Un d e r normal circumstances, the anteroposterior. Hirayama disease. Clinical article

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1 J Neurosurg Spine 12: , 2010 Hirayama disease Clinical article Mu h-sh i Lin, M.D., 1 3 Wo o n-ma n Ku n g, M.D., 1,2 We n-ta Ch i u, M.D., Ph.D., 4,5 Ro n g -Ku o Ly u, M.D., 6 Ch i-je n Ch e n, M.D., 7 a n d Tz u-yu n g Ch e n, M.D. 8 1 Department of Neurosurgery, Taipei Medical University Wan Fang Hospital; 2 Division of Neurosurgery, Department of Surgery, Taipei County Hospital; 3 Graduate Institute of Clinical Medicine, College of Medicine, and 5 Graduate Institute of Injury Prevention and Control, Taipei Medical University; Departments of 4 Neurosurgery and 7 Diagnostic Radiology, Taipei Medical University Shuang Ho Hospital, Taipei; 8 Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung; and 6 Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan Object. Controversy exists over the choice of surgical candidates and prognosis of Hirayama disease. The purpose of this study was to examine the outcomes of patients with cervical flexion myelopathy who received surgical treatment. Methods. A retrospective study was conducted. From May 2002 through December 2006, 6 young patients with cervical flexion myelopathy were seen in the Department of Neurosurgery at Chang Gung Memorial Hospital. The neurological and radiological findings in all 6 patients met the criteria for Hirayama disease. All patients had evidence of a tight dural canal or forward migration of the posterior wall of the dural canal in dynamic MR imaging studies. Five patients were treated with surgical decompressive procedures (4 anterior and 1 posterior) and 1 patient received conservative treatment. Duration of follow-up ranged from 13 months to 4 years. Results. Motor function improved in 3 of 5 surgically treated patients and sensory function improved in 2. Neurological symptoms were unchanged in the conservatively treated patient. During follow-up MR imaging in the surgical group, anterior effacement during neck flexion was noted in 1 patient treated with a posterior approach. Conclusions. Hirayama disease is so rare that it is easily misdiagnosed. Diagnosis is achieved via clinical presentation, neurophysiological examination, and neuroradiological imaging studies (dynamic MR imaging). The anterior decompressive approach may be better for patients showing anterior effacement and severe cervical kyphosis during neck flexion in MR imaging. (DOI: / SPINE09431) Ke y Wo r d s Hirayama disease cervical flexion myelopathy dynamic MR imaging Un d e r normal circumstances, the anteroposterior diameter of the cervical spinal canal decreases during neck extension, and cervical myelopathy associated with compression during neck flexion is uncommon. In patients with cervical myelopathy, the cord lesion may be caused by stenosis, segmental instability, and vessel insufficiency. Hirayama disease is considered a category of cervical flexion myelopathy 15,17,25 and is characterized by unilateral juvenile muscle atrophy of the upper extremity. 4,7 9 Interestingly, Hirayama disease has mainly been reported in Asian countries, especially Abbreviation used in this paper: JOA = Japanese Orthopedic As so ci ation. Japan. 7,8,16 The diagnosis of Hirayama disease is based on the clinical scenario, neurophysiological findings, and dynamic MR images of the cervical region that show atrophy of the lower cervical spinal cord with forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion. On neck flexion, the spinal cord is compressed anteroposteriorly at the C-7 and C-8 neurological segmental levels. 6,21 Clinically, juvenile muscular atrophy of the upper limb (Hirayama disease) is an extremely rare disease, often accompanied by vague symptoms, leading to a delay in diagnosis. The paucity of information available regarding Hirayama disease prompted us to review the experience at Chang Gung Memorial Hospital. From J Neurosurg: Spine / Volume 12 / June

2 M. S. Lin et al to 2006, 6 patients met the criteria for Hirayama disease; 5 were treated with decompressive surgery, and 1 was treated conservatively. In this article we present the cases, treatments, and outcomes along with an overview of the pathogenesis and neurophysiology. Methods From May 2002 through December 2006, 6 patients who exhibited characteristic muscular weakness and atrophy of the forearm and hand on the medial side consistent with Hirayama disease were treated at the Department of Neurosurgery at Chang Gung Memorial Hospital. All patients had normal results on neurophysiological studies and forward displacement of the dural canal or a tight dural canal in dynamic MR imaging, thus excluding peripheral nerve entrapment syndrome. In neuroradiological studies, a forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion is seen in patients with Hirayama disease, and this finding is presumed to represent the main pathogenic mechanism. On neck flexion, the spinal cord is compressed anteroposteriorly at the C-7 and C-8 segmental levels. 6,21 We graded the severity of myelopathy according to the JOA scoring system. 19 The JOA scoring system was designed to evaluate neurological conditions, specifically peripheral motor function, sensory function, and urinary bladder function. The duration of patient follow-up ranged from 13 months to 4 years. Results The demographic data are presented in Table 1. All 6 patients were male. Their mean age at treatment was 25.2 years (range years). The mean duration of disease at the time of treatment was 4.1 years (range 7 months to 10 years). All patients exhibited muscle weakness and wasting confined to the thenar, hypothenar, and interossei muscles, wrist flexors and extensors, biceps, and triceps. The brachioradialis muscle was spared in all patients. None of the patients had a family history of similar symptoms or immunological disorders. Neurological, electrophysiological, and radiological findings are presented in Table 2. Five patients (Cases 1 and 3 6) were affected unilaterally and 1 (Case 2) bilaterally. Four patients had normal sensation and 2 (Cases 2 and 6) had slight sensory disturbance limited to the hands. Biceps, triceps, and supinator reflexes were normal in all patients, but knee reflexes were exaggerated in one (Case 4). Nerve conduction studies demonstrated normal motor and sensory conduction velocity, and electromyography revealed high amplitude polyphasic action potentials of long duration with reduced recruitment of the atrophic muscles (a neurogenic pattern). Under routine and extension cervical MR imaging, no definitive cord compression pathology was visualized. However, under flexion cervical MR imaging, forward migration of the dural sac (mean 1.15 mm, range mm) and cord atrophy in the lower cervical segments were demonstrated in 4 patients (Cases 3 6). A tight dural canal in flexion, although no cord atrophy, was demonstrated in the other 2 patients (Cases 1 and 2). The above dynamic changes in the spinal canal induced by neck flexion are consistent with the neuroradiological findings of Hirayama disease; thus, the diagnosis was established. Operative technique, findings, postoperative course, and follow-up are presented in Table 3. Four patients (Cases 1 3 and 5) underwent an anterior procedure with corpectomy and discectomy, supplemented with metallic plate fixation. The patient in Case 4 underwent a laminectomy and dural graft augmentation procedure. Preoperative and postoperative MR images from Cases 5 and 4 are presented in Figs All surgically treated patients wore a neck collar (orthosis) postoperatively, and all had an uneventful postoperative course without complications. Patients were discharged on the 3rd to the 9th postoperative day and were followed up on a regular basis in our outpatient department. Within 3 months after surgery, muscle strength had improved significantly in 3 of the 5 patients (Cases 1 3). In the patient in Case 2, slight improvement of muscle strength was noted and the slight hand dysesthesia was alleviated. The muscular atrophy of the upper extremities improved in only 1 patient (Case 4). The patient in Case 6 was treated with conservative medical therapy and a neck collar and received regular outpatient follow-up. In contrast to the results of surgical treatment, in this patient there was little improvement of muscle strength, and muscular atrophy of the upper extremity remained unchanged 33 months later. TABLE 1: Patient demographic data and preoperative symptoms* Case No. Age (yrs), Sex Age at Onset (yrs) Duration of Illness at Dx Symptoms Location of Muscle Atrophy 1 24, M 21 7 mos rt claw hand, rt hand weakness rt interosseous muscle 2 35, M yrs bilat hand weakness rt interosseous muscles 3 23, M 17 4 yrs rt arm & hand weakness rt triceps, hypothenar muscle 4 25, M 17 2 yrs rt finger weakness rt arm, forearm, hand 5 25, M yrs lt hand weakness lt hand, interosseous muscle 6 20, M 17 3 yrs lt hand weakness lt hand, interosseous muscle * There was no family history of similar symptoms or immunological disorders in any of the cases. 630 J Neurosurg: Spine / Volume 12 / June 2010

3 Hirayama disease TABLE 2: Summary of clinical findings* Case No. Sensory Disturbance Deep Tendon Reflexes EMG Abnormality Forward Dural Canal Migration Forward Migration Distance (mm) Epidural Venous Congestion Cervical Cord Atrophy (on MRI) 1 none normal rt APB, FDI, FCU, IOD; none 0 none none lt IOD 2 bilat hand numbness normal rt tri, FCU, IOD; lt FCU none 0 none none 3 none normal rt tri, EDC, ECR, AbDM, FCU, FDI; lt FCU present 1.0 present C5 6 4 none bilat patellar rt tri, EDC, FDI, bi, FCU present 0.9 present C5 6 5 none normal lt bi, tri, EDC, FCU present 1.5 present C5 6 6 ulnar distribution normal lt bi, tri, EDC, FCU present 1.2 present C5 6 * AbDM = abductor digiti minimi; APB = abductor pollicis brevis; bi = biceps; ECR = extensor carpi radialis; EDC = extensor digitorum communis; FCR = flexor carpi radialis; FCU = flexor carpi ulnaris; FDI = flexor digiti interosseus; IOD = interossei dorsalis; PT = patellar tendon; tri = triceps; = increased. On dynamic MR imaging studies. Discussion Hirayama disease, a cervical flexion myelopathy, is characterized by unilateral muscle atrophy of the upper limbs. The condition is extremely rare and occurs primarily in young male Asian patients, especially in Japan. In Taiwan, most degenerative myeloradiculopathies are readily diagnosed and occur in elderly patients; however, Hirayama disease exists and tends to be misdiagnosed as tardy ulnar palsy. 10 We herein reported on 6 patients with Hirayama disease; on the basis of JOA scores, surgical intervention (5 cases) produced a better outcome than conservative treatment (1 case) in this patient group. In this report, Hirayama disease is presented as a syndrome, rather than a simple disease. Therefore, we included patients who fulfilled more than one of the criteria for Hirayama disease. The diagnosis of Hirayama disease is based on the clinical scenario, neurophysiological findings, and dynamic MR imaging of the cervical region, which shows atrophy of the lower cervical spinal cord with forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion. As always, a careful history and physical examination are the first steps in diagnosis. There are many possible causes of cervical myelopathy, most of which will be distinguished by the history, physical examination, and other testing. Although plain radiographs of the cervical spine may show evidence of spondylosis and stenosis, MR imaging is a much better diagnostic tool as it can reveal the cause of the pressure on the spinal cord. It also shows whether spinal cord injury or atrophy is present. Occasionally, cervical myelography and postmyelogram CT are used. Postmyelogram CT may help define the bone structures somewhat better than MR imaging. Generally, however, MR imaging is the study of choice. Electrophysiological studies in the form of somatosensory evoked response (or potential) testing may be ordered to determine conduction in the spinal cord. The primary characteristics of Hirayama disease 6 8,17,21 are: 1) a preponderance in young men aged years; 2) insidious onset of unilateral muscular atrophy in the hand and ulnar side of the forearm muscles, sparing the brachioradialis muscle (oblique atrophy); 3) fasciculation in the extensor side of the forearms or tremor-like TABLE 3: Operative findings and treatment results* Case No. Treatment Op Time (hrs) JOA Score Blood Loss (ml) Pre-Tx Post-Tx % Recovery Discharge (postop day) Change Muscle Strength Muscle Atrophy 1 C5 7 AF & I rd 4 5 min impr 46 2 C5 6 AF & I th sl impr (3 3) unchngd 32 3 C4 6 AF & I th 3 4 unchngd 42 4 C4 7 laminectomy & dural th unchngd (4 4) impr 39 graft augmentation 5 C5 6 AF & I th unchngd (3 3) min impr 13 6 fludiazepam, cobamamide NA NA NA unchngd (3 3) unchngd 34 * impr = improved; min = minimally; NA = not applicable; sl = slightly; unchngd = unchanged. All 5 surgically treated patients wore a neck collar postoperatively; the management of the conservatively treated patient also included a collar. FU in mos J Neurosurg: Spine / Volume 12 / June

4 M. S. Lin et al. Fig. 1. Case 5. Preoperative dynamic MR imaging. Images obtained in neutral position (right) and flexion (left) showing cord compromise (C5 6) during flexion. movement of the fingers during stretching; 4) absence of abnormality or presence of only minimal abnormality in sensory findings or deep tendon reflexes; 5) neurogenic patterns in the arms and hands and normal nerve conduction velocity demonstrated on electromyography; and 6) atrophy of the lower cervical spinal cord with forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion. On neck flexion, the spinal cord is compressed anteroposteriorly at the C-7 and C-8 segmental levels. 6,21 Based on the report by Gandhi et al., 6 there is unilateral involvement in the majority of patients, but asymmetrical and symmetrical bilateral involvement are also observed. In Hirayama disease, symptoms generally progress for 3 4 years after onset, and then stop. Early arrest of the progression is essential for any possibility of improvement. The pathogenesis of Hirayama disease remains puzzling despite advances in imaging and neurophysiological techniques. Under normal circumstances, hyperflexion of the neck tends to apply compressive forces on the anterior column of the spine, which causes the posterior anulus to bulge. This may cause anterior impingement on the cord; however, such a situation rarely causes clinical symptoms in healthy people. 15,17 Primary theories regarding the pathological mechanism of flexion cervical myelopathy include anterior anatomical compression, cord overstretching, or a tight canal. 1,2,13,18,22 In Hirayama disease, a tight cervical canal may result from forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion. The pathological lesion of Hirayama disease involves the anterior horn cells, and the pathogenesis of anterior horn cell impairment is considered to be due to a microcirculation disturbance in the territory of the anterior spinal artery caused by mechanical force. 8,9,11,14 Repeated microcirculatory disturbances are believed to lead to ischemic necrosis of the anterior horn cells. A number of alternative theories regarding the pathophysiological mechanism of Hirayama disease have been presented. Based on electrophysiological studies, Fig. 2. Case 5. Postoperative dynamic MR imaging (after anterior approach). Images obtained in neutral position (right) and flexion (left) showing anterior column decompression. Misra and Kalita 20 regard Hirayama disease as a motor neuron disease. Kira and Ochi 15 described an association of Hirayama disease with atopic or allergic disorders. Based on a familial occurrence, Robberecht et al. 23 presented a hypothesis that Hirayama disease might be related to superoxide dismutase 1 associated familial amyotrophic lateral sclerosis. In our review, we did not find any evidence of a significant association between any genes and the phenotype of Hirayama disease. 5 Thus, no diagnostic testing is available to determine an individual s risk of developing the condition. In our study, the patients in Cases 2 and 6 exhibited hypesthesia and slight numbness in the hand. The literature reports of Hirayama disease indicate that some patients do present with hypoesthesia in a localized area of the hand. 8 In Cases 1 and 2, although no dural forward migration was noted during neck flexion in dynamic MR imaging studies, the dural canal became narrow and tight (tight dural canal in flexion mechanism) a finding consistent with Hirayama disease. The dural displacement is frequently obvious in young patients and with short disease duration; however, it may gradually decrease and finally disappear with increasing age and disease duration. 6,8 Thus, it is important to note that dural displacement might be absent in patients with long-standing disease. Hirayama disease has been noted to have a progressive course of 3 to 4 years after onset of symptoms, followed by a stationary stage. 3,8,24 Conservative treatments have been reported for cervical flexion myelopathy, and if recognized early, avoidance of neck flexion has been shown to stop the progression of Hirayama disease. 3,24 Treatment consists of application of a cervical collar for 3 to 4 years. 3,24 Decompressive surgery is indicated for patients with persistent neurological deficits resulting from spinal cord compression by forward displacement of the posterior wall of the dura during neck flexion. 8,12,17 The advantages of either anterior decompressive or posterior fusion therapy for cervical flexion myelopathy have been well discussed in recent literature; however, which route is superior is undecided. 8,12,17 In our patients, we found no 632 J Neurosurg: Spine / Volume 12 / June 2010

5 Hirayama disease Fig. 3. Case 4. Preoperative dynamic MR imaging. Images obtained in neutral position (right) and flexion (left) showing cord compromise (C5 6) during flexion. marked clinical difference in outcomes with respect to the anterior or posterior approach. However, the results from follow-up images and the degree of clinical improvement suggest that the anterior approach at a lower cervical spine level may lead to a better prognosis than posterior laminectomy. According to Wilkins and Rengachary, 25 the folding-unfolding mechanism and tensile properties of the spinal cord during the accommodation of change in position may explain the clinical and imaging findings. Thus, we believe an anterior procedure is likely to be more effective in patients with cervical anterior effacement and a large degree of cervical kyphosis noted in MR imaging. Our previous experience with neurological deficit diseases such as syringomyelia suggests that neurological deficits can be treated either conservatively or nonconservatively. 10 Some patients who show no signs or symptoms during disease progression for many years are candidates for conservative treatment. Patients who exhibit progressive deterioration should receive surgical management. In our current study, patients who were treated surgically experienced better outcomes than the patient who Fig. 4. Case 4. Postoperative dynamic MR imaging. Images obtained in neutral position (right) and flexion (left) showing persistent anterior effacement and cervical kyphosis. J Neurosurg: Spine / Volume 12 / June 2010 was treated conservatively. Patients treated surgically had improvement of muscle strength and/or sensation, especially those who received the anterior decompressive procedure. In contrast, the patient who received conservative treatment showed no improvement. In conclusion, Hirayama disease is extremely rare and tends to be easily misdiagnosed as a peripheral nerve disorder. It should be suspected in young male patients with the clinical presentation of unilateral muscular atrophy of hand and/or ulnar side of forearm muscles and absence of sensory disturbances. Electromyography studies and dynamic MR imaging are necessary to confirm the diagnosis. Conservative treatment may be effective in patients with disease of short duration; however, surgical decompressive treatment is indicated for nerve compression. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: TY Chen. Acquisition of data: WM Kung, WT Chiu, RK Lyu, CJ Chen. Analysis and interpretation of data: WT Chiu, RK Lyu, CJ Chen. Drafting the article: MS Lin. Critically revising the article: MS Lin, WM Kung. Reviewed final version of the manuscript and approved it for submission: TY Chen. Study supervision: TY Chen. References 1. Breig A, el-nadi AF: Biomechanics of the cervical spinal cord. Relief of contact pressure on and overstretching of the spinal cord. Acta Radiol Diagn (Stockh) 4: , Breig A, Turnbull I, Hassler O: Effects of mechanical stresses on the spinal cord in cervical spondylosis. A study on fresh cadaver material. J Neurosurg 25:45 56, Chen CJ, Chen CM, Wu CL, Ro LS, Chen ST, Lee TH: Hirayama disease: MR diagnosis. AJNR Am J Neuroradiol 19: , Drozdowski W, Baniukiewicz E, Lewonowska M: [Juvenile monomelic amyotrophy: Hirayama disease.] Neurol Neurochir Pol 32: , 1988 (Polish) 5. Gamez J, Also E, Alias L, Corbera-Bellalta M, Barceló MJ, Centeno M, et al: Investigation of the role of SMN1 and SMN2 haploinsufficiency as a risk factor for Hirayama s disease: clinical, neurophysiological and genetic characteristics in a Spanish series of 13 patients. Clin Neurol Neurosurg 109: , Gandhi D, Goyal M, Bourque PR, Jain R: Case 68: Hirayama disease. Radiology 230: , Hirayama K: [History of Hirayama disease.] Spine Spin Cord 5:89 96, 1992 (Jpn) 8. Hirayama K: Juvenile muscular atrophy of distal upper extremity (Hirayama disease). Intern Med 39: , Hirayama K: Juvenile muscular atrophy of distal upper extremity (Hirayama disease): focal cervical ischemic poliomyelopathy. Neuropathology 20 (Suppl):S91 S94, Huang YC, Ro LS, Chang HS, Chen CM, Wu YR, Lee JD, et al: A clinical study of Hirayama disease in Taiwan. Muscle Nerve 37: , Imai T, Shizukawa H, Nakanishi K, Kouge N, Hiura K, Kashiwagi M, et al: Hyperexcitability of cervical motor neurons during neck flexion in patients with Hirayama disease. Electromyogr Clin Neurophysiol 40:11 15, Imamura H, Matsumoto S, Hayase M, Oda Y, Kikuchi H, Ta- 633

6 M. S. Lin et al. kano M: [A case of Hirayama s disease successfully treated by anterior cervical decompression and fusion]. No To Shinkei 53: , Iwasaki Y, Tashiro K, Kikuchi S, Kitagawa M, Isu T, Abe H: Cervical flexion myelopathy: a tight dural canal mechanism. Case report. J Neurosurg 66: , Kaye KL, Ramsay D, Young GB: Cervical flexion myelopathy after valproic acid overdose. Spine 26:E459 E462, Kira J, Ochi H: Juvenile muscular atrophy of the distal upper limb (Hirayama disease) associated with atopy. J Neurol Neurosurg Psychiatry 70: , Kitagawa M, Tashiro K, Kikuchi S, Matsuura T: [Correlation between clinical features and neuroradiological findings in juvenile muscular atrophy of unilateral upper extremity (Hirayama disease) with and without tight dural canal in flexion.] Rinsho Shinkeigaku 32: , 1992 (Jpn) 17. Kohno M, Takahashi H, Ide K, Yamakawa K, Saitoh T, Inoue K: Surgical treatment for patients with cervical flexion myelopathy. J Neurosurg 91 (1 Suppl):33 42, Kohno M, Takahashi H, Yagishita A, Tanabe H, Inoue K: Disproportion theory of the cervical spine and spinal cord in patients with juvenile cervical flexion myelopathy. A study comparing cervical magnetic resonance images with those of normal controls. Surg Neurol 50: , Lin JW, Lin MS, Lin CM, Tseng CH, Tsai SH, Kan IH, et al: Idiopathic syringomyelia: case report and review of the literature. Acta Neurochir Suppl 99: , Misra UK, Kalita J: Central motor conduction in Hirayama disease. Electroencephalogr Clin Neurophysiol 97:73 76, Oguro K, Kita M, Mori Y, Watanabe Y, Taniguchi Y: A case of Hirayama disease. Brain Dev 30: , Reid JD: Effects of flexion-extension movements of the head and spine upon the spinal cord and nerve roots. J Neurol Neurosurg Psychiatry 23: , Robberecht W, Aguirre T, Van den Bosch L, Theys P, Nees H, Cassiman JJ, et al: Familial juvenile focal amyotrophy of the upper extremity (Hirayama disease). Superoxide dismutase 1 genotype and activity. Arch Neurol 54:46 50, Tokumaru Y, Hirayama K: [Cervical collar therapy for juvenile muscular atrophy of distal upper extremity (Hirayama disease): results from 38 cases.] Rinsho Shinkeigaku 41: , 2001 (Jpn) 25. Wilkins RH, Rengachary SS (eds): Neurosurgery, Vol 3. New York: McGraw-Hill, 1996, pp 2220 Manuscript submitted May 18, Accepted December 3, Address correspondence to: Tzu-Yung Chen, M.D., Department of Neurosurgery, Buddhist Tzu Chi General Hospital, No. 66, Sec. 1, Fongsing Road, Tanzih Township, Taichung County 427, Taiwan, Republic of China. neurosurgery2005@yahoo.com.tw. 634 J Neurosurg: Spine / Volume 12 / June 2010