabbe disease Globoid cell leukodystrophy Adult onset Acute progression Diffusion-weighted imaging
1. Introduction Krabbe disease, or globoid cell leukodystrophy, is a rare autosomal recessive hereditary disease caused by a deficiency of lysosomal galactocerebrosidase (GALC) activity [1]. GALC deficiency causes the accumulation of the intermediate metabolites galactosylceramide and cytotoxic galactosylsphingosine (psychosine), which results in the demyelination of both the central and peripheral nervous system [1]. Although most cases are diagnosed in infancy, recently, there has been increased reporting of cases of late-onset Krabbe disease first exhibiting symptoms at 7 months or older [2]. Although the clinical manifestation of adult-form Krabbe disease is heterogeneous and varied, typical symptoms are slowly progressive spastic paraplegia/quadriplegia and sensorimotor neuropathy. Acute progression is very rare [3]. Here, we report a case of adult-onset Krabbe disease that initially presented with acute hemiplegia followed by repetitive remission and exacerbation. As the MRI findings during the acute phase were quite distinctive, we considered that MRI would be useful in evaluating the progression of Krabbe disease. 2. Case report A 24-year-old Japanese woman, who had suddenly developed difficulty writing with her right hand when she was 20 years old, had gradually developed right-sided hemiparesis. Initially, she was diagnosed with acute brain infarction based on the abnormality of her brain MRI. However, because of her age and atypical manifestation, she visited our hospital for further investigation of her illness. She had no family history of neurological diseases, and her parents were not consanguineous. Neurological examination revealed mild right-sided hemiparesis with markedly decreased deep tendon reflexes, right Babinski and Chaddock signs, bilateral pes cavus, and decreased vibratory sensation in distal limbs. Right-sided hemiparesis was temporarily exacerbated by warming, which is similar to Uhthoff's phenomenon as seen in multiple sclerosis (MS). Brain MRI disclosed high signal intensity lesions in the left precentral cortex and along the left pyramidal tract on T2-weighted images (T2WI) and fluid-attenuated inversion recovery (FLAIR) images. No gadolinium
http://dx.doi.org/10.1016/j.jns.2016.06.026 0022-510X/© 2016 Elsevier B.V. All rights reserved.
enhancement was observed in the lesion. The pyramidal tract showed restricted water diffusion at the level of the cortex on Diffusion-weighted image (DWI) with correlation on apparent diffusion coefficient (ADC) maps (Fig. 1A). Routine laboratory tests and cerebrospinal fluid analysis, including the oligoclonal band and myelin basic protein, were normal. Nerve conduction studies showed decreased motor and sensory conduction velocity in all tested nerves, and a sural nerve biopsy revealed the loss of small fiber and thin myelin sheaths, which were consistent with a demyelinating polyneuropathy. After hospitalization, the patient's condition gradually improved with only conservative management, and the patient was discharged after approximately 1 month. One year later, when the patient was 21 years old, the patient's left upper and lower limbs suddenly weakened. According to a brain MRI at that time, the restricted diffusion seen previously in the left pyramidal tract had disappeared, and a new hyperintense area on T2WI images with a partial diffusion restriction was found in the right pyramidal tract (Fig. 1B). Again, the patient's condition gradually improved, and she was discharged without any treatment. Thereafter, her muscle weakness gradually advanced, showing repeated remission and exacerbation. Neurological examination showed mild spastic tetraparesis with bilateral Babinski's sign and increased muscle tone on bilateral limbs. Further, she experienced gradual mental deterioration. A nerve conduction study indicated that her demyelinating polyneuropathy did not worsen significantly. A follow-up MRI performed at age 24 revealed that the hyperintensity on T2WI and FLAIR images along bilateral corticospinal tracts was slightly enlarged and extended across the corpus callosum. High signal areas on DWI disappeared (Fig. 1C). Progressive bilateral pyramidal tract lesions with a demyelinating polyneuropathy raised the possibility of metabolic diseases, and enzymatic studies were performed. It revealed decreased GALC activity in the leucocytes (0.1–0.2 nmol/h/mg; normal range N 1) and in the skin fibroblasts (0.2–0.2 nmol/h/mg), confirming the diagnosis of Krabbe disease. The GALC activity in the leucocytes of her parents was also low; therefore, the parents were considered to be genetic carriers. Results of other tests, including very long chain fatty acids and arylsulfatase A, were normal.
3. Discussion The MRI findings of the present case include changes in the posterior predominant white matter, a lesion of the corpus callosum, and hyperintense lesions along the pyramidal tract on T2WI and FLAIR images. These findings are consistent with previous reports of MRI findings in adult-onset Krabbe disease [3–5]. The incidence of lesions along the pyramidal tract, as observed in the present case, was as high as 82–94% in late-onset Krabbe disease patients. This observation is important in differentiating Krabbe disease from MS [3,5]. Meanwhile, the present case exhibited increased signal intensity on DWI and decreased ADC, which indicate restricted diffusion. No previous reports have mentioned a case of Krabbe disease with restricted diffusion corresponding to the exacerbation of the condition. In other
Letter to the Editor
327
Fig. 1. Brain MRI findings. A: MRI at 20 years of age: Hyperintensity on T2WI (TR 3000 ms, TE 100 ms) in the subcortical white matter of the motor area (arrow) extending along the corticospinal tract. The lesion with high DWI (TR 3768.7 ms, TE 88.0 ms) signals and low ADC, which represent restricted diffusion, was observed in the area of T2WI signal abnormalities. B: At 21 years of age: A brain MRI was taken due to the patient's weakness of the left upper and lower limbs. A hyperintense area appeared along the right upper corticospinal tract on T2WI (arrow). The lesion with restricted diffusion previously seen in the left pyramidal tract disappeared, and high signal intensity on DWI was observed within the T2WI signal abnormalities of the right subcortical lesion. C: At 24 years of age: High intensity lesions on T2WI in the bilateral pyramidal tract have slightly extended (arrow). High DWI signal lesions have disappeared. T2WI: T2-weighted images; DWI: Diffusion-weighted image; ADC: apparent diffusion coefficient.
lysosomal diseases, restricted diffusion, similar to the present case, has been observed, reflecting progressive demyelination [6]. Meanwhile, some MS cases have shown restricted diffusion consistent with acute demyelinating lesions [7]. As for the mechanism of demyelinating lesions that manifest with restricted diffusion, Inal et al. mentioned cellular infiltration induced by the process of inflammation, cytotoxic edema, demyelination, and remyelination [7]. The possible cause of demyelination in Krabbe disease is the involvement of inflammatory conditions induced by the activation of microglia or astrocytes [8]. If localized, inflammation may have induced demyelination. The progression of demyelination in the present case could then be detected by the restricted diffusion. In general, the clinical course of late-onset Krabbe disease, particularly the adult form, is considered to be mostly chronic and slowly progressive. There have been only two reported cases of acute exacerbation similar to the present one. Tomás reported a case of adolescent-onset Krabbe disease, initially diagnosed as MS due to subacute hemiplegia [9]. Arenson reported a case of late-onset Krabbe disease, initially diagnosed as acute disseminated encephalomyelitis; the patient experienced rapid deterioration after infection, becoming bedridden in less than three months [10]. The present report is significant in that it shows the possibility of using MRI to obtain data that reflects the progressive demyelinating process, even though the clinical course of adult-form Krabbe disease
from acute onset to acute exacerbation is very rare. It has the important implication that diffusion-weighted MR imaging is helpful in assessing the progression of Krabbe disease during the follow-up period. Disclosure The authors report no conflicts of interest. Acknowledgments This study was funded by a Scientific Research Grant (C) (No. 26460901) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Dr. A. Ishii (Department of Neurology, Faculty of Medicine, University of Tsukuba), for the findings of nerve biopsy of the patient. References [1] K. Suzuki, Globoid cell leukodystrophy (Krabbe's disease): update, J. Child Neurol. 18 (2003) 595–603. [2] M.A. Hossain, T. Otomo, S. Saito, K. Ohno, H. Sakuraba, Y. Hamada, et al., Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form, Gene 534 (2014) 144–154. [3] R. Debs, R. Froissart, P. Aubourg, C. Papeix, C. Douillard, B. Degos, et al., Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review, J. Inherit. Metab. Dis. 36 (2013) 859–868.
328
Letter to the Editor
[4] L. Farina, A. Bizzi, G. Finocchiaro, D. Pareyson, A. Sghirlanzoni, B. Bertagnolio, et al., MR imaging and proton MR spectroscopy in adult krabbe disease, AJNR Am. J. Neuroradiol. 21 (2000) 1478–1482. [5] A.N. Abdelhalim, R.A. Alberico, A.L. Barczykowski, P.K. Duffner, Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype, Pediatr. Neurol. 50 (2014) 127–134. [6] Z. Seidl, M. Vaneckova, T. Vitak, Metachromatic leukodystrophy: magnetic resonance imaging (diffusion weighted image–DWI), Neuro Endocrinol. Lett. 29 (2008) 428–430. [7] M. Inal, B. Unal, I. Kala, Y. Turkel, Y.K. Bilgili, ADC evaluation of the corticospinal tract in multiple sclerosis, Acta Neurol. Belg. 115 (2015) 105–109. [8] I. Mohri, M. Taniike, H. Taniguchi, T. Kanekiyo, K. Aritake, T. Inui, et al., Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher, J. Neurosci. 26 (2006) 4383–4393. [9] J. Tomás, J. Durães, L. Lacerda, M.C. Macário, Adolescent-onset Krabbe disease with an initial diagnosis of multiple sclerosis and a novel mutation, BMJ Case Rep. (2015)http://dx.doi.org/10.1136/bcr-2015-210625. [10] N.E. Arenson, P.T. Heydemann, Late-onset Krabbe's disease mimicking acute disseminated encephalomyelitis, Pediatr. Neurol. 33 (2005) 208–210.
Naomi Mamada Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Kiyotaka Nakamagoe Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Corresponding author. E-mail address: [email protected]
Ayako Shioya Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Junichi Furuta Department of Dermatology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Norio Sakai Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Suita, Japan Akiko Ishii Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan Akira Tamaoka Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan 16 March 2016