Monitoring spinal muscular atrophy with three-dimensional optoacoustic imaging.

BACKGROUND: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. METHODS: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). FINDINGS: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. CONCLUSIONS: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. FUNDING: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.

Shear Wave Elastography in Patients with Spinal Muscular Atrophy Types 2 and 3.

INTRODUCTION: This study aimed to investigate selective muscle involvement by shear wave elastography (SWE) in patients with spinal muscular atrophy (SMA) types 2 and 3 and to compare SWE values with magnetic resonance imaging (MRI) in demonstrating muscle involvement. METHODS: Seventeen patients with SMA types 2 and3 were included in the study. SWE was used to evaluate stiffness of the upper and lower extremities and paraspinal muscles. Involvement of the paraspinal muscles was evaluated using 1.5-T MRI. RESULTS: Among the upper extremity muscles, SWE values were the highest for the triceps brachii; however, no significant difference was noted (p = 0.23). In post hoc analysis, a significant difference was observed between triceps brachii and biceps brachii (p = 0.003). Patients with a longer disease duration have the highest SWE values for the triceps brachii (r = 0.67, p = 0.003). Among the lower extremity muscles, SWE values for the iliopsoas were significantly higher than the gluteus maximus (p < 0.001). A positive correlation was found between SWE values and MRI scores of paraspinal muscles (r = 0.49, p = 0.045; r = 0.67, p = 0.003). CONCLUSION: This is the first study to report muscle involvement assessed by SWE in patients with SMA types 2 and 3. Our findings are similar to the presence of selective muscle involvement demonstrated in previous studies, and also SWE and MRI values were similar. SWE is an alternative noninvasive practical method that can be used to demonstrate muscle involvement in patients with SMA, to understand the pathogenesis of segmental involvement, and to guide future treatments or to monitor the effectiveness of existing new treatment options.

Hirayama Disease: A 15-Year-Old Male With Progressive Distal Right Upper Extremity Weakness.

INTRODUCTION: Hirayama disease is a rare neuromuscular disorder characterized by abnormal forward displacement of the cervical spinal cord, resulting in focal ischemic changes of anterior horn cells. CASE REPORT: A 15-year-old male presented with 6 months of progressive right upper extremity weakness. Electromyography/nerve conduction study indicated a chronic neurogenic process involving the C8-T1 myotome. Cervical spine magnetic resonance imaging in the neutral position demonstrated minor disk bulges without significant spinal canal narrowing. With flexion, there was a forward displacement of the dorsal dural sac and marked effacement of the subarachnoid spaces from vertebral levels C5 through C7. In addition, prominent flow voids were now seen in the dorsal epidural space consistent with engorged venous structures. CONCLUSION: The diagnosis of Hirayama disease requires a high index of suspicion, and imaging should include a series with the neck in a flexed position, as imaging in the neutral position is often unrevealing and the disorder can otherwise easily be missed.

Hirayama Disease: Case Report / Doença de Hirayama: Relato de caso

Abstract A 26-year-old previously healthy patient who, at the age of 18 years, began progressive loss of distal strength, rest tremor, and muscle atrophy in the left upper limb. Upon examination, the patient presented moderate distal atrophy, degree 4 in muscular strength, and minipolymioclonus. Electromyoneurography revealed (EMNG) chronic preganglionic bilateral involvement of bilateral C7/C8/T1, worse on the left, with signs of active C8/T1 denervation. A cervical spine magnetic resonance imaging (MRI) scan showed spondylodiscal degenerative changes with central protrusions in C4-C5, C6-C7, and right central in C5-C6, which touched the dural sac. The anteroposterior diameter of the medulla in neutral position, in the C5-C6 plane, was of 5.1 mm. There was a reduction of the spinal cord caliber to 4.0 mm after the dynamic maneuver of forced flexion of the spine, as well as signal increase in the anterior horns. The clinical findings and those of the complementary tests were compatible with Hirayama disease (HD), a rare benign motor neuron disease that affects cervical spinal segments and is most prevalent in men, with onset in the early 20s. Unilateral and slowly progressive weakness is typical, but self-limited. Sensory disturbances, and autonomic and upper motor neuron signals are rare. Management is usually conservative, with the use of a soft cervical collar. Although rare, HD should be considered in young patients with focal asymmetric atrophy in the upper limbs. The early diagnosis of HD depends on the degree of suspicion, as well as on the cooperation and communication among the various specialties involved in the investigation.

Resumo Paciente de 26 anos, previamente hígido, que, aos 18 anos, iniciou perda progressiva de força distal, tremor de repouso, e atrofia muscular no membro superior esquerdo. Ao exame, apresentou atrofia moderada, distal, força muscular de grau 4, e minipolimioclonus. A eletroneuromiografia (ENMG) revelou comprometimento pré-ganglionar crônico de C7/C8/T1 bilateral pior à esquerda, com sinais de desnervação ativa em C8/T1. A ressonância magnética (RM) de coluna cervical mostrou alterações degenerativas espondilodiscais com protrusões centrais em C4-C5, C6-C7, e central direita em C5-C6, que tocavam o saco dural. O diâmetro anteroposterior da medula na posição neutra, no plano de C5-C6, era de 5,1 mm. Houve redução do calibre da medula para 4,0 mm após a manobra dinâmica de flexão forçada da coluna, e aumento de sinal nos cornos anteriores. Os achados clínicos e os dos exames complementares eram compatíveis com doença de Hirayama (DH), uma doença benigna rara dos neurônios motores, que afeta os segmentos espinhais cervicais e é mais prevalente em homens e de início próximo aos 20 anos. É típica a fraqueza unilateral e lentamente progressiva, porém autolimitada. Perturbações sensoriais, sinais autonômicos e do neurônio motor superior são raras. O manejo geralmente é conservador, com uso de colar cervical macio. Apesar de rara, a DH deve ser considerada em pacientes jovens que apresentam atrofias assimétricas focais de membros superiores. O diagnóstico precoce de DH depende do grau de suspeição, e da cooperação e comunicação entre as diversas especialidades envolvidas na investigação.

Juvenile muscular atrophy of the distal upper extremity (Hirayama syndrome): a systematic review.

INTRODUCTION: Hirayama syndrome is likely caused by a forward displacement of the posterior dura during cervical flexion leading to changes in the muscles of the fingers and wrist. The aim of this systematic review was to document the number of reported cases, the necessity of dynamic MRI of the cervical spine and the subsequent treatment. METHODS AND MATERIALS: A systematic review was conducted and the Pubmed/Medbase, Cochrane, Google, Embase and Ovid database were searched for (Hirayama) AND ((disease) OR (syndrome)). A total of 42 studies were included for analysis reporting 2311 patients. RESULTS: The mean age was 20.2 ± 2.26 years and predominantly males (92.8%) were identified. On MRI the "snake eyes" appearance of the spinal cord was present in 27.8% and the typical time between onset of symptoms and diagnosis was 41.5 ± 16.4 months. A variety of different treatments have been reported, although there is no substantial evidence that any of them are superior to observation. CONCLUSION: The delay in diagnosis from initial presentation of symptoms shows that this condition may be underdiagnosed in a variety of cases. Further, this study shows the necessity of either a dynamic MRI in flexion or a static MRI scan in neutral position and in flexion, to identify functional spinal and/or foraminal stenosis for a prompt diagnosis and subsequent treatment.

Hirayama disease: Nosological classification and neuroimaging clues for diagnosis.

Hirayama disease (HD) is a rare, benign, and nonprogressive motor neuron disease (MND) affecting the upper limbs. It usually presents with weakness and amyotrophy in a single upper extremity with an insidious onset between adolescence and the third decade of life. Since its description in 1959, HD has been known under several names and eponyms in Europe and in Asian countries probably due to its heterogeneous clinical features. Thus, the unclear nosological classification makes challenging the differential diagnosis between HD and other neuromuscular conditions, such as MNDs. However, apart from the nosological difficulties and the lack of evidence-based guideline for diagnosis, the neuroimaging is the mainstay for the diagnosis of HD. Indeed, the specific findings on cervical flexion MRI usually lead to a prompt diagnosis. Here, we reviewed the nosological classifications of HD and its neuroimaging features. Also, we report a case of a 18-year-old boy who presented to our Clinic complaining of muscle weakness of the left distal upper limb without other neurological signs. The cervical MRI, in the neutral position, revealed a high T2 signal intensity in the C5-C7 cervical myelomeres as well as the loss of cervical lordosis, whereas, during neck flexion, it showed the anterior displacement of the posterior dura ad the post-gadolinium T1-weighted imaging enhancement of the posterior epidural plexus. These findings are typical for HD allowing the diagnosis as well as the differential diagnosis from other neuromuscular diseases.

Why the patients with Hirayama disease have abnormal cervical sagittal alignment? A radiological measurement analysis of posterior cervical extensors.

PURPOSE: To explore the relationship between the strength of posterior cervical extensors (PCEs) and cervical sagittal alignment in Hirayama disease (HD) patients. METHODS: We analyzed the (magnetic resonance imaging) MRI T2WI and X-rays of 60 HD patients who visited Huashan Hospital from June 2017 to February 2020. Symptoms of these patients include adolescent onset, manifestation of unilateral upper limb muscle weakness and muscle atrophy of the forearm and hand. MRI images were used to measure (the cross-sectional area) CSA of cervical PCEs. The ratio of muscle CSA to vertebral body areas at the same level is defined as R-CSA. Cervical sagittal alignment includes the C2-7 Cobb angle, T1 slope and C2-7 sagittal vertical axis (SVA). The geometric center of the C3-6 vertebral body was determined using the line connecting the C2 inferior endplate and the C7 upper endplate. When located behind the line, it is defined as a "local kyphotic deformity." The number of vertebral bodies involved in kyphotic deformity was determined by measuring the local kyphosis angle (LKA). Spearman correlation analysis (α = 0.05) was used to determine the relationship between R-CSA and sagittal parameters. ROC curves were used to analyze the sensitivity and specificity of relevant variables. RESULTS: Spearman correlation test revealed that R-CSA negatively correlated with T1S (S = 0.34, r = 0.34, p = 0.01) and LKA (S = 0.44, r = 0.5, p = 0.01), but did not correlate with the C2-C7 Cobb angle (S = 0.20, p = 0.12) or C2-C7 SVA (S = - 0.17, p = 0.46). (p < 0.05). ROC curve analysis showed that the areas under the curve (AUCs) of the T1 slope and LKA was 0.6696 and 0.7646, respectively. T1 slope, cutoff value: 17.2°; sensitivity: 0.5806; specificity: 0.7241; p < 0.05. LKA: cutoff value: - 14°; sensitivity: 1; specificity: 0.5333; p < 0.05. CONCLUSIONS: In patients with Hirayama disease, the strength of posterior cervical extensors and cervical sagittal alignment are closely related. The local kyphosis angle can be used as a reference for the strength of posterior cervical extensors. These results indicate the weakness of PCEs, which may predispose the cervical spine of HD patients to a less stable situation. Therefore, patients with Hirayama disease should strengthen the exercise of the PCEs.

Electrical impedance tomography detects changes in ventilation after airway clearance in spinal muscular atrophy type I.

The effect of mechanical insufflation-exsufflation (MIE) for airway clearance in patients with spinal muscular atrophy type I (SMA-I) on the distribution of ventilation in the lung is unknown, as is the duration of its beneficial effects. A pilot study to investigate the feasibility of using three dimensional (3-D) electrical impedance tomography (EIT) images to estimate lung volumes pre- and post-MIE for assessing the effectiveness of mechanical insufflation-exsufflation (MIE) was conducted in 6 pediatric patients with SMA-I in the neuromuscular clinic at Children's Hospital Colorado. EIT data were collected before, during, and after the MIE procedure on two rows of 16 electrodes placed around the chest. Lung volumes were computed from the images and compared before, during, and after the MIE procedure to assess the ability of EIT to estimate changes in lung volume during insufflation and exsufflation. Images of pulsatile pulmonary perfusion were computed in subjects able to perform breath-holding. In four of the six subjects, lung volumes during tidal breathing increased after MIE (average change from pre to post MIE was 58.8±55.1 mL). The time-dependent plots of lung volume computed from the EIT data clearly show when the MIE device insufflates and exsufflates air and the rest periods between mechanical coughs. Images of pulmonary pulsatile perfusion were computed from data collected during breathing pauses. The results suggest that EIT holds promise for estimating lung volumes and ventilation/perfusion mismatch, both of which are useful for assessing the effectiveness of MIE in clearing mucus plugs.

An Atypical Presentation of Hirayama Disease With Lower Limb Myelopathic Symptoms Only.

ABSTRACT: Hirayama disease is a rare neuromuscular disease, which classically presents as lower motor neuron weakness and atrophy in the upper limbs and specifically the C7-T1 myotomes. Proposed pathogenesis relates to microcirculatory dysfunction in the territory of the anterior spinal artery caused by epidural venous plexus engorgement with forward displacement of the posterior dura and spinal cord during neck flexion, leading to chronic ischemic changes in the lower cervical anterior horn cells. Diagnosis hinges upon clinical and radiographic findings, and treatment is generally conservative given the self-limited nature of the disease. Here, we present a case with classic radiologic findings of Hirayama disease with lower limb myelopathic findings alone. This case raises the question of whether the pathophysiology leading to focal anterior cervical myelopathy in forward flexion could present along a broader clinical spectrum than previously recognized, from complete asymptomaticity, to classic Hirayama disease with C7-T1 atrophy, to cervical myelopathy with long tract signs.

Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study.

OBJECTIVE: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. METHODS: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. RESULTS: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. CONCLUSIONS: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.

Spinal Muscular Atrophy Type 3 Showing a Specific Pattern of Selective Vulnerability on Muscle Ultrasound.

A 23-year-old woman was admitted for slowly progressive proximal limb muscle weakness from childhood with elevated muscle enzyme levels. Although muscular diseases were suspected, an electromyogram showed remarkable neurogenic changes, and a muscle echogram indicated selective muscle involvement, including dissociation between the soleus and gastrocnemius, which was consistent with previous reports using magnetic resonance imaging (MRI). She was diagnosed with SMA type 3 following genetic testing, and nusinersen was soon initiated. An early diagnosis is mandatory to maximize the benefit of treatment. A muscle echogram may facilitate an early diagnosis in a non-invasive and time-saving manner compared to MRI.

The Influence of "Loss of Attachment" on the Outcome of Anterior Cervical Fusion Procedures in Patients With Hirayama Disease.

The objective of this study was to identify the influence of the measurements of "loss of attachment" on the surgical outcome in Hirayama disease (HD). Forty-two patients with HD underwent neutral and cervical-flexion magnetic resonance imaging (MRI) before surgery, and the cervical-flexion MRI was repeated at the 3-month postoperative visit. The longitudinal separation range (LSR) of loss of attachment, the maximum forward-shifting (MFS) degree in the cervical cord, and the relative morphological changes of the cervical cord were measured on MRI. Additionally, all patients underwent handgrip strength (HGS) testing, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and Medical Research Council scales at the 1-year postoperative visit. Postoperatively, the cervical-flexion X/Y and the LSR decreased significantly at a mean of 94.17±8.65 days (range, 75-110 days) (P<.01), while the cervical-flexion A/B increased (P<.01). Loss of attachment was resolved in fused segments in all 42 patients, but there were 7 instances of residual loss of attachment at adjacent segments. Twenty (47.6%) of the 42 patients' DASH scores decreased at the 1-year postoperative visit. According to the logistic regression analysis, both LSR and MFS were related to the surgical outcomes. Receiver operating characteristic curve analysis found that area under the curve and cutoff values were 0.959 and 4.5, respectively (P<.05) for LSR and 0.782 and 0.215, respectively (P<.05) for MFS. Anterior cervical fusion procedures can effectively improve the abnormal loss of attachment and prevent further progression of HD. The LSR is an important risk factor for the prognosis, and longer fused segments may be required when the LSR is 5 segments or more. [Orthopedics. 2021;44(1):30-37.].

The diagnostic quandary of magnetic resonance imaging-negative Hirayama disease: a case report.

BACKGROUND: Magnetic resonance imaging (MRI) features are typical findings in Hirayama disease (HD) and are useful diagnostic entities but may not be present in all patients. CASE PRESENTATION: We present the case of a 22-year-old Nepalese man who presented with insidious onset of weakness of his right upper limb of more than 5 years duration. His weakness was progressive for the first 3 years, and then remained static. On examination, weakness of the interossei, thenar, hypothenar, flexor, and extensor muscles were present in his right upper limb, power was normal in his left upper and bilateral lower limbs. Minipolymyoclonus was present in both upper limbs, less prominent on the left side. Electrophysiological findings showed motor axonal neuropathy in his right upper limb, neurogenic discharges and fibrillations, and fasciculations in both upper limbs. Contrast magnetic resonance imaging (MRI) of his cervical spine in flexion was normal. Our patient was diagnosed with HD based on clinical and electrophysiological findings. Our patient was advised to use a cervical collar and regular physiotherapy and was found to have subjective benefit. CONCLUSION: A normal cervical MRI does not rule out HD and the diagnosis can also be made based on clinical and electrophysiological studies. Progressive distal upper limb weakness or tremor in young patients should be evaluated for HD, because early diagnosis and intervention might halt the progression.

Vietnamese Case Series of Hirayama Disease.

BACKGROUND/AIM: Hirayama disease, a rare neurological disorder, is characterized by progressive, asymmetric muscle atrophy of the forearm and hand in young male patients. CASE REPORT: We noted two cases of Hirayama disease that appeared in the right upper limb and identified the cervical neutral and flexion position magnetic resonance imaging (MRI) characteristics. CONCLUSION: In the flexion posture, the cervical MRI allows early diagnosis of Hirayama disease and should be considered in patients with the typical clinical symptoms.