Continuing Education Activity

Hirayama is a rare nonfamiliar monomelic amyotrophy also known as benign juvenile brachial spinal muscular atrophy, juvenile asymmetric segmental spinal muscular atrophy, juvenile muscular atrophy of the distal upper extremity, monomelic amyotrophy, and oblique amyotrophy. Classically, it presents with muscle atrophy and weakness of bilateral or unilateral forearms and hands in the absence of sensory alterations, progressing for one to two years before plateauing. The condition is caused by a tight dural sac in the cervical canal that leads to chronic ischemic changes to the anterior horn cells. Although commonly considered a non-progressive and self-limiting disease, this has been a source of significant disability for some affected individuals. This activity reviews the evaluation and management of patients with this condition and highlights the role of the interprofessional team in caring for these patients.

Objectives:

• Describe the clinical presentation of Hirayama disease.
• Review the etiology of Hirayama disease.
• Summarize the typical clinical course of Hirayama disease.
• Explain strategies to improve care coordination between the interprofessional teams caring for patients with Hirayama disease to improve proper disease recognition and treatment and improve patient outcomes.

Introduction

Hirayama is a rare, nonfamiliar, monomelic amyotrophy originally described by Dr. Hirayama in 1959.[1] Classical findings include muscle atrophy and weakness of the forearms and hands, either unilateral or bilateral, and without sensory loss. This usually progresses for one or two years before plateauing and eventually showing an abrupt arrest.[2][3] The condition is caused by chronic ischemic changes to the anterior horn cells of the cervical spine secondary to a limited dural sac laxity. This is predominantly a lower motor neuron pattern of the lesion.[4]

Although commonly considered a non-progressive and self-limiting disease, this has been noted to cause significant disability for some subsets of individuals. Early intervention has been shown to limit the progression of the disease and minimize the disability. Other names used to describe this entity include benign juvenile brachial spinal muscular atrophy, juvenile asymmetric segmental spinal muscular atrophy, juvenile muscular atrophy of the distal upper extremity, monomelic amyotrophy, and oblique amyotrophy.[5][6][7] However, Hirayama disease is the most common name and was coined in 1991.[6][8]

Etiology

Many theories have been postulated in the pathogenesis of this entity.[9][10] The ''contact pressure theory'' inferred from cadaveric studies in 1960 postulated degenerative spurs during flexion to compress the cord.[1] The ''tight dural canal theory in flexion'' was proposed in 1987.[1] This most commonly accepted theory describes an increased laxity of the dura mater from its superior anchors on the dorsal surfaces of C2 and C3, harbingering forward cord movement during cervical flexion. This increased laxity permits anterior displacement of the spinal cord, causing multiple episodes of subclinical cervical trauma and resulting in micro ischemia during cervical flexion to the anterior horn of the spinal cord.[1] This eventually leads to myelopathy and degeneration, as evidenced by asymmetric lower cervical cord thinning within the C7 and C8.[4]

It has also been further suggested that this laxity may be caused by a ''growth imbalance between the vertebral column and dural canal''.[4] This imbalance is particularly noted during growth spurts and may lead to increased laxity, allowing for the anterior displacement of the posterior dura.[1] As growth slows down or stops, dural displacement decreases, causing a plateau in the disease process. Another theory is based on the posterior longitudinal ligament structure. Two cellular matrixes have been described, one with fine elastic ligaments and the other with larger elastic ligaments. It has been proposed that these ligaments designed to secure the posterior dura mater are unequally dispersed, allowing only part of the cord to have anterior displacement, based on some surgical and cadaveric studies.[11][12][13]

Hirayama postulated that increased intramedullary pressure during neck flexion causes ''stagnation of the posterior epidural venous plexus'' causing cord compression.[1] ''loss of dorsal dural attachment from the pedicle due to immunological abnormalities of the dura and posterior ligaments'' has also been implicated in the pathogenesis.[9]

Epidemiology

This entity has been noted to have a male preponderance.[4][6][10] The highest prevalence is found among the Asian population, with the most prevalence in Japan and noted in China, Taiwan, Malaysia, India, and Sri Lanka, with a few cases from Europe and North America.[7][1][14]

The insidious unilateral weakness onset usually has been reported to occur at the start of puberty, in the early to mid-teens. The peak onset age is approximately two years later than the longitudinal peak on the growth curve of juvenile males in Japan.[6][14] The plateau occurs on average 1 to 4 years after onset but occasionally lasts until the early twenties.

Most reported cases have shown more involvement of the right upper limb (2.8 to 1 ratio), regardless of the hand dominance. However, the few described cases of bilateral upper limb involvement are seen among this same age group and are considered the most severe clinical subtypes of the entity.[8]

Pathophysiology

Findings on autopsy demonstrated a reduction in the anterior-posterior diameter of the cervical cord by greater than 50%, central necrosis, and diminished large and small nerve cells without macrophage infiltration at the C7-C8 levels correlating well with reported symptoms and also indicative of a chronic ischemic process.[4][10] However, there was no indication of any vascular changes to explain the cause of ischemic insult.

History and Physical

Patients usually complain of progressive decline in functional ability in the right hand caused by decreased hand strength and compromised dexterity. Such limitations may manifest as difficulty in carrying out activities of daily living requiring fine motor functions such as eating, dressing, and grooming. Patients report that cold temperatures worsen symptoms.

Based on the rate of progression, the initial complaint may be of the deformity related to muscular atrophy. Sensory changes are rarely reported, and patients do not complain of pain until the atrophy involves the upper arm and shoulder girdle, as evident in more severe cases.

The patient may also report increased fatigue and may have associated atopy or allergies.[15] They may also have 'cold paresis.'[6][10]

This constellation of symptoms compels them to quit or have diminished participation in sports and other leisure activities, making them socially aloof.

Appearance

Common presentation is unilateral atrophy in the distal upper limb. Most atrophy occurs in the thenar, intrinsic hand muscles, hypothenar, and forearms. Depending on its severity, patients may also have limb length discrepancies. There is characteristic oblique atrophy due to sparing of the brachioradialis.[2][3]

Strength

Weakness is most often noted in flexors and extensors of the wrist and digits owing to the involvement of the C7-T1 nerve roots. Fine motor actions and grasp are limited, and patients may be unable to perform pinch or key grasp. The contralateral hand and digits will exhibit full strength and dexterity. Typically, elbow flexion, extension, pronation, and supination are unaffected. Proximal muscle groups are also mostly spared.

Neurologic Exam

The sensory exam is intact for vibration, temperature, sharp, dull, and light touch modalities on all extremities. Muscle stretch reflexes are generally normal and symmetric. Hoffman and Holman are noncontributory.

Cardiovascular

Pulses are normal. The limbs are warm, and there is a good capillary refill.

The clinical diagnostic criteria for the HD include the following:

• Distal upper limb muscle weakness and atrophy
• Onset at between 10-20 years of age
• Unilateral or predominantly asymmetric pattern
• Insidious onset, gradual progression followed by an arrest
• Lack of pyramidal signs or sensory disturbance, and
• Exclusion of other mimics.[6][7][13]

Evaluation

Radio-imaging and electromyogram (EMG)/nerve conduction studies are beneficial in distinguishing this entity from other differentials. Routine blood work is often noncontributory. Other blood tests, specifically serum IgE has shown a noted increase. However, the clinical significance of this finding is not affirmative. Traditional x-rays also show nonspecific findings. Occasionally, a degeneration of C2 may be noted.

MRI imaging

MRI shows a crescent-shaped lesion in the posterior epidural space of the lower cervical cord or an atrophic spinal cord, mild asymmetric cord flattening, and increased signal intensity. It is only with specialized flexion MRIs that the diagnosis can become confirmatory. Flexion MRIs have shown a distinct change in the alignment of the soft tissue structures, specifically an anterior shift of the cervical dural sac from the lamina at the C4 -C7 region allowing for chronic microtrauma, with a corresponding post-contrast enhancement of the posterior epidural venous plexus indicative of ischemia.[5] Epidural venous dilatation is also observed.[16] The 'snake eye' sign has a poor clinical outcome.[3] The fractional anisotropy from the tractography study found no correlation between the pyramidal signs and the cord atrophy.[17] The longitudinal separation range (LSR) is an important MR marker in determining loss of attachment and the need for long-segment fixation.[18] The MRI study also has revealed reduced cross-sectional areas of the superficial neck flexors and extensor muscles that can cause instability.[19]They also have revealed evidence of sagittal imbalance of the cervical spine.[20]

Electromyogram/Nerve Conduction Study

EMG and NCS show significant findings in the C7, C8 and T1 innervated muscles. NCS has intermittently demonstrated decreased compound muscle action potential (CMAP) amplitude, most noticeable in the median nerve. The low ulnar/medial compound motor action potential within C7-T1 myotomes is very helpful in differentiating it from other mimics.[1]

EMG findings indicate chronic denervation seen as a high amplitude of action potential with prolonged duration, without active denervation (absence of positive sharp waves or fibrillation potentials), and no resting fasciculations in the C7, C8, and T1  innervated muscles. Findings are increased when the temperature is decreased. SSEP is not a marker for the disease.[15]

“Reverse split hand syndrome,” which shows decreased/absent CMAP amplitude in the abductor digiti minimi while preserved in the abductor pollicis brevis, is observed in Hirayama disease helps to differentiate it from amyotrophic lateral sclerosis, which shows ''reverse hand syndrome''.[14] The progression of the lesion is associated with progressive decrement followed by loss of the F wave.[14]

Treatment / Management

Although considered to be a self-limited condition, the long-term effects warrant treatment.  A cervical collar to decrease cervical movement and prevent neck flexion is the first line of treatment.[7] The mandate of using a cervical collar and the cervical decompression with fusion/fixation is based on 'contact pressure theory.'[1] The protocol is to wear the collar for 3 to 4 years until growth spurts are completed or the expected plateau of the condition is seen. This treatment is focused on limiting the progression of symptoms. The physiotherapy to increase the strength of the posterior cervical extensors is also beneficial since it improves the cervical sagittal alignment.[21]

Surgical options may be recommended for more advanced, severe, or refractory presentations. Such patients will present with atypical muscular involvement and severe spinal cord atrophy seen on MRI. Surgical intervention (duroplasty with tenting) has been associated with an improved success rate and prognosis.[22] Immediate effects of the procedure can be noted with intraoperative ultrasound, demonstrating decreased spinal cord pulsation and increased amplitude of conductive spinal cord potentials noted after dural incision. Later, hand strength increases following typical rehabilitation.

The Huashan classification system has been shown to be useful for the diagnosis and treatment of HD and is classified as

• Type 1- atrophy of hand and forearm muscles or asymmetric bilateral atrophy in upper limbs with type 1a(stable) and type 1b(progressive)
• Type 2- atrophy alongside pyramidal tract damage
• Type 3- atypical with atrophy of proximal upper limb muscle or symmetric upper limbs or presence of sensory dysfunction.[23] 

A conservative approach is initially recommended for type 1 and 3 diseases, whereas surgery is recommended for type 2 entities.[23] A meta-analysis study found equivocal clinical improvement between anterior and posterior approaches.[1] The surgeries are based on the anterior cervical discectomy with fusion and plating showed the best outcome. Maintaining the physiological local lordosis angle is extremely important in preventing adjacent segment disease following ACDF.[24] It is preferred over fusion since it minimizes the risk of adjacent segment disease owing to the provision of its removal after the disease stabilizes compared to corpectomy.  The surgical principle behind cervical duraplasty with tenting sutures and laminoplasty is based upon the theory of 'tight dural canal theory in flexion.'[1] The duraplasty and coagulation of the venous plexus have been associated with an increased risk of bleeding and meningitis. The basis of the coagulation of the posterior epidural venous plexus is based on the principle given by Hirayama himself.[1]

The guidelines on the diagnosis and treatment based on the modified Delphi technique have also been formatted.[4]

Differential Diagnosis

There are many upper motor neuron (UMN) lesions that mimic the entity, including amyotrophic lateral sclerosis, spinal muscular atrophy, cervical spondylotic myelopathy, ossified posterior longitudinal ligament, and toxic neuropathy.[4][15] The lower motor neuron (LMN) entities mirroring the Hirayama disease include:

1. Myotonic dystrophy: An autosomal dominant genetic disorder, commonly seen in middle-aged men and traditionally identified with a tonic contraction of muscles in the upper limbs. It is associated with systemic changes, including cataracts, pulmonary dysfunction, endocrine pathology, infertility, and cardiac conduction changes. It is distinguished from Hirayama by systemic involvement and muscle biopsy characteristics.[25]
2. Tephromalacie Anterieure: Anterior horn infarction demonstrated with muscle wasting of the distal upper limbs, caused by an occlusion of spinal arteries, commonly seen in middle-aged adults, and associated with arteriosclerosis. It presents bilaterally.
3. Syringomyelia: Chronic central degeneration associated with motor and sensory changes seen in bilateral upper limbs, commonly seen after injury in geriatric populations without any gender preponderance. Structural changes can be observed in radiographic imaging.[26] 
4. Pronator syndrome: Commonly presents unilaterally and is associated with a chronic injury. Symptoms increase with specific activities. The associated pain is an important hallmark of the condition[27]
5. Peripheral nerve entrapment syndrome

Prognosis

Although the natural history of the Hirayama disease has a self-limiting course over the long term, the weakness can progress from 1 month to 5 years.  In general, the prognosis of Hirayama disease is thought to be better than other motor neuron disorders, with longer survival and lesser morbidity. The cervical collar alone is effective in almost 58% of cases.[7] However, it should be noted that the residual symptoms may last for decades. It has been estimated that approximately 70% of the cases will have some mild disabilities.[28]

Nerve conduction studies and electromyography may help determine the extent and degree of nerve injury and the extent of reinnervation. In some cases, the extent of neurophysiological involvement may exceed the clinical involvement anticipated on presentation.[29] These features may help clinicians to dichotomize prognosis.

Complications

The complications in Hirayama disease are mostly due to chronic motor deficits. These may include weakness in the functions of the hand, forearm, or arm. This may result in chronic disuse atrophy of the muscles and permanent contractures. There may be spasticity, or the disease may recur after many years of being stable.[7] Physical therapy has shown varying degrees of improvement in published case reports.[30][31][32] Tendon transfer surgeries may also merit consideration.[12][2]

Deterrence and Patient Education

Education regarding prognosis and prevention of chronic motor complications can facilitate informed decisions on behalf of patients regarding their personal and professional lives. 

Enhancing Healthcare Team Outcomes

While mostly considered a self-limited condition with a subsequent plateau, some subsets from the cohorts warrant occupational therapy for adaptive strategies to accomplish functional independence and social participation. Severe, rapidly progressive, and refractory presentations require an early neurosurgical consult to evaluate the need for surgical management.[13] Long-term follow-up is justified since neurological deteriorations have been observed despite many years of observed stationary phase.[1]