Indian Pediatrics 2003; 40:780-783 

Distal Spinal Muscular Atrophy of Upper Limb (Hirayama Disease) Associated with High Serum Lead Levels

The spinal muscular atrophies are a group of genetically determined disorders characterised by degeneration of the anterior horn cells of the spinal cord, that usually manifest as proximal muscle weakness and wasting. Predominantly distal involvement in patients without demonstrable neuropathy is, however, uncommon. Since the first report of distal spinal muscular atrophy localised to upper extremity by Hirayama, et al. in 1959, many patients have been reported in the literature mainly from Asia, with more than 300 from Japan(1). Although there have been quite a few reports from India describing adolescent and adults with this condition, we herein describe what is to our knowledge the youngest case reported with this condition. Associated high serum lead level was an interesting and unique feature.

Case Report

A 6½-year-old, right handed female child was brought with a history of gradually progressive weakness of both upper limbs for one year, and wasting of muscles of the hand for 5 month. The family resided in Mahendragarh, Haryana. The father was a small-scale farmer and the source of water supply was a shallow bore-well. There were no industrial units involved in petroleum products, battery manufacture and toy painting in the neighborhood. There was no history of any neurological illness or any other chronic illness in the family or in the village. The child was a product of a non-consanguineous marriage, had a normal birth-history, was fully immunized and her development was age-appropriate. There was no history of recurrent fetal/early neonatal death in the previous pregnancies and no history of decreased fetal movements during the present pregnancy. There was no history of pica or heavy metal ingestion, poor school performance, recurrent abdominal pain or vomiting, constipation or any behavioral changes. A 10½ year male, and an 8-year-old female sibling of the patient were normal.

The weakness had an insidious onset, appeared simultaneously in both upper limbs and was gradually progressive in severity. There was no history of sensory or autonomic symptoms and abnormal movements. The parents had also noticed a gradually increasing wasting of the small muscles of the hand over the last 5-6 months, which was more marked in the right hand. There was no change in posture and gait and no history of incontinence. There was no history of preceding trauma, viral illness, rash, and fever or visual disturbances. On specific questioning, a history of using an indigenous cosmetic in the eyes (surma) was elicited.

On examination, the child had normal speech, vision and hearing, and her anthropometric examination was within the normal limits. General physical examination and examination of the cardiovascular and respiratory system revealed no other abnormality, except for obvious wasting of the muscles of the hand and distal forearm, which was more prominent on the right side. Nervous system examination showed normal higher functions and sensations. No abnormal movements and no evidence of meningeal irritation or raised intracranial tension were detected. Cranial nerve examination was normal and there was no wasting or fasciculations of the tongue. There were no cerebellar signs and fundus was normal.

Muscle bulk of lower limb muscles and, biceps, triceps and deltoid was normal whereas there was an asymmetric wasting of intrinsic muscles of the hand and the forearm muscles. The brachioradialis was however spared. The tone was normal in both lower limbs and at the shoulder, but reduced in the forearm and hand. Superficial reflexes were present and deep tendon reflexes at ankle, knee and the elbow were preserved. The supinator jerk was equivocal. On the basis of history and clinical examination, a lower motor neuron type of gradually progressive distal weakness and atrophy localized to distal upper extremity was considered.

Hemogram, liver and renal function tests, CPK, LDH, aldolase, blood sugar, calcium, phosphorus and ESR were normal. CSF examination was normal and peripheral smear showed normocytic, normochromic red blood cells with no basophilic stippling. Radiographs of the chest and cervical spine were within normal limits. Serum lead levels were markedly elevated at 91 µg/dL (Perkin-Elmer Atomic absorption spectrophotometer, A Analyst 600, with Zeenin background correction and THGA; Perkin-Elmer Inc., Switzerland). Nerve conduction velocity studies showed normal peripheral nerve conduction (ulnar and median nerve) in both the limbs. Electromyography showed fibrillation and positive waves in C8/T1 and C7 myotomes with single discrete motor unit activity in hand muscles. These electro-diagnostic studies were suggestive of denervation in C8/T1 and C7 root distribution bilaterally with normal peripheral nerve conduction. This was compatible with a focal lesion at C8/T1 spinal segment (anterior horn cell level). In view of these findings, serum lead levels were repeated and again found to be high at 76 µg/dL. A muscle biopsy and nerve biopsy was done but adequate nerve tissue could not be obtained. The muscle biopsy revealed predominantly atrophic muscle fibers. Occasional fibers were rounded and a few showed internalization of nuclei. Some normal fibers were also seen. MRI of the cervical and upper thoracic spine did not reveal any abnormality, although MRI of the neck in full flexion was not done. A non-contrast CT scan of the head was normal. Chelation therapy with BAL and EDTA was proposed in view of the high lead levels but refused by the parents. A repeat muscle biopsy to obtain tissue for enzyme immuno-histochemistry and a repeat nerve biopsy were planned, but the parents refused permission.

Discussion

Various causes of wasting and weakness of small muscles of hand include spinal cord lesions like syringomyelia and spinal cord tumors, nerve root compression, cervical rib, motor neuron disease (amyotrophic lateral sclerosis), and distal myopathy. The lack of sensory symptoms and evidence of long tract involvement, normal X-ray chest and cervical spine and the normal MRI spine rule out the possibility of cervical rib, nerve root compression, syringomyelia and cord tumour. The absence of upper motor neuron signs, lack of bulbar/facial involvement and absence of sensory signs also rule out amyotrophic lateral sclerosis (including, the Madras type). The EMG findings rule out a distal myopathy, and the normal motor and sensory nerve conduction studies exclude peripheral nerve lesions. Therefore, a diagnosis of juvenile muscular atrophy of distal upper extremity (Hirayama Disease) was made mainly by a process of exclusion.

Hirayama disease is characterized by initially progressive muscular weakness and wasting of the distal upper limb, unilaterally or bilaterally in young people (teens or early twenties; earliest reported age at onset of disease, 10 year), predominantly male (male to female ratio 20 : 1), followed by spon-taneous arrest within several years (five years in 73% of patients). Juvenile asymmetric segmental spinal muscular atrophy (JASSMA), Monomelic amyotrophy, and Juvenile muscle atrophy of unilateral upper extremity are some other terms used for this condition. Familial occurrence is rare and the onset is insidious with muscular weakness and wasting in the hand and forearm sparing the brachioradialis muscle. It is mostly unilateral but some patients have asymmetrically bilateral involvement. However, in 90% of patients with unilateral involvement, homonymous muscles on the opposite side show features of denervation and a significant number of non-atrophic muscles on the affected side also show these features. Abnormalities of the sensory system and the muscle stretch reflexes are not found. EMG changes are suggestive of denervation whereas peripheral motor and sensory nerve conduction studies are normal. Muscle biopsy shows ‘group atrophy’ and ‘type grouping’; which represent myopathological evidence of denervation and reinveration, respectively. Nerve biopsy is normal in all cases.

The etiology of Hirayama disease has been debated for long and has included unidentified viral illness, atypical poliomyelitis, toxins and indirect trauma to the spine. Hirayama et al. reported gross and microscopically evident features of ischaemic lesions involving bilateral lower cervical anterior horns (most severely at C7-C8 levels), which were different from those seen in degenerative motor neuron disease and spinal vascular disorders(2). Neuroradiological studies in neutral neck position and with full flexion of neck suggested the disease to be a flexion-induced ischaemic cervical myelopathy localised to lower cervical cord(1). Certain authors have argued against the proposed pathophysio-logical mechanism and consider it to be an intrinsic motor neuron disease(3,4). Cases with normal cervical spine and adjacent structures with absence of dynamic compression of the cord, and late clinical progression of the disease to the lower extremities, have also been reported(4,5).

The significance of high serum lead levels in this patient is unclear. Peripheral neuropathy is common in adults but rarely seen in children, except those with sickle cell disease(6). Chronic lead poisoning causes mainly a motor neuropathy involving selective large nerves, such as the common peroneal, radial or median nerves. In peripheral nerves, axonal degeneration occurs with loss of large myelinated fibers, but with no demyelination. Occasionally, the anterior horn cells are also degenerated(7). Isolated anterior horn cell involvement without demonstrable peripheral neuropathy has, however, not been reported with lead poisoning. Reports in literature have reported intranuclear lead inclusion bodies in the anterior horn cells of the cervical cord of monkeys chronically exposed to lead(8), and asymmetric proximal arm and intrinsic hand muscle involvement resembling a progressive muscular atrophy in lead poisoning(9). The clinical significance of these findings still remains to be elucidated. Among the published cases of Hirayama disease, only Peiris, et al.(10) reported on the serum lead levels of the patients. They found normal lead levels in the 10 patients in whom these levels were estimated. Based on the high serum lead levels, and an uncharacteristically early presentation of the disease in this child, one may speculate on the role of lead in accelerating the rate of disease progression thereby leading to an earlier clinical presentation. However, the increased lead levels can also be a coincidental finding and only a systematic study can comment on the pathophysiologic role of lead in this disorder.

Acknowledgement

The authors wish to thank Dr. K.K. Sidhu, former Head, Department of Pediatrics and Dr. K.S. Anand, Sr. Neurologist, Department of Medicine, Dr. Ram Manohar Lohia Hospital for their help in the investigative workup and manuscript preparation.

Contributors: All the authors were involved in the management and workup of the patient. DM drafted the manuscript with AA’s help. VKG supervised the drafting of the manuscript and will act as guarantor for the case.

Funding: None.

Competiting interests: None stated.

 References