Jung-Joon Sung

Diffusion tensor MRI as a diagnostic tool of upper motor neuron involvement in amyotrophic lateral sclerosis

BACKGROUND Clinical identification of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS) is often difficult, particularly early in the course of the disease, or when lower motor neuron (LMN) dysfunction is prominent. Diffusion tensor MR imaging (DTI) can provide unique information on axonal organization by measuring diffusion anisotropy and the directionally independent diffusion. OBJECTIVE The purpose of this study was to assess water diffusion changes along pyramidal tracts of the brainstem in patients with ALS and to investigate possible correlations between changes of diffusion properties and various clinical parameters. METHODS We studied 16 patients (M:F=9:7, 50.5+/-12.4 years) with ALS as defined by clinical and electrophysiological examinations. These patients were compared with 11 healthy, age and sex-matched controls (M:F=5:6, 54.5+/-9.9 years). DTI was performed using a single shot SE-EPI with 25 noncollinear diffusion gradient directions (b=1000 s/mm(2)) and with no diffusion gradient on a 3.0-T MR system. RESULTS By multifactorial ANOVA, the effects of group (patient versus control) and anatomical level on fractional anisotropy (FA) and mean diffusivity (MD) were significant (p<0.001 for both parameters), whereas the effect of side (left versus right) and interactions between factors (group by side and group by anatomical level) were not (p>0.05). In all subjects, FA and MD varied greatly depending on the anatomical level, and FA was highly variable even between contiguous slices in the pons and medulla, whereas relatively constant FA values were noted at the level of the midbrain. Cerebral peduncle was the only area that showed significant differences of diffusion properties between patients and controls (p<0.001 for FA, p=0.001 for MD). Correlation analysis revealed a significant inverse relationship between the FA value and the extent of UMN signs (r=-0.81, p<0.001). CONCLUSIONS Alteration of diffusion properties in the cerebral peduncle in ALS may reflect pathological changes in structures rather than regional architectural variations of the corticospinal tracts or experimental artifacts.

Reproducibility of the motor unit number index (MUNIX) in normal controls and amyotrophic lateral sclerosis patients

The motor unit number index (MUNIX) refers to an electrophysiologic technique that measures the approximate number of motor units using the surface electromyographic interference pattern (SIP) recorded during voluntary contraction. This study was done to assess the reproducibility of MUNIX performed on hypothenar muscles in 62 normal controls and 22 amyotrophic lateral sclerosis (ALS) patients. Inter‐ and intraoperator correlation coefficients for MUNIX were 0.74 and 0.86, respectively, in normal controls, and 0.95 and 0.93, respectively, in ALS patients (P < 0.01 in all). Inter‐ and intraoperator coefficients of variation for MUNIX measurements were 17.5% and 15.3%, respectively, in normal controls, and 23.7% and 24.0%, respectively, in ALS patients. This study shows a good correlation for MUNIX between intra‐ and interoperator results in both normal controls and ALS patients. The test–retest variability seems to be greater in ALS patients compared with normal controls, but this will need to be confirmed in future studies. Sources of variability should be identified and corrected for clinical use. Muscle Nerve 42: 808–813, 2010

Painful Tonic Spasm in Neuromyelitis Optica Incidence, Diagnostic Utility, and Clinical Characteristics

OBJECTIVES To evaluate the diagnostic utility and clinical characteristics of painful tonic spasm (PTS) in neuromyelitis optica (NMO). DESIGN Retrospective study. SETTING Two referral hospitals. PATIENTS Forty patients who had NMO spectrum disorder with anti-aquaporin 4 autoantibody or met the revised diagnostic criteria for definite NMO; 35 patients with multiple sclerosis; and 41 patients with idiopathic acute transverse myelitis without anti-aquaporin 4 antibody. MAIN OUTCOME MEASURES The incidence and clinical characteristics of PTS in the different groups, diagnostic value of PTS in identifying patients with NMO, and predictors of PTS in NMO. RESULTS The incidence of PTS was significantly higher in the patients with NMO (10 patients [25.0%]) than in those with multiple sclerosis (1 patient [2.9%]) or idiopathic acute transverse myelitis without anti-aquaporin 4 antibody (1 patient [2.4%]). Most PTS episodes (in 8 of 10 patients [80.0%]) in the NMO group occurred after a mean interval of 48.13 days from the onset of the first myelitis episode and were not accompanied by another demyelinating episode with its onset. Painful tonic spasm associated with myelitis had a specificity of 98.7% for identifying the NMO group. Myelitis at disease onset was a predictor of PTS in the NMO group (odds ratio = 6.545, presence vs absence). CONCLUSIONS Painful tonic spasm is a common symptom in NMO. When associated with myelitis, it is relatively specific to patients with NMO and is most commonly observed during recovery from the first myelitis episode. Patients with NMO presenting with myelitis at disease onset appear to be at higher risk for developing PTS compared with other patients with NMO.

Brain abnormalities in Sjogren syndrome with recurrent CNS manifestations: association with neuromyelitis optica.

Background and objectives Optic neuritis or longitudinally extensive myelitis in Sjogren syndrome (SS) suggests a neuromyelitis optica spectrum disorder (NMOSD). However, brain abnormalities of SS remain to be elucidated for the association with neuromyelitis optica (NMO). Methods Twelve primary SS patients (all women, 42 ± 13.2 years) who had recurrent central nervous system (CNS) manifestations with brain involvement were retrospectively identified. Brain MRI, and neurologic and serologic findings were analyzed with the measurement of anti-aquaporin-4 antibody (AQP4-Ab). Results All patients showed brain lesions characteristic of NMO as follows: 1) the involved sites adjacent to the third and fourth ventricles and in the posterior limb of the internal capsule, 2) unique configurations, such as the longitudinal course from the internal capsule to the midbrain, large cerebral or cerebellar lesions over 3 cm, and cavity-like formations. AQP4-Ab was positive in six of eight patients tested, and all the seropositive patients showed lesions with increased diffusion, suggestive of vasogenic edema. Four patients met the revised criteria of NMO, and nine had features of NMOSDs. Of the remaining three patients showing only brain involvement, one had AQP4-Ab. Conclusions This study demonstrates that SS patients with recurrent CNS involvement have brain abnormalities characteristic of NMO and AQP4-Ab in Korea. The presence of AQP4-Ab in one SS patient with only brain involvement may suggest that the coexistence of NMO should be explored in SS patients with recurrent CNS manifestations, even without optic neuritis or myelitis.

Sjogren's syndrome myelopathy: spinal cord involvement in Sjogren's syndrome might be a manifestation of neuromyelitis optica.

Objective To evaluate clinical characteristics, aquaporin (AQP)-4 antibody results, and probability of developing symptoms of neuromyelitis optica (NMO) in patients with Sjögren’s syndrome myelopathy (SSM). Methods We identified eight patients with spinal cord involvement from 112 patients with Sjögren’s syndrome (SS) referred to the neurology department. The clinical characteristics and AQP-4 antibody status, based on immunoprecipitation of EGFP-tagged AQP-4, of the patients with SSM were assessed. Results All patients with SSM had extensive spinal cord lesions, high mean annual relapse rates, and poor response to steroid treatment. Of the eight patients with SSM, seven patients satisfied the revised diagnostic criteria for NMO or showed positive results from AQP-4 antibody testing; one patient had incomplete follow-up. The clinical manifestations and AQP-4 autoantibody status of patients with SSM did not differ significantly from those of NMO patients without SS. Conclusion All patients with SSM had poor prognosis with high mean annual relapse rates, and most seemed to have the clinical and immunological characteristics of NMO. Early aggressive immune therapies should be considered in patients with SSM irrespective of the presence or absence of optic neuritis.

Brain abnormalities in neuromyelitis optica

BACKGROUND Differentiating neuromyelitis optica (NMO) from multiple sclerosis (MS) is a real challenge in the clinical field. In the past, NMO (not MS), was inferred when abnormality was not detected in the brain magnetic resonance imaging (MRI). Recently, some studies have reported abnormalities in the brain MRIs of NMO, but only few among the Asian population. The aim of this study was to evaluate the frequency of brain MRI among Korean NMO patients and characterize findings that might be helpful to distinguish NMO from MS. METHODS Medical records, NMO-IgG, and brain MRI of 17 patients diagnosed with NMO by the revised diagnostic criteria of Wingerchuk et al. (2006) [6] from 2008 to 2010, were reviewed. RESULTS 11 out of 17 patients (64.7%) had abnormal MRI findings. More than two lesions were detected in most patients. The majority of patients with brain MRI abnormality showed nonspecific (5 patients) or atypical (6 patients) findings. Cerebral white matter was most frequently involved (58.8%). 3 patients (17.6%) involved corpus callosum, 4 (23.5%) with internal capsule, 2 (11.8%) with cerebellum, and 3 (17.6%) with brainstem. There were 5 (29.4%) patients who met the Paty et al. criteria (1988) [15] and 3 patients (35.3%) who met the multiple sclerosis (MS) spatial distribution diagnostic criteria of Barkhof et al. (1997) [14] in their brain MRI. CONCLUSIONS Brain abnormalities have been frequently found among Korean NMO patients and the frequencies have been reported to be higher than that of Caucasians. Current MS spatial distribution criteria, such as Paty et al. (1988) [15] or Barkhof et al. (1997) [14], are not sufficient to discriminate NMO from MS in brain MRI findings. Our results will provide valuable information that would be useful in establishing future revising criteria for NMO.

Amyotrophic Lateral Sclerosis Is Associated with Hypolipidemia at the Presymptomatic Stage in Mice

Objective To demonstrate that hypolipidemia is a typical feature of the mouse model of amyotrophic lateral sclerosis (ALS) and to assess the association between hypolipidemia and disease stage, dietary intake, and sex. Methods We compared daily dietary intake, body weight, and serumlipid and glucose levels in ALS mice and wild-type controls at different stages of the disease. Findings Total cholesterol low-density lipoprotein (LDL) and LDL/high-density lipoprotein (HDL) ratio were significantly lower in ALS mice compared with controls. Subgroup analysis revealed that the incidence of hypolipidemia was significantly greater in male, but not female, ALS mice compared with control mice and that hypolipidemia was present at the presymptomatic stage of the disease. This hypolipidemia can be found without a decrease in the serum levels of other energy sources, such as glucose, in the presymptomatic stage. Conclusions Hypolipidemia is present at the presymptomatic stage of the ALS mouse model in the absence of malnutrition, significant neuromuscular degeneration or regeneration, and respiratory difficulty. Our findings suggest that hypolipidemia might be associated with the pathomechanism of ALS and/or lipid-specific metabolism rather than simply an epiphenomenon of neuromuscular degeneration or energy imbalance.

Clinical and electrophysiologic features of HNPP patients with 17p11.2 deletion

Objectives – Although the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is important for correct prognostic evaluation and genetic counseling, the diagnosis is frequently missed or delayed. Our main aim on undertaking this study was to characterize the electrodiagnostic features of HNPP.

Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by selective motor neuron death, and currently no effective treatment is available for ALS. In this study, we investigated the neuroprotective effects of pyruvate, which acts as an anti-oxidant and as an energy source. We treated G93A SOD1 transgenic mice with pyruvate (from 70 days of age, i.p., at 1000 mg/kg/week), and found that it prolonged average lifespan by 12.3 days (10.5%), slowed disease progression, and improved motor performance, but did not delay disease onset. Pyruvate treatment was also associated with reduced nitrotyrosine immunoreactivity, gliosis, and increased Bcl-2 expression in the spinal cords of G93A SOD1 transgenic mice. These results suggest that pyruvate treatment may be a potential therapeutic strategy in ALS.

Relation between cognitive dysfunction and reduced vital capacity in amyotrophic lateral sclerosis

Background: Many patients with amyotrophic lateral sclerosis (ALS) with cognitive impairment have fronto-temporal dysfunction. Whereas in some patients with ALS the fronto-temporal dysfunction is undoubtedly due to the degenerative process associated with the disease, in others dysfunction cannot be accounted for by an irreversible degenerative process alone, as it also appears to involve a reversible process. We hypothesised that reduced vital capacity can be a key contributor to the fronto-temporal dysfunction observed in patients with ALS. Objective: To investigate the association between fronto-temporal dysfunction and reduced vital capacity in ALS. Methods: 16 consecutive patients who conformed to a diagnosis of definite or probable ALS (El escorial criteria) were grouped by vital capacity, and their clinical characteristics and cognitive functions, including disease duration, attention, executive function and memory, were measured. Results: Patients with a reduced vital capacity performed significantly poorer in memory retention (p = 0.028), retrieval efficacy (p = 0.003), spoken verbal fluency (p = 0.03) and spoken verbal fluency indexes (p = 0.016) than those with a normal vital capacity. Conclusion: The fronto-temporal dysfunction in ALS might be attributable to potentially reversible secondary effects associated with reduced vital capacity, as well as to the primary degenerative process.