Summary

Rheumatological conditions, as a group, are among the more common diseases that family physicians encounter in their daily practice. However, recognition of neuromuscular system involvement additionally, in the presence of pain, joint deformity and immobility that are often present in these patients, is difficult. Therefore, the objectives of this update are to review rheumatological diseases in which the neuromuscular system is either commonly affected or is sometimes the primary target and, secondly, conditions in which neurological manifestation may be one of the earliest signs of the disease. In addition to tests specific for the neuromuscular system, other useful ancillary tests are also discussed. Although newer potent medications have markedly improved the prognosis of many rheumatological diseases, these agents are themselves often also associated with neuromuscular complications. These complications are reviewed because the distinction of these from the underlying conditions could have important therapeutic implications.

摘要

風濕病是家庭醫生常見的一組疾病。由於這些病人往往有疼痛、關節變形和關節活動困難，要鑒別所影響的神經肌肉系統是有一定困難的。本文著重討論風濕病中神經肌肉系統所受到的影響，有時可能是主要的侵襲目標；某些情況下神經系統的表現有可能是疾病最早的病徵之一。除了一些神經肌肉系統的特異性試驗之外，文章亦討論到其他有用的輔助試驗。雖然強力而有效的新藥已顯著地改善許多風濕疾病的預後，但是這些藥物也可能有神經肌肉系統的併發症。鑑別這些併發症與原有病況具有重要的治療意義。

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Introduction

Although articular involvement is a major feature of many rheumatological diseases, multi-systemic manifestations including the neuromuscular system are common. In patients with arthritis, especially during acute flare up, the clinical evaluation of weakness and sensory symptoms in addition to pain can be difficult. Therefore, a high index of suspicion for possible involvement of the neuromuscular system is critical and ancillary tests are often necessary to confirm the diagnosis.

Family practitioners are well placed in the diagnosis and management of such complications because many rheumatological diseases, e.g. rheumatoid arthritis and Sjogren's syndrome are common. Therefore, a good working knowledge of these entities is helpful for prompt referrals and early institution of treatment. This consideration is particularly important in conditions that are potentially fatal unless they are aggressively treated.

Instead of providing an exhaustive list of all known rheumatological disease related neurological complications, for which a number of recent reviews are available,^1,2 the intent of this article is to concentrate on rheumatological diseases in which the neuromuscular system is either commonly affected or is sometimes the primary target and conditions in which neurological manifestation may be one of the earliest signs of the disease. Involvement of the central nervous system will only be briefly mentioned while the main effort will be concentrated on the peripheral nervous system.

We hope that the information presented in this update will be useful in aiding the family physician to reaching an earlier diagnosis so that appropriate referrals and treatment can be promptly instituted.

Rheumatoid arthritis

Rheumatoid arthritis is the most common inflammatory arthritis, affecting about 1% of the general population worldwide. Although rheumatoid arthritis is properly considered a disease of the joints, it is important to recognise that in up to 20% of patients, it can exhibit a variety of extra-articular manifestations.³ These manifestations clearly show that rheumatoid arthritis has features of a systemic disease, capable of involving a variety of major organs including the neuromuscular system. Although the following discussion will mainly concentrate on the peripheral nervous system, it is important to remember that the brain and the cervical spinal cord can also be affected. These include nodules in the central nervous system, cerebral vasculitis, cervical myelopathy due to atlantoaxial subluxation, compression neuropathy and neuropathies.^1,4

The most common peripheral nerve complication is compression neuropathy, often as a result of joint deformity and proliferation of the synovium. Common sites of compression include the median nerve in the carpal tunnel, the ulnar nerve at the elbow and the tibial nerve in the tarsal tunnel. Peripheral neuropathies can also occur. Mild distal sensory neuropathy and severe sensorimotor neuropathy are the two predominant clinical patterns. In each, the major aetiologic factor is vasculitis. In a classic study by Dyck et al nerve fiber degeneration was related to sites of vessels occluded due to arteritis.⁵ The pathogenesis for the distal sensory neuropathy is thought to be a result of vasa nervorum ischaemia from thrombosis and prognosis is relatively good. It has been reported in up to 18% of rheumatoid arthritis patients.⁶ The patients most commonly complain of tingling and burning sensations in their feet.

Sensorimotor neuropathy is much less common, affecting less than 1% of rheumatoid arthritis patients but it may be a sign of poor prognosis. It can either present as a mononeuritis multiplex or a symmetrical polyneuropathy. In mononeuritis multiplex, sites of involvement are more prominent in the mid upper arm and thigh because these "watershed sites" are particularly vulnerable to ischaemia with poor perfusion and little collateral circulation. Compared with distal sensory neuropathy, sensorimotor polyneuropathy tends to progress more rapidly. The major damage is in the epineural arteries, which leads to vessel ischaemia and subsequent neuronal demyelination and axonal degeneration. Nerve biopsies often display a striking central fascicular pattern.⁵ They are usually associated with long-standing seropositivity, nodular disease, systemic constitutional features and are more common in men. Other manifestations of vasculitis such as nailfold and digital infarcts, skin ulceration, palpable purpura, and Raynaud's phenomenon are also often present. These patients are also likely to have high rheumatoid factor titres, polyclonal elevations of immunoglobulins, and low complement levels, supporting the concept of immune complex mediated pathogenesis. The acute presentation of this type of neuropathy can be drastic and disabling. Patients typically suffer from severe asymmetric pain and paresthesias throughout the body; within hours or days of onset, weakness may develop, particularly wrist drop and foot drop.⁴ No well controlled studies have been undertaken and therefore no standard treatment regimen exists. Corticosteroid, cyclophosphamide and plasmapheresis have been advocated but even with these, the prognosis is relatively poor.

Less commonly, patients with rheumatoid arthritis may also develop myositis. The first type resembles progressive muscular dystrophy with gross fiber caliber variations, fibrosis, replacement by adipose tissue, and a striking loss of muscle tissue.⁷ Because of the virtual absence of inflammatory infiltrates, it may represent the end stage of a chronic myositis. Also, true myositis associated with myofiber necrosis and regeneration can present as either nodular or diffuse infiltrates of endomysium, perimysium and perivascular area by lymphocytes, plasma cells, and mononuclear cells. Although there are some overlapping features to polymyositis, rheumatoid arthritis associated myositis tends to be more patchy and the patients demonstrate a dramatic response to a small daily dose of prednisone which is not typical of polymyositis.⁸ Because of the therapeutic implications, rheumatoid arthritis associated myositis must be differentiated from other causes, such as drug-related myopathies, disuse muscle atrophy and weakness. Although less generally appreciated, autonomic neuropathy has also been described.⁹

Systematic necrotising vasculitis

The neuromuscular system is frequently affected early in polyarteritis nodosa and Wegener's granulomatosis. Prognosis for these conditions is poor unless treatments are promptly instituted. Therefore, they are presented here for discussion.

Polyarteritis nodosa

Polyarteritis nodosa is an uncommon disease with an incidence ranges from 0.5 to 1 case per 100,000. It may affect any organ; but the skin, joints, peripheral nerves, gut and kidney are most commonly involved (Figure 1). There is also a spectrum of severity from progressive fulminant to limited disease. At present, two different forms of idiopathic polyarteritis nodosa are recognised: systemic polyarteritis nodosa with visceral involvement and limited polyarteritis nodosa in which vasculitis is restricted to the skin, nerves, and/or musculoskeletal system. Polyarteritis nodosa is a diagnosis of exclusion and therefore its diagnosis can only be made when the disease cannot be fitted into other presently recognised forms of systemic necrotising vasculitis. Biopsies from nodular skin lesions and affected peripheral nerves, typically reveal involvement of medium sized blood vessels, provide the highest diagnostic yields.

Neurologic complications are common, affecting the peripheral nerves, cranial nerves as well as the central nervous system. Peripheral neuropathies including mononeuropathy, mononeuritis multiplex and polyneuropathy are particularly common. They may occur in 50 to 70% of cases^10-12 and can indeed be the initial manifestation.^10,13 The upper and lower extremities are affected with about the same frequency. The onset may be sudden and dramatic, with pain and paresthesia radiating in the distribution of the peripheral nerve, followed in hours or days by motor deficit of the same peripheral nerve. This may progress asymmetrically to involve other peripheral nerves and may produce a mononeuritis multiplex. With additional nerve damage, the final result may be a symmetrical polyneuropathy involving all sensory and motor modalities. Less commonly, a slowly evolving distal sensory neuropathy may occur. Brachial plexopathy has been reported.¹¹ Central nervous system involvement includes cerebral infarct and haemorrhage and transverse myelitis. Among the cranial nerves, cranial nerves II to VIII are particularly vulnerable.

The prognosis of most forms of systemic necrotising vasculitis, including polyarteritis nodosa, involving the peripheral nervous system is extremely poor if no treatment is initiated. Hawke et al reported long term follow up studies of patients with peripheral neuropathy caused by necrotising systemic vasculitis.¹⁴ A 5-year survival rate of only 37% was found. In contrast, the prognosis of limited polyarteritis nodosa is much better. Immunosuppressive therapy has improved outcome dramatically. In a study by Guillevin et al in the later 1980s, the prognosis in 165 patients with systemic polyarteritis nodosa and Churg-Strauss angiitis was followed.¹² Ninety-two per cent of the patients survived for at least 1 year after diagnosis of the disease, 79% for 2 years, and 63% for 5 years. Four factors including older age, gastrointestinal involvement, cardiomyopathy and renal signs were found to be associated with a poorer prognosis.

Wegener's granulomatosis

This condition was first described by Kling in 1936. It is a rare disease with an estimated incidence rate of 0.4 cases per 100,000. The disease is characterised by chronic systematic inflammatory lesions of the respiratory tract, usually accompanied by glomerulonephritis. Neurological manifestations are present in about one-third of the patients.¹⁵ Nervous system involvement may be due to vasculitis or to granulomatous inflammatory lesions. Cranial and peripheral neuropathies are most common. Less frequent complications are meningismus and focal lesions in the brain and spinal cord. Involvement of the peripheral nervous system is often present in an early phase of the disease and indeed can occasionally be the initial presentation, or as a presenting symptom of a relapse of the disease. Mononeuritis multiplex or symmetrical polyneuropathy are caused by vasculitis of the vasa nervorum. Muscle weakness is often observed and is usually the result of neuropathy. In contrast, only infrequently is vasculitic myositis found in Wegener's granulomatosis.

Pulmonary tissue, preferably obtained by open thoracotomy, offers the highest diagnostic yield by revealing granulomatous vasculitis. A high percentage of patients with Wegener's granulomatosis develop antineutrophil cytoplasmic antibodies (ANCAs) which are helpful in differentiating Wegener's granulomatosis from other systemic necrotising vasculitic disorders including Churg-Strauss angiitis and Goodpasture's syndrome.

Before the 1960s, Wegener's granulomatosis was almost invariably fatal. Kidney involvement appears to be the most significant prognostic factor during the first year after diagnosis. Thereafter, lung involvement is the most significant factor. Glucocorticoid therapy results in improvement in some cases but with serious side-effects following chronic use. The use of cytotoxic agents, especially cyclophosphamide therapy has significantly reduced the incidence of neurological complications of Wegener's granulomatosis.¹⁶

Sjogren's syndrome

Sjogren's syndrome is defined clinically by the presence of the sicca complex. The term "autoimmune exocrinopathy" has been used to describe the sicca manifestations. Apart from the "glandular" manifestations, it may also have "extra-glandular" manifestations. The frequency of primary Sjogren's syndrome in the general population has been an issue of considerable debate, in part due to the lack of a commonly agreed set of diagnostic criteria. Its estimated incidence ranges from <0.1 to 3% of the population. Secondary Sjogren's syndrome is most commonly associated with rheumatoid arthritis and, less commonly, with systemic lupus erythematosus and progressive systemic sclerosis.

Diagnosis of Sjogren's syndrome is based on the presence of the following manifestations: keratoconjunctivitis sicca, xerostomia, and arthropathy. However, its diagnosis is often delayed especially in milder cases in which the symptoms are often vague. Biopsy of minor salivary glands showing lymphoid infiltrates provides important supporting evidence for the diagnosis.

The clinical manifestations of central nervous system disease in Sjogren's syndrome are diverse. Involvement of the brain can cause focal and diffuse non-focal neurological manifestations. Spinal cord involvement can result in transverse myelitis. The neurological abnormalities may be subtle, usually of insidious onset. However, occasionally, they can be of acute or subacute onset. Early in the course of disease, neurological symptoms or deficits are characteristically transient and usually resolve. However, as the disease progresses, central nervous system disease becomes multifocal, recurrent, additive and fixed.

Peripheral neurological complications of primary Sjogren's syndrome could inflict as many as 10 to 20% of patients.¹⁷ Among the most common peripheral nervous system manifestations of primary Sjogren's syndrome is a distal symmetric pansensory polyneuropathy that tends to affect the lower more than the upper extremities, characterised by pain, paresthesias and global sensory loss. The symptoms are usually relatively mild and non-disabling. Approximately 40% of patients improved spontaneously. Response to immunosuppressive therapy is variable. Dorsal root ganglionitis and small vessel vasculopathy have been implicated in its immunupathogenesis.¹⁸ An important feature to bear in mind is that pure sensory neuropathy tends to occur early in the course of Sjogren's syndrome. It may antedate clinical glandular involvement and serological abnormalities may be absent. Therefore, Sjogren's syndrome should be included in the differential diagnosis of middle aged patients with sensory neuropathy. Other common peripheral nervous system complications are compression neuropathies. These abnormalities may occur in the setting of active synovitis but also in the absence of demonstrable arthritis or obvious inflammation. The most well recognised cranial nerve syndrome is a trigeminal sensory neuropathy in the distribution of the maxillary or mandibular divisions.¹⁹ Trigeminal neuropathy may be secondary to a localised ganglionitis affecting the gaserrian ganglion. Optic nerve disease occurs more commonly in association with multifocal central nervous system disease. Autonomic neuropathy can occur alone or in association with a sensory neuronopathy and is characterised by a mixture of sympathetic and parasympathetic dysfunction. The most common problems include pupillary and lid abnormalities, tonic pupils, Adie's pupil, Horner's syndrome, orthostatic hypotension, motility disorder of the bowels and bladder, genital organ dysfunction and autonomic insufficiency. Motor involvement, mononeuritis multiplex, chronic and acute inflammatory demyelinating polyneuropathy have been described but are uncommon.

Inflammatory myositis

The inflammatory myositis is a heterogenous group of conditions characterised by proximal muscle weakness and non-suppurative inflammatory skeletal muscles of which dermatomyositis and polymyositis are but just two examples. Indeed, secondary inflammatory myositis can occur in a wide variety of conditions (see Table 1). Therefore, as part of the workup of a patient's inflammatory myopathy, it is imperative that potential secondary causes be ruled out. The diagnostic criteria proposed by Bohan and Peter are commonly used.²⁰

As a group, inflammatory myositis are relatively rare and the reported incidence varied between 0.05 to 0.84 cases per 100,000. Racial differences are apparent. For example, in adults in the United States, the lowest rates are reported among the Japanese and the highest in blacks.

Dermatomyositis

Dermatomyositis affects both children and adults, females more often than males. Compared with polymyositis, dermatomyositis is a more distinct clinical entity identified by a characteristic rash that accompanies or, more often, precedes the muscle weakness. The skin manifestations include a heliotrophic rash on the upper eyelid, with oedema, a flat red rash on the face and upper trunk, erythema of the knuckles accompanied by a raised violaceous scaly eruption (Gottron's sign) (Figure 2). The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and upper chest (often V-shaped), or the upper back and shoulders (shawl sign) (Figure 3). Dilated capillary loops at the base of the fingernails are also characteristic. The fingernails may be irregular, thickened and distorted (mechanic's hand sign). Dermatomyositis in children resembles the disease in adults, except that extramuscular manifestations such as vasculitis, ectopic calcification and lipodystrophy are more frequent.²¹ Dermatomyositis may occasionally be associated with systemic sclerosis, mixed connective tissue disease, other autoimmune conditions, or malignancy.

Characteristic needle electromyographic findings include myopathic potentials, unduly early motor unit recruitment, increased insertional and spontaneous activities. In more chronic cases, repetitive complex discharge may also be present. However, definitive diagnosis requires muscle biopsy. In dermatomyositis, the inflammatory infiltrates are predominantly perivascular or in the interfascicular septa, rather than within the fascicles. The intramuscular blood vessels show endothelial hyperplasia, fibrin thrombi and consequent obliteration of capillaries. Perifascicular atrophy is diagnostic of dermatomyositis. The affected muscle fibers tend to be localised in groups involving a portion of a muscle fasciculus. The natural history is unclear and, to date, only a small handful of blinded, controlled studies have been done.^22,23 Therefore, treatment remains empirical. Glucocorticoids remain the mainstay of treatment. Other immunosuppressive agents such as azathioprine and methotrexate have also been used for their "steroid sparing" effects with some success. The prognosis for patients with idiopathic inflammatory myopathies has improved with the availability of immunosuppressive therapy even though the exact extent is still controversial. The 5-year survival rate in the adult is around 80% in more recent reports as compared to only about 60% in earlier studies in the pre-glucocorticoid era. In general, children tend to have a slightly better prognosis. In adults, the longer the duration of disease and the more severe the weakness at the time of diagnosis, the worse the prognosis.

Polymyositis

The pattern of muscle weakness in polymyositis is also shared by many other types of inflammatory myositis (Table 1). Idiopathic polymyositis has no unique clinical features and its diagnosis is one of exclusion. Typically, it has a rather slow onset and steady progression that occurs mainly in adults. In addition, patients may also develop systemic symptoms such as morning stiffness, arthralgia, fatigue, anorexia, weight loss and fever. Pulmonary and cardiac complications may also occur and are important contributory factors to morbidity and mortality.

Electromyographic features are the same as in dermatomyositis and other inflammatory myositis. However, on muscle biopsy, in contrast to dermatomyositis, the infiltrates are mostly in the fascicles surrounding or invading individual non-necrotic muscle fibers. The necrotic, degenerating, and regenerating fibers tend to be scattered or isolated and are not necessarily near the areas of inflammation.

As a result of the lack of distinct characteristics, the risk of misdiagnosis is higher.²¹ For example, inclusion body myositis is often diagnosed only after the patients fail to respond to steroid.

Miscellaneous conditions

Neurologic manifestations in systemic lupus erythematosus primarily involve the central nervous system. Peripheral neuropathy has only been reported in 8% of cases and the pattern of neuropathy is variable.²⁴ Some patients have had symmetrical distal motor and sensory loss similar to that seen in nutritional polyneuritis, Gullain-Barre syndrome and mononeuropathies; and mononeuritis multiplex have also been reported. Neurological complications are uncommon in systemic scleroderma but compression neuropathy and trigeminal sensory neuropathy have been reported.^25,26 In ankylosing spondylitis, as a result of spinal deformity, subluxation and fracture, myelopathy, radiculopathy and cauda equina syndrome may occur.^27,28

Drug related neuromuscular complications

It is not uncommon that patients with rheumatological disorders may be on one or more immunosuppressive agents, many of which could cause neuromuscular complications. This possibility must be borne in mind to avoid erroneously attributing the neuromuscular involvement as part of the disease. Once recognised, stopping or curtailing the drugs may result in improvement of the symptoms.

The glucocorticoids are probably the most commonly used immunosuppressive agents. Steroid myopathy resulting in proximal muscle atrophy and weakness commonly occurs with high dosage and prolonged administration. This sometimes presents a dilemma in patients with inflammatory myopathy who may show good initial response to steroid therapy but only subsequently to start deteriorating again. One will then have to determine whether the decline is due to disease progression or a complication of the medication. Fortunately, a number of features help to differentiate the two. First, on needle EMG study, increased insertional activity and spontaneous activity are uncommon in steroid myopathy. Also, in steroid myopathy, inflammatory changes are not seen on muscle biopsy.

Neurologic complications from gold therapy are estimated to occur in 0.2 to 0.5% of patients with rheumatoid arthritis.²⁹ Known neurological manifestations include peripheral neuropathy, Gullain-Barre syndrome, cranial nerve palsies and encephalopathy. The duration of gold therapy in most cases was from one to three months. Chloroquine, is known to produce vacuolar myopathy and a polyneuropathy.³⁰ Colchicine could infrequently induce a proximal myopathy and neuropathy which usually resolve within several weeks after the medication is stopped.³¹ High dose penicillamine administered on a prolonged basis in individuals who are genetically susceptible could also uncommonly cause an inflammatory myositis and myasthenia gravis.^32,33

Thalidomide, better known for its potential for teratogenesis, has regained popularity in the treatment of a number of rheumatological conditions including Behcet's syndrome and discoid lupus erythematosis. The most common complication is a length dependent sensory axonal polyneuropathy that is related to dose and duration of use.

Key messages

1. Multi-system involvement is common in many rheumatological conditions.
2. The recognition of neuromuscular system involvement in patients with pain, joint deformity, and immobility can be challenging. Careful examination and ancillary tests are often needed to definitively establishing the diagnosis.
3. Some neuromuscular complications are markers of grave prognosis (e.g. rapidly progressive sensorimotor polyneuropathy in rheumatoid arthritis) for which urgent aggressive treatments are needed.
4. Neuromuscular system involvement are among the earliest manifestations in some rheumatological conditions (e.g. sensory ganglionitis in Sjogren's syndrome). Recognising the possible link could be helpful in establishing the underlying diagnosis.
5. Many medications used in treating these rheumatological conditions are also capable of causing neuromuscular complications. Differentiation from the underlying process could have important therapeutic implications.

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References