PSMA is a non-hereditary, progressive disease of the anterior horn cells and motor nuclei of the brainstem. In 1850, Aran was the first to describe this disease entity and designated the term progressive muscular atrophy (PMA).¹ In 1952, Müller also reported patients with a sporadic pure lower motor neuron syndrome. He introduced the term progressive spinal muscular atrophy (PSMA), since then synonymously used with PMA.² A subgroup of the reported patients had muscle wasting and weakness of limbs with slow progression over years to decades. However, a proportion of patients with PSMA developed amyotrophic lateral sclerosis (ALS) in due course, manifesting with rapid progression of muscle weakness, appearance of upper motor neuron signs and/or bulbar symptoms.^3-5 Recently, in a prospective study of PSMA, we showed that most of our PSMA patients had an ‘ALS-like’ disease course with relentless disease progression and early death.⁶ In addition, corticospinal tract involvement was demonstrated in 70% of patients with progressive spinal muscular atrophy in autopsy series.^3;5;7  Therefore, evidence is accumulating that PSMA belongs to the spectrum of ALS. In the UK, PSMA is classified with ALS in the group of motor neuron diseases (MND). 

Clinical features

Patients with PSMA demonstrate clinical signs of lower motor neuron degeneration (flaccid weakness, atrophy, fasciculation and hypo- or areflexia). Typically, weakness and wasting start asymmetrically in an arm or leg, with subsequent spreading to other limb muscles in the following months or years. Clearly, this may result in difficulty with activities of daily living (ADL) and ambulation. Muscles of the thoracic region can also become involved, resulting in respiratory insufficiency. Although none of our prospectively studied patients had a bulbar debut, 16/37 (43%) patients demonstrated bulbar symptoms (dysarthria, dysphagia) at inclusion, i.e. within (median) 19 months from onset of weakness. The notion in earlier reports that bulbar motor neurons are rarely affected in PSMA⁸ might be true for patients with a slowly progressive form of spinal muscular atrophy only.⁹
Painful cramps may occur both in weak and normal muscles.¹⁰

Natural course and prognosis

PSMA is not curable and disease progression varies from slow to very rapid. Patients with slowly progressive spinal muscular atrophy have a relatively good prognosis with progression over years to decades. Nevertheless, a few of these patients may ultimately evolve to severe disability and respiratory insufficiency.^9;24 In patients with a rapidly progressive form of PSMA prognosis may be as poor as in ALS.⁶ The three year mortality rate of 33% in our PSMA patients comes near the reported rate of 50% in ALS.³³ Our data showed that the factors which determine this poor prognosis are VC at baseline lower than 90% of predicted and/or declining VC during the first six months.⁶

Epidemiology
PSMA can occur at any age in the adult population. Median age at onset was 57 years (25-72 year s) in a recent study.⁶ Previous studies reported earlier age at onset, but this may be due to the inclusion of patients with MMN which usually has a younger age at onset.^2;8;23  The estimated incidence of PSMA is (extrapolated from US) approximately 0.2/100.000 annually.⁸

Pathophysiology / etiology
The pathogenesis of  PSMA is largely unknown. In contrast to childhood-onset spinal muscular atrophy (SMA), PSMA is not a monogenic disease that follows a Mendelian inheritance. The current concept is that PSMA has a complex multifactorial aetiology in which genetic factors interact with environment factors, which are not yet unravelled.³² Moreover, mutations in the superoxide dismutase (SOD1) gene have been associated with familial ALS (FALS) with a predominant lower motor neuron syndrome. The most frequent of these mutations is the A4V mutation, which is also the most common SOD1 mutation in FALS worldwide.²⁵ 

Differential diagnosis

Recently, we showed that less severe or even treatable diseases can mimic PMSA. Nineteen percent of patients who were initially diagnosed as PSMA were found to have another diagnosis after re-assessment.^11;12 The misdiagnoses included myopathy (1), syringomyelia (1), ALS (1), idiopathic chronic axonal polyneuropathy (1), idiopathic brachial plexus neuropathy (1) and a spontaneously recovered herniated lumbar disk syndrome in one patient. For the other patients with a revised diagnosis (>50%) a potential treatment was available: multifocal motor neuropathy (MMN) (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and myasthenia gravis (1). Although the diagnosis of MMN was missed because the entity was not known at the time of first investigation, we concluded that patients with ‘early’ PSMA should be followed up long enough in order to detect development of features or a course atypical of PSMA, which may lead to correction into a less severe and even treatable diagnosis. PSMA has to be distinguished from other sporadic spinal muscular atrophies,  inherited spinal muscular atrophies, postpolio syndrome, and multifocal motor neuropathy (MMN), an immune-mediated form of lower motor neuron disease. It is of utmost importance to recognise MMN since it is a treatable condition.^13;14 Differentiation between PSMA and MMN relies on the finding of motor nerve conduction block on nerve conduction studies.¹⁵ The other sporadic spinal muscular atrophies have been described under various names and include Hirayama disease (‘juvenile muscular atrophy of distal upper extremity’), focal or segmental spinal muscular atrophy, scapulohumeral spinal muscular atrophy, monomelic amyotrophy of lower limb, wasted leg syndrome, chronic asymmetrical spinal muscular atrophy and (sporadic) distal spinal muscular atrophy.^16-23 The latter usually carry a more benign prognosis and have recently been classified by us into distal spinal muscular atrophy, segmental distal spinal muscular atrophy, and segmental proximal spinal muscular atrophy.²⁴ Since PSMA often presents with localized weakness and atrophy, it is initially clinically indistinguishable from the more benign forms of spinal muscular atrophy and therefore, for the individual disease course one had to rely on the follow-up. For patient management it is of utmost importance to find prognostic factors that distinguish the rapidly progressive forms of PSMA (with disease progression in months, comparable to ALS) from the more slowly progressive forms (with progression over years to decades). Recently, we have demonstrated a strong relation between respiratory function parameters and outcome in PSMA. We identified low VC at baseline and decline in VC in the first 6 months as the most powerful predictors of rapid progression.⁶
Hereditary spinal muscular atrophies in the differential diagnosis of PSMA include the adult-onset forms of hereditary spinal muscular atrophy (SMA type IV), bulbospinal muscular atrophy (Kennedy disease), familial ALS with predominant lower motor signs, and hexosaminidase deficiency B (Sandhoff disease).^25-29
Postpolio syndrome is a term used to describe new neuromuscular complaints including new or slowly increasing muscle atrophy and/or weakness which are reported in 50-60% of polio survivors with sequelae, and occur decades after recovery from paralytic poliomyelitis acuta.³⁰

Ancillary investigations

There is no biological marker for the diagnosis of PSMA. The diagnosis depends on the presence of clinical and subclinical (i.e., electrophysiological) evidence of lower motor neuron degeneration in one or more regions (brainstem, cervical, thoracic and lumbosacral spinal cord) according to the revised [1998] El Escorial criteria.³¹ The diagnosis also requires progressive spread of symptoms and signs within one region or extension to other regions. Ancillary investigations required to exclude other diseases which may simulate PSMA include electrophysiological studies and neuroimaging. The former is used to search for conduction block(s), to identify (subclinical) lower motor neuron degeneration and to exclude other neuromuscular diseases. Electrophysiologic features of LMN loss provide evidence of denervation and reinnervation and can be found in a varying relative proportion from muscle to muscle. Neuroimaging studies are performed to rule out structural lesions. The following laboratory tests should be carried out to exclude diseases that may mimic PSMA (e.g. myeloproliferative diseases, Lyme’s disease, HIV, MMN, hyperparathyreodism, hyperthyreoidism): creatine kinase activity (CK), sedimentation rate, glucose, hemoglobin, hematocrit, thyroid stimulating hormone, serum protein electrophoresis and serum immunoelectrophoresis with immunofixation, phosphate, calcium (and, if elevated, parathyroid hormone), serological tests for Lyme’s disease, and serum IgM anti-GM1 antibodies. When suspected as (treatable) cause of the lower motor neuron syndrome, CSF examination can be considered for examination of Borrelia burgdorferi and syphilis.

Therapy

A small, but significant effect of the glutamate-inhibitor riluzole on survival in ALS has been demonstrated in two randomized, double blind, placebo-controlled, clinical trials.³⁴ Patients with PSMA were included into the category ‘suspected ALS’ according to the [1994] El Escorial criteria. However, this subgroup was omitted in the [1998] revised El Escorial criteria.^31;35 As a result, patients with PSMA are not included in ALS research studies. Since progression in PSMA can be as rapid as in ALS we recommend that patients with ALS-like PSMA are treated with riluzole. Even slowly progressive forms of PSMA can ultimately evolve to severe disability and respiratory insufficiency.^9;24 Therefore, it might well be that these patients could also benefit from treatment with the glutamate-inhibitor riluzole, although there are no robust data to corroborate this assumption. With regard to the care of PSMA patients at multidisciplinary ALS/MND clinics and the management of symptoms: see ALS.

Links

http://www.wfnals.org
http://www.als-centrum.nl (dutch)
http://www.vsn.nl/spierziekten/diagnose.php?diagnose_id=55 (dutch)

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