Clinical Neurology and Neurosurgery 127 (2014) 1–4
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Clinical characteristics associated with corticospinal tract hyperintensity on magnetic resonance imaging in patients with amyotrophic lateral sclerosis Yu Kono ∗ , Renpei Sengoku, Hidetaka Mitsumura, Keiko Bono, Kenichi Sakuta, Mikihito Yamasaki, Soichiro Mochio, Yasuyuki Iguchi Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 3 February 2014 Received in revised form 22 August 2014 Accepted 19 September 2014 Available online 2 October 2014 Keywords: Amyotrophic lateral sclerosis Biomarker Conventional magnetic resonance imaging Corticospinal tract Diagnosis
a b s t r a c t Objective: The usefulness of conventional magnetic resonance imaging (C-MRI) for diagnosing amyotrophic lateral sclerosis (ALS) remains controversial. The aim of this study was to investigate the utility of C-MRI in identifying ALS, specifically the association between corticospinal tract (CST) hyperintensity on C-MRI and clinical characteristics in patients with ALS. Methods: Between June 2008 and April 2012, we retrospectively enrolled consecutive patients diagnosed with sporadic ALS who underwent C-MRI. Patients with ALS were classified as definite-phase ALS (D-ALS) and indefinite-phase ALS (ID-ALS). We focused on the hyperintensity of T2-weighted images in the CST in patients with ALS. Based on the MRI results, we divided patients into two groups: a positive CST group showing CST hyperintensity; and a negative CST group with no such findings. Clinical characteristics of the two groups were compared. Results: Seventeen patients (median age, 62 years; 8 women, 9 men) were enrolled in this study, with D-ALS in eight (47%) and ID-ALS in nine (53%). Eight patients (47%) showed CST positivity. The rate of CST positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p = 0.03). Conclusions: CST positivity appears significantly increased in D-ALS patients. C-MRI can play an important role in diagnosing ALS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the lower motor neurons (LMN) and upper motor neurons (UMN) [1]. Despite technical advances in medicine over the last century, the diagnosis of sporadic ALS, particularly in the early stage, is often difficult and delayed diagnosis is not rare. This is because no robust biomarkers for diagnosis have been identified, the region of onset is typically within the UMN or LMN, and disease progression is highly variable. Electromyography can be used as a reliable examination to ascertain the involvement of LMN, but adequate biomarkers for the involvement of UMN are not yet available [2,3].
Previously, a large number of studies have focused on ascertaining the usefulness of conventional magnetic resonance imaging (C-MRI) for determining the involvement of UMN. Hyperintensity on T2-weighted imaging in the corticospinal tract (CST) can be pronounced on some studies, but the associations between clinical characteristics and hyperintensity in the CST remain controversial [3–7]. The aim of this retrospective study was thus to investigate the frequency of brain MRI lesions in patients with ALS and to clarify the association between CST hyperintensity on C-MRI and prognosis or clinical characteristics in patients with ALS. 2. Materials and methods 2.1. Patient selection
∗ Corresponding author at: Department of Neurology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Tel.: +81 33433 1111x3282; fax: +81 33578 8071. E-mail address: [email protected] (Y. Kono). http://dx.doi.org/10.1016/j.clineuro.2014.09.011 0303-8467/© 2014 Elsevier B.V. All rights reserved.
We retrospectively enrolled consecutive patients who had been diagnosed with sporadic ALS and underwent conventional MRI between June 2008 and April 2012. The diagnosis of ALS was established according to the criteria of El Escorial in the revised form of the Airlee House criteria [8]. Differentiation from other
2
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
pathological conditions was conducted with appropriate blood tests, electrophysiological examinations, and neuroimaging. None of the patients showed cognitive symptoms or extrapyramidal associated disorders. 2.2. MRI acquisition We performed C-MRI using echo-planar imaging on a 1.5-T system (Magnetom Avanto; Siemens, Germany). The following sequences were applied (according to the possibilities of the MR system). T2-weighted turbo spin-echo was performed with the following variables: repetition time (TR), 3500 ms; echo time (TE), 96 ms; echo train length, 9; slice thickness, 5 mm; slice gap, 1.5 mm; matrix size, 220 × 210; rectangular field of view, 210 cm × 210 cm; and measurement time, 2 min 15 s. Visual analyses of the T2weighted images, particularly regarding hyperintensity of the CST, were made by a neurologist and a radiologist [9,10]. Based on the results of C-MRI, we divided patients into two groups: a CST-positive group showing hyperintensity of the CST, and a CSTnegative group showing no such findings.
Table 1 Baseline clinical characteristics between positive and negative CST groups. Positive CST group (n = 8)
Negative CST group (n = 9)
p-Value
Age (years) Female (%) BMI (kg/m2 )
60 (50–65) 2 (25) 22.3(20.0–24.6)
0.413 0.402 0.386
Age at onset (y) Diagnosis latency (m) Prognosis latency (m) Bulbar/limb onset D-ALS/ID-ALS
61 (50–71) 12 (7–18) 11 (9–12) 3/5 6/2
65 (60–69) 3 (33) 18.7 (15.3–20.0) 67 (61–72) 12 (10–19) 12 (10–19) 5/5 2/7
0.413 0.718 1.000 0.772 0.030
CST, corticospinal tract; BMI, body mass index; y, years; m, months; D-ALS, definite amyotrophic lateral sclerosis; ID-ALS, probable, possible and probable laboratorysupported amyotrophic lateral sclerosis.
2.3. Clinical variables We retrospectively obtained the following clinical data from all patients based on a review of the medical records: (1) age and sex at diagnosis; (2) height in centimeters, weight in kilograms and body mass index (BMI) at diagnosis; (3) age at onset; (4) diagnosis latency; (5) symptoms at onset; (6) survival time; and (7) El Escorial diagnostic criteria fulfilled. BMI was calculated as weight/height2 . Age at onset was defined as the time when the first symptom was noticed by the patient. Diagnosis latency was defined as the time in months from symptoms onset as reported by the patient to the time of diagnosis. We categorized symptoms at onset as limb-onset or bulbar-onset. Survival time was defined as the time when the patient underwent percutaneous endoscopic gastrostomy (PEG), tracheotomy or was placed on a ventilator. Patients with ALS were classified by the El Escorial diagnostic criteria [8] as definite-phase ALS (D-ALS), which consisted of patients with definite ALS, and indefinite-phase ALS (ID-ALS), which comprised patients with probable, possible and probable laboratory-supported ALS. 2.4. Statistical analysis We initially compared clinical characteristics between CSTpositive and CST-negative groups. Continuous variables are presented as the median and interquartile range (IQR). We used the non-parametric Mann–Whitney U test for comparison of continuous variables and Fisher’s exact test for comparison of categorical variables. Values of p < 0.05 were considered significant. Statistical analysis was performed using the Statistical Package for the Social Science for Windows version 18.0 software (SPSS, Chicago, IL). This study complied with the Declaration of Helsinki with regard to investigations in humans, and the study protocol was approved by the Ethics Committee of the Jikei University School of Medicine for Biomedical Research. 3. Results We enrolled 17 ALS patients (8 women; median age, 62 years; 25th–75th percentile, 56–69 years) in this study. Eight of the 17 patients (47%) showed abnormal intensity of the CST (CST-positive group). Table 1 shows baseline clinical characteristics of the CSTpositive and -negative groups. The frequency of CST-positivity was similar between patients who initially suffered bulbar dysfunction
Fig. 1. Frequency of positive CST in patients. (A) No significant differences in frequency of CST positivity are seen between patients with symptom onset involving bulbar dysfunction (43%) and those with limb dysfunction (50%, p = 0.77). (B) Significant differences in frequency of CST-positivity are seen between D-ALS (75%) and ID-ALS (22%, p = 0.03).
(43%) and those with initial limb dysfunction (50%, p = 0.77; Fig. 1A). Interestingly, the rate of CST-positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p = 0.03; Fig. 1B). 3.1. Representative CST-positive case A 41-year-old man presented to our clinic with a 12-month history of gradually progressive weakness of bilateral upper and lower limbs. Neurological examination revealed that his memory, intelligence and other cognitive functions were normal. Cranial nerves and speech were also normal, but jaw jerk was brisk. Distal dominant weakness was evident in all four limbs. According to the Medical Research Council scale, the muscle strength of the distal upper and lower limbs was 4/5. Fasciculations were visible on the biceps, first dorsal interosseous and tibialis anterior muscles. Tendon reflexes were generally brisk, and the plantar response was bilaterally extensor. Abdominal reflex was absent. Sensory and autonomic functions were normal. Hemogram and routine biochemical investigations were normal. Results of nerve conduction studies showed normal sensory and motor conduction, including normal amplitudes of compound muscle action potentials. Needle electromyography in the right upper and lower limbs showed reduced recruitment and polyphasic motor unit potentials with the increased amplitude, and positive sharp waves were revealed in the first dorsal interosseous and tibialis anterior muscles, indicating neurogenic changes. Based on these results, D-ALS was diagnosed. Cranial MRI showed hyperintense lesions bilaterally in the posterior limbs of the internal capsules on T2-weighted imaging (Fig. 2).
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
3
Fig. 2. T2-weigheted imaging in as ALS patient. Arrows showed hyperintense lesions bilaterally in the posterior limbs of the internal capsules.
4. Discussion Our results showed that the frequency of CST-positive findings in ALS patients was approximately 47%. Factors associated with CST-positivity were the number of upper and lower motor neuron disturbances. Approximately half of ALS patients showed hyperintensity of the CST in our series. Previous studies showed that the frequencies of such qualitative findings in ALS patients vary between studies (15–76%); therefore, our results partially support a previous report [2,4]. Positive CST lesions have also been observed in healthy controls or in patients with liver failure and X-linked Charcot-Marie-Tooth disease [11,12]. However, in such cases, the hyperintensity is usually limited to the internal capsule and does not extend to the corona radiata or brainstem. In addition, Heccht et al. [13] indicated that ALS patients had significantly more hyperintense signals than age-matched controls at the precentral gyrus, centrum semiovale, capsula interna and crus cerebri. Furthermore, Pradhan et al. [14] reported that the frequencies of such qualitative findings in healthy controls are 22%. We therefore consider that hyperintensity of the CST is more sensitive findings in ALS patients. A CST-positive result could be caused by axon lysis and myelin degradation into proteins and lipids with local release of water contents. Furthermore, Mirowitz et al. [15] speculated that hyperintense foci at the posterior limb of the capsula interna in T2-weighted images from healthy subjects are due to reduced myelination of fibers. As mentioned above, we suggested that CSTpositive lesions may reflect the loss of myelinated fibers of the CTS, caused by the degeneration of motor neurons. In this study, CST-positivity was significantly more frequent in definite ALS, which has UMN involvement in three parts. This result is consistent with a previous report that CST hyperintensity on CMRI is highly sensitive for definite or probable ALS and primary lateral sclerosis (PLS) compared to possible ALS [7]. These results indicate that CST-positivity on MRI correlate with UMN involvement, which results from degeneration of pyramidal fibers [15]. We therefore consider that CST-positivity should become an important biomarker in the diagnosis of ALS. Finally, we did not find any correlations between CST positivity on C-MRI and the prognosis or clinical phenotype of ALS. Although our results are still consistent with previous reports, Charil et al. reported that CST-positivity was significantly higher in patients with limb onset compared to those with bulbar onset [7].
Regarding prognosis, CST positivity was significantly associated with the rate of deterioration in the ALS functional rating scale [5]. Such discrepancies may have arisen due to differences in sample sizes and MRI acquisition. The present study had some limitations. First, the study used a retrospective design at a single center, so the number of patients was small. Second, we did not evaluate MRI sequences other than T2-weighted imaging. Finally, we have only qualitatively evaluated CST-positivity on C-MRI. Quantitative determination of tissue parameters such as measurement of T2 relaxation time or relative proton density may be valuable for more reliable approach to evaluate pathological changes on C-MRI [6]. Actually, some reports have suggested that CST-positivity on C-MRI in ALS patients offers low sensitivity with limited specificity [2], and a weak correlation to clinical findings. These differences were attributed to the dishomogeneous samples of patients and MRI analysis. In conclusion, we found that CST-positivity was significantly increased in D-ALS patients; MRI findings may thus support physicians in making a diagnosis of ALS. Competing interests None. References [1] Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688–700. [2] Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009;8:94–109. [3] Rocha AJ, Maia Junior AC. Is magnetic resonance imaging a plausible biomarker for upper motor neuron degeneration in amyotrophic lateral sclerosis/primary lateral sclerosis or merely a useful paraclinical tool to exclude mimic syndromes? A critical review of imaging applicability in clinical routine. Arq Neuropsiquiatr 2012;70:532–9. [4] Agosta F, Chio A, Cosottini M, De Stefano N, Falini A, Mascalchi M, et al. The present and the future of neuroimaging in amyotrophic lateral sclerosis. Am J Neuroradiol 2010;31:1769–77. [5] Agosta F, Pagani E, Petrolini M, Sormani MP, Caputo D, Perini M, et al. MRI predictors of long-term evolution in amyotrophic lateral sclerosis. Eur J Neurosci 2010;32:1490–6. [6] Ding XQ, Kollewe K, Blum K, Korner S, Kehbel S, Dengler R, et al. Value of quantitative analysis of routine clinical MRI sequences in ALS. Amyotroph Lateral Scler 2011;12:406–13. [7] Charil A, Corbo M, Filippi M, Kesavadas C, Agosta F, Munerati E, et al. Structural and metabolic changes in the brain of patients with upper motor neuron disorders: a multiparametric MRI study. Amyotroph Lateral Scler 2009;10:269–79.
4
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
[8] Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293–9. [9] Cheung G, Gawel MJ, Cooper PW, Farb RI, Ang LC, Gawal MJ. Amyotrophic lateral sclerosis: correlation of clinical and MR imaging findings. Radiology 1995;194:263–70. [10] Waragai M. MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology 1997;39:847–51. [11] Filippi M, Agosta F, Abrahams S, Fazekas F, Grosskreutz J, Kalra S, et al. EFNS guidelines on the use of neuroimaging in the management of motor neuron diseases. Eur J Neurol 2010;17:526–33.
[12] Kassubek J, Bretschneider V, Sperfeld AD. Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease. J Clin Neurosci 2005;12:588–9. [13] Hecht MJ, Fellner F, Fellner C, Hilz MJ, Heuss D, Neundorfer B. MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1- and proton-density-weighted images. J Neurol Sci 2001;186:37–44. [14] Pradhan S, Yadav R, Mishra VN, Aurangabadkar K, Sawlani V. Amyotrophic lateral sclerosis with predominant pyramidal signs – early diagnosis by magnetic resonance imaging. Magn Reson Imaging 2006;24:173–9. [15] Mirowitz S, Sartor K, Gado M, Torack R. Focal signal-intensity variations in the posterior internal capsule: normal MR findings and distinction from pathologic findings. Radiology 1989;172:535–9.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Clinical characteristics associated with corticospinal tract hyperintensity on magnetic resonance imaging in patients with amyotrophic lateral sclerosis Yu Kono ∗ , Renpei Sengoku, Hidetaka Mitsumura, Keiko Bono, Kenichi Sakuta, Mikihito Yamasaki, Soichiro Mochio, Yasuyuki Iguchi Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 3 February 2014 Received in revised form 22 August 2014 Accepted 19 September 2014 Available online 2 October 2014 Keywords: Amyotrophic lateral sclerosis Biomarker Conventional magnetic resonance imaging Corticospinal tract Diagnosis
a b s t r a c t Objective: The usefulness of conventional magnetic resonance imaging (C-MRI) for diagnosing amyotrophic lateral sclerosis (ALS) remains controversial. The aim of this study was to investigate the utility of C-MRI in identifying ALS, specifically the association between corticospinal tract (CST) hyperintensity on C-MRI and clinical characteristics in patients with ALS. Methods: Between June 2008 and April 2012, we retrospectively enrolled consecutive patients diagnosed with sporadic ALS who underwent C-MRI. Patients with ALS were classified as definite-phase ALS (D-ALS) and indefinite-phase ALS (ID-ALS). We focused on the hyperintensity of T2-weighted images in the CST in patients with ALS. Based on the MRI results, we divided patients into two groups: a positive CST group showing CST hyperintensity; and a negative CST group with no such findings. Clinical characteristics of the two groups were compared. Results: Seventeen patients (median age, 62 years; 8 women, 9 men) were enrolled in this study, with D-ALS in eight (47%) and ID-ALS in nine (53%). Eight patients (47%) showed CST positivity. The rate of CST positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p = 0.03). Conclusions: CST positivity appears significantly increased in D-ALS patients. C-MRI can play an important role in diagnosing ALS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the lower motor neurons (LMN) and upper motor neurons (UMN) [1]. Despite technical advances in medicine over the last century, the diagnosis of sporadic ALS, particularly in the early stage, is often difficult and delayed diagnosis is not rare. This is because no robust biomarkers for diagnosis have been identified, the region of onset is typically within the UMN or LMN, and disease progression is highly variable. Electromyography can be used as a reliable examination to ascertain the involvement of LMN, but adequate biomarkers for the involvement of UMN are not yet available [2,3].
Previously, a large number of studies have focused on ascertaining the usefulness of conventional magnetic resonance imaging (C-MRI) for determining the involvement of UMN. Hyperintensity on T2-weighted imaging in the corticospinal tract (CST) can be pronounced on some studies, but the associations between clinical characteristics and hyperintensity in the CST remain controversial [3–7]. The aim of this retrospective study was thus to investigate the frequency of brain MRI lesions in patients with ALS and to clarify the association between CST hyperintensity on C-MRI and prognosis or clinical characteristics in patients with ALS. 2. Materials and methods 2.1. Patient selection
∗ Corresponding author at: Department of Neurology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Tel.: +81 33433 1111x3282; fax: +81 33578 8071. E-mail address: [email protected] (Y. Kono). http://dx.doi.org/10.1016/j.clineuro.2014.09.011 0303-8467/© 2014 Elsevier B.V. All rights reserved.
We retrospectively enrolled consecutive patients who had been diagnosed with sporadic ALS and underwent conventional MRI between June 2008 and April 2012. The diagnosis of ALS was established according to the criteria of El Escorial in the revised form of the Airlee House criteria [8]. Differentiation from other
2
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
pathological conditions was conducted with appropriate blood tests, electrophysiological examinations, and neuroimaging. None of the patients showed cognitive symptoms or extrapyramidal associated disorders. 2.2. MRI acquisition We performed C-MRI using echo-planar imaging on a 1.5-T system (Magnetom Avanto; Siemens, Germany). The following sequences were applied (according to the possibilities of the MR system). T2-weighted turbo spin-echo was performed with the following variables: repetition time (TR), 3500 ms; echo time (TE), 96 ms; echo train length, 9; slice thickness, 5 mm; slice gap, 1.5 mm; matrix size, 220 × 210; rectangular field of view, 210 cm × 210 cm; and measurement time, 2 min 15 s. Visual analyses of the T2weighted images, particularly regarding hyperintensity of the CST, were made by a neurologist and a radiologist [9,10]. Based on the results of C-MRI, we divided patients into two groups: a CST-positive group showing hyperintensity of the CST, and a CSTnegative group showing no such findings.
Table 1 Baseline clinical characteristics between positive and negative CST groups. Positive CST group (n = 8)
Negative CST group (n = 9)
p-Value
Age (years) Female (%) BMI (kg/m2 )
60 (50–65) 2 (25) 22.3(20.0–24.6)
0.413 0.402 0.386
Age at onset (y) Diagnosis latency (m) Prognosis latency (m) Bulbar/limb onset D-ALS/ID-ALS
61 (50–71) 12 (7–18) 11 (9–12) 3/5 6/2
65 (60–69) 3 (33) 18.7 (15.3–20.0) 67 (61–72) 12 (10–19) 12 (10–19) 5/5 2/7
0.413 0.718 1.000 0.772 0.030
CST, corticospinal tract; BMI, body mass index; y, years; m, months; D-ALS, definite amyotrophic lateral sclerosis; ID-ALS, probable, possible and probable laboratorysupported amyotrophic lateral sclerosis.
2.3. Clinical variables We retrospectively obtained the following clinical data from all patients based on a review of the medical records: (1) age and sex at diagnosis; (2) height in centimeters, weight in kilograms and body mass index (BMI) at diagnosis; (3) age at onset; (4) diagnosis latency; (5) symptoms at onset; (6) survival time; and (7) El Escorial diagnostic criteria fulfilled. BMI was calculated as weight/height2 . Age at onset was defined as the time when the first symptom was noticed by the patient. Diagnosis latency was defined as the time in months from symptoms onset as reported by the patient to the time of diagnosis. We categorized symptoms at onset as limb-onset or bulbar-onset. Survival time was defined as the time when the patient underwent percutaneous endoscopic gastrostomy (PEG), tracheotomy or was placed on a ventilator. Patients with ALS were classified by the El Escorial diagnostic criteria [8] as definite-phase ALS (D-ALS), which consisted of patients with definite ALS, and indefinite-phase ALS (ID-ALS), which comprised patients with probable, possible and probable laboratory-supported ALS. 2.4. Statistical analysis We initially compared clinical characteristics between CSTpositive and CST-negative groups. Continuous variables are presented as the median and interquartile range (IQR). We used the non-parametric Mann–Whitney U test for comparison of continuous variables and Fisher’s exact test for comparison of categorical variables. Values of p < 0.05 were considered significant. Statistical analysis was performed using the Statistical Package for the Social Science for Windows version 18.0 software (SPSS, Chicago, IL). This study complied with the Declaration of Helsinki with regard to investigations in humans, and the study protocol was approved by the Ethics Committee of the Jikei University School of Medicine for Biomedical Research. 3. Results We enrolled 17 ALS patients (8 women; median age, 62 years; 25th–75th percentile, 56–69 years) in this study. Eight of the 17 patients (47%) showed abnormal intensity of the CST (CST-positive group). Table 1 shows baseline clinical characteristics of the CSTpositive and -negative groups. The frequency of CST-positivity was similar between patients who initially suffered bulbar dysfunction
Fig. 1. Frequency of positive CST in patients. (A) No significant differences in frequency of CST positivity are seen between patients with symptom onset involving bulbar dysfunction (43%) and those with limb dysfunction (50%, p = 0.77). (B) Significant differences in frequency of CST-positivity are seen between D-ALS (75%) and ID-ALS (22%, p = 0.03).
(43%) and those with initial limb dysfunction (50%, p = 0.77; Fig. 1A). Interestingly, the rate of CST-positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p = 0.03; Fig. 1B). 3.1. Representative CST-positive case A 41-year-old man presented to our clinic with a 12-month history of gradually progressive weakness of bilateral upper and lower limbs. Neurological examination revealed that his memory, intelligence and other cognitive functions were normal. Cranial nerves and speech were also normal, but jaw jerk was brisk. Distal dominant weakness was evident in all four limbs. According to the Medical Research Council scale, the muscle strength of the distal upper and lower limbs was 4/5. Fasciculations were visible on the biceps, first dorsal interosseous and tibialis anterior muscles. Tendon reflexes were generally brisk, and the plantar response was bilaterally extensor. Abdominal reflex was absent. Sensory and autonomic functions were normal. Hemogram and routine biochemical investigations were normal. Results of nerve conduction studies showed normal sensory and motor conduction, including normal amplitudes of compound muscle action potentials. Needle electromyography in the right upper and lower limbs showed reduced recruitment and polyphasic motor unit potentials with the increased amplitude, and positive sharp waves were revealed in the first dorsal interosseous and tibialis anterior muscles, indicating neurogenic changes. Based on these results, D-ALS was diagnosed. Cranial MRI showed hyperintense lesions bilaterally in the posterior limbs of the internal capsules on T2-weighted imaging (Fig. 2).
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
3
Fig. 2. T2-weigheted imaging in as ALS patient. Arrows showed hyperintense lesions bilaterally in the posterior limbs of the internal capsules.
4. Discussion Our results showed that the frequency of CST-positive findings in ALS patients was approximately 47%. Factors associated with CST-positivity were the number of upper and lower motor neuron disturbances. Approximately half of ALS patients showed hyperintensity of the CST in our series. Previous studies showed that the frequencies of such qualitative findings in ALS patients vary between studies (15–76%); therefore, our results partially support a previous report [2,4]. Positive CST lesions have also been observed in healthy controls or in patients with liver failure and X-linked Charcot-Marie-Tooth disease [11,12]. However, in such cases, the hyperintensity is usually limited to the internal capsule and does not extend to the corona radiata or brainstem. In addition, Heccht et al. [13] indicated that ALS patients had significantly more hyperintense signals than age-matched controls at the precentral gyrus, centrum semiovale, capsula interna and crus cerebri. Furthermore, Pradhan et al. [14] reported that the frequencies of such qualitative findings in healthy controls are 22%. We therefore consider that hyperintensity of the CST is more sensitive findings in ALS patients. A CST-positive result could be caused by axon lysis and myelin degradation into proteins and lipids with local release of water contents. Furthermore, Mirowitz et al. [15] speculated that hyperintense foci at the posterior limb of the capsula interna in T2-weighted images from healthy subjects are due to reduced myelination of fibers. As mentioned above, we suggested that CSTpositive lesions may reflect the loss of myelinated fibers of the CTS, caused by the degeneration of motor neurons. In this study, CST-positivity was significantly more frequent in definite ALS, which has UMN involvement in three parts. This result is consistent with a previous report that CST hyperintensity on CMRI is highly sensitive for definite or probable ALS and primary lateral sclerosis (PLS) compared to possible ALS [7]. These results indicate that CST-positivity on MRI correlate with UMN involvement, which results from degeneration of pyramidal fibers [15]. We therefore consider that CST-positivity should become an important biomarker in the diagnosis of ALS. Finally, we did not find any correlations between CST positivity on C-MRI and the prognosis or clinical phenotype of ALS. Although our results are still consistent with previous reports, Charil et al. reported that CST-positivity was significantly higher in patients with limb onset compared to those with bulbar onset [7].
Regarding prognosis, CST positivity was significantly associated with the rate of deterioration in the ALS functional rating scale [5]. Such discrepancies may have arisen due to differences in sample sizes and MRI acquisition. The present study had some limitations. First, the study used a retrospective design at a single center, so the number of patients was small. Second, we did not evaluate MRI sequences other than T2-weighted imaging. Finally, we have only qualitatively evaluated CST-positivity on C-MRI. Quantitative determination of tissue parameters such as measurement of T2 relaxation time or relative proton density may be valuable for more reliable approach to evaluate pathological changes on C-MRI [6]. Actually, some reports have suggested that CST-positivity on C-MRI in ALS patients offers low sensitivity with limited specificity [2], and a weak correlation to clinical findings. These differences were attributed to the dishomogeneous samples of patients and MRI analysis. In conclusion, we found that CST-positivity was significantly increased in D-ALS patients; MRI findings may thus support physicians in making a diagnosis of ALS. Competing interests None. References [1] Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688–700. [2] Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009;8:94–109. [3] Rocha AJ, Maia Junior AC. Is magnetic resonance imaging a plausible biomarker for upper motor neuron degeneration in amyotrophic lateral sclerosis/primary lateral sclerosis or merely a useful paraclinical tool to exclude mimic syndromes? A critical review of imaging applicability in clinical routine. Arq Neuropsiquiatr 2012;70:532–9. [4] Agosta F, Chio A, Cosottini M, De Stefano N, Falini A, Mascalchi M, et al. The present and the future of neuroimaging in amyotrophic lateral sclerosis. Am J Neuroradiol 2010;31:1769–77. [5] Agosta F, Pagani E, Petrolini M, Sormani MP, Caputo D, Perini M, et al. MRI predictors of long-term evolution in amyotrophic lateral sclerosis. Eur J Neurosci 2010;32:1490–6. [6] Ding XQ, Kollewe K, Blum K, Korner S, Kehbel S, Dengler R, et al. Value of quantitative analysis of routine clinical MRI sequences in ALS. Amyotroph Lateral Scler 2011;12:406–13. [7] Charil A, Corbo M, Filippi M, Kesavadas C, Agosta F, Munerati E, et al. Structural and metabolic changes in the brain of patients with upper motor neuron disorders: a multiparametric MRI study. Amyotroph Lateral Scler 2009;10:269–79.
4
Y. Kono et al. / Clinical Neurology and Neurosurgery 127 (2014) 1–4
[8] Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293–9. [9] Cheung G, Gawel MJ, Cooper PW, Farb RI, Ang LC, Gawal MJ. Amyotrophic lateral sclerosis: correlation of clinical and MR imaging findings. Radiology 1995;194:263–70. [10] Waragai M. MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology 1997;39:847–51. [11] Filippi M, Agosta F, Abrahams S, Fazekas F, Grosskreutz J, Kalra S, et al. EFNS guidelines on the use of neuroimaging in the management of motor neuron diseases. Eur J Neurol 2010;17:526–33.
[12] Kassubek J, Bretschneider V, Sperfeld AD. Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease. J Clin Neurosci 2005;12:588–9. [13] Hecht MJ, Fellner F, Fellner C, Hilz MJ, Heuss D, Neundorfer B. MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1- and proton-density-weighted images. J Neurol Sci 2001;186:37–44. [14] Pradhan S, Yadav R, Mishra VN, Aurangabadkar K, Sawlani V. Amyotrophic lateral sclerosis with predominant pyramidal signs – early diagnosis by magnetic resonance imaging. Magn Reson Imaging 2006;24:173–9. [15] Mirowitz S, Sartor K, Gado M, Torack R. Focal signal-intensity variations in the posterior internal capsule: normal MR findings and distinction from pathologic findings. Radiology 1989;172:535–9.
