Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 30

Connective tissue disorders: systemic lupus erythematosus, Sj€ogren’s syndrome, and scleroderma JONATHAN Y. STREIFLER1* AND YAIR MOLAD2 Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Neurology Unit, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel

1

2

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Rheumatology Unit, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel

INTRODUCTION

SYSTEMIC LUPUS ERYTHEMATOSUS

Connective tissue disorders (CTD) are a group of autoimmune, multisystem, chronic inflammatory diseases driven by an antibody or T-cell response directed against a selfantigenthatultimatelyleadstotissuedamageandorganfailure. A genetic background of the immune system together with environmental triggers culminates in an overt CTD. Neurologic complications of CTD may involve the central nervous system (CNS), the peripheral nervous system (PNS), or the autonomic nervous system (ANS). Though some complications are similar in most diseases and not disease-specific, they will be discussed for each disorder separately. Common complications, however, such as side-effects of drugs, will mostly be covered in separate chapters. Sometimes infections result from the treatment itself. An example is progressive multifocal leukoencephalopathy (PML), which results from reactivation of the JC virus and has lately been associated with the use of different antimonoclonal antibody medications (Eric et al., 2008). The main autoimmune multisystem rheumatic disorders are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sj€ ogren’s syndrome (SS), scleroderma, and mixed connective tissue disease (MCTD). As RA and related disorders are dealt with in another chapter (Ch. 000), here we cover the neurologic manifestations of SLE, SS, and scleroderma (Table 30.1).

Systemic lupus erythematosus (SLE) is an autoimmune multiorgan, autoantibody-mediated disease characterized by a myriad of clinical and serologic features (D’Cruz et al., 2007; Rahman and Isenberg, 2008; Bertsias et al., 2010a) including arthritis, malar rash, photosensitivity, oral ulcers, pleuritis, pericarditis, nephritis, cytopenias, and antibodies targeted against nuclear components (ANA). Involvement of the nervous system is one of the most serious manifestations of SLE. Although seizures and psychoses are the only neurologic features included in the American College of Rheumatology (ACR) classification criteria of SLE, a universal classification for neuropsychiatric lupus (NPSLE) published in 1999 included various SLE-related and non-SLE neurologic manifestations that must be considered in SLE patients presenting with any neurologic symptoms (ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999). NPSLE manifestations involve both the CNS and the PNS, and can be divided to SLE-specific and non-SLEspecific. Neurologic symptoms can range from mild abnormalities of cognitive function, headache, anxiety, mild depression or mild polyneuropathy, to severe abnormalities such as seizures, psychosis, stroke, myelopathy, and aseptic meningitis (Table 30.2).

*Correspondence to: Jonathans Y. Streifler, M.D., Senior Lecturer in Neurology, Sackler Faculty of Medicine, Tel Aviv University, Neurology Unit, Hasharon Hospital, Rabin Medical Center, Petah Tikva 49372, Israel. Tel: 972-3-9372661, Fax: 972-3-9372605, E-mail: [email protected]

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Table 30.1 The distribution and frequency of the neurological manifestation in systemic lupus erythematosus (SLE), SSc (systemic sclerosis), and Sj€ogren’s syndrome (SS)

Central nervous system Cognitive dysfunction Headache (including migraine and idiopathic intracranial hypertension) Seizure disorders Mood disorder Cerebrovascular disease Anxiety disorder Acute confusional state Psychosis Myelopathy Aseptic meningitis Peripheral nervous system Polyneuropathy Sensory ataxic Painful sensory Entrapment neuropathy (e.g., Carpal Tunnel Syndrome) Cranial neuropathy (e.g., trigeminal neuralgia) Mononeuropathy multiplex Plexopathy Demyelinating syndromes Acute inflammatory demyelinating polyradiculopathy (Guillain–Barre´ syndrome) Autonomic disorder Myopathy Myositis Myasthenia gravis

SLE

SSc

SS

þþþ þþþ

þ þ

þ

þþþ þþþ þþþ þþþ þþ þþ þþ þ

þ

þ

þþ

þþþ

þ þ þ þ þ þ þ

þ þ

þþþ þþþ þþ þ

þþ þþþ þþ

þþþ þþ þþþ þþþ þþþ þþ þþ þ þþ þþþ þ þ

þþþ Common, þþUncommon, þ Rare

Incidence The reported frequency of NPSLE varies among different studies. However, based on data derived from recent cohort studies the prevalence of at least one NPSLE event was 28–40.3% (Hanly et al., 2007, 2009, 2010), and 17.4% had multiple neurologic events (Hanly et al., 2009). In an international inception cohort of 572 SLE patients, 28% of the enrolled patients experienced at least one NPSLE event; up to 38% were pathogenetically attributed to SLE (Hanly et al., 2007). In a follow-up study of 1206 patients with SLE conducted by the Systemic Lupus International Collaborating Clinics (SLICC), 40.3% had
1 NPSLE events that were attributed to SLE in 13–23.6% of the patients (Hanly et al., 2010). NPSLE manifestations were recorded in 23% of southern Chinese patients with SLE during a mean follow-up of 6.7 years (Mok et al., 2006), a lower incidence than that reported in a Maryland SLE cohort (51%) (Mikdashi and Handwerger, 2004).

Neuropsychiatric manifestations in systemic lupus erythematosus The ACR committee on NPSLE nomenclature has developed reporting standards, recommendations for laboratory and imaging evaluation, and case definitions for 19 neuropsychiatric disorders observed in SLE (ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999) (Table 30.2).

COGNITIVE DYSFUNCTION Cognitive dysfunction, as measured by neuropsychologic assessment techniques, has been reported in up to 80% of SLE patients (Ainiala, 2001), although most studies have found a prevalence between 17% and 66% (Hanly, 2005). For most patients, cognitive dysfunction is subclinical and includes difficulty in attention/ concentration/speed of thought, memory, orientation, language, or as a combination of these problems

CONNECTIVE TISSUE DISORDERS Table 30.2 Neuropsychiatric syndromes as defined by the American College of Rheumatology nomenclature and case definitions (adapted from ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999) Central nervous system Common

Uncommon

Rare

Cognitive dysfunction Headache (including migraine and benign intracranial hypertension) Seizure disorders Mood disorder Cerebrovascular disease Anxiety disorder Acute confusional state Movement disorder (chorea, mainly children) Psychosis Myelopathy Aseptic meningitis

Peripheral nervous system

Polyneuropathy

Demyelinating syndromes Cranial neuropathy Mononeuropathy single/multiplex Myasthenia gravis Plexopathy Autonomic disorder Acute inflammatory demyelinating polyradiculopathy (Guillain–Barre´ syndrome)

(Olazara´n et al., 2009). These difficulties can be attributed to diffuse brain damage due to the disease and to adverse effects of medications, mostly corticosteroids, as well as to depression (Olazara´n et al., 2009).

HEADACHE The reported prevalence of headache has varied widely between 24% and 72%, but recent studies did not find an increased prevalence of headache in SLE as compared to the general population (Fernandez-Nebro, 1999). Headache is related to the disease itself or to stress and tension. The headache features include migraine without aura (13–27%), migraine with aura (26–42%), tension headache (15–29%), and idiopathic intracranial hypertension (1%)

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(Bruns and Meyer, 2006). Intracranial venous thrombosis should be excluded in patients with SLE who test positive for the antiphospholipid antibodies (APLA) and present with new-onset headache. For most patients, the headache is probably unrelated to SLE.

PSYCHOSIS, MOOD CHANGES, AND ANXIETY Psychosis is reported in up to 8% of SLE patients, and it is characterized by either the presence of delusions or hallucinations. The latter are most frequently auditory. Psychosis is a rare but dramatic manifestation of NPSLE, and when present it must be distinguished from other causes, including drug abuse, schizophrenia, and major depression (Bruns and Meyer, 2006). Other psychiatric manifestations that occur in SLE patients are depression, anxiety, neuroses, dementia, and delirium. Lupus psychosis may become chronic and devastating and is more common among those patients who take high-dose corticosteroid therapy (Bruns and Meyer, 2006). Lupus psychosis has been associated with the presence of serum antibody to phosphorylated ribosomal (P ribosomal) proteins with a specificity of 99.3%, as was shown in an international multicenter study (Mahler et al., 2006) (see later). An acute confusional state must initiate a search for underlying precipitating causes such as infection, metabolic disturbances, and adverse effects of drugs.

SEIZURES Generalized and focal seizures are reported in 6–51% of patients with SLE and are usually related to active disease, but other causes, such as infection, electrolyte or metabolic abnormalities, chronic renal failure, malignant hypertension, toxicity of glucocorticoids or antimalarials, as well as APLA-related brain infarcts, should be ruled out (Bruns and Meyer, 2006). EEG abnormalities are common (60–70%) in SLE patients with seizure disorder, but typical epileptiform EEG patterns are only reported in 24–50% and are usually predictive of recurrence (Bertsias et al., 2010b).

CEREBROVASCULAR DISEASE The most common focal neurologic manifestations in SLE are stroke and transient ischemic attack (TIA). Cerebral vasculitis is rare in SLE. Cerebrovascular atherosclerosis occurs in a younger age than in the general population and has been related to disease activity in addition to systemic hypertension. Other mechanisms include APLA and heart valve disease (Urowitz et al., 2010). Patients with stroke or recurrent TIAs should be evaluated for a valvular source of emboli (Libman-Sacks endocarditis), and for the presence of APLA.

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DEMYELINATING LESIONS Several neurologic demyelinating disorders have rarely been reported as associated with SLE, including lupoid sclerosis (multiple sclerosis-like manifestations associated with APLA in SLE) and Devic’s syndrome. Lupus myelopathy presents as a rapidly evolving transverse myelitis. Acute inflammatory demyelinating polyneuropathy is a rare manifestation of neurologic involvement of SLE. PML has been recently found to be more common in SLE compared to other rheumatic diseases (Molloy and Calabrese, 2009) yet, as stated above, this disease is generally considered as related to immunosuppressive treatment.

PERIPHERAL NERVOUS SYSTEM DISORDERS Polyneuropathy is an uncommon feature of NPSLE, occurring in 2–3% of patients with SLE. Even less common manifestations of the peripheral nervous system include mononeuropathy, acute inflammatory demyelinating polyneuropathy, plexopathy, and sensory neuropathy. Muscle weakness and atrophy and myasthenia gravis were rarely reported in association with SLE.

Neurologic presentations of the antiphospholipid syndrome APLA are prothrombotic autoantibodies that occur in about a third of patients with SLE. APLA are associated with venous and arterial thrombosis and obstetric morbidity – mainly as recurrent abortions and fetal loss. The laboratory evidence for APLA is the presence of a moderate to high titer of antibodies to cardiolipin and b2 glycoprotein IgG and IgM, and/or positive lupus anticoagulant (Cohen et al., 2010). Several SLE manifestations are associated with the presence of APLA, such as thrombocytopenia, livedo reticularis, noninfective endocarditis (Libman–Sacks endocarditis), pulmonary hypertension, as well as neurologic manifestations. The most common neurologic manifestations that are associated with APLA are stroke and TIA (including amaurosis fugax), but other neurologic morbidities have been described in association with APLA including ocular ischemia, seizures, chorea, multi-infarct dementia, transverse myelopathy, lupoid sclerosis, Sneddon’s syndrome (stroke or TIA and livedo reticularis), acute demyelinating syndrome of peripheral nervous system, and migraine (Muscal and Brey, 2010). Such neurologic disorders in a patient with SLE should prompt a thorough investigation for the presence of APLA and an MRI study of the brain and spinal cord; this usually discloses high-intensity white matter subcortical and periventricular lesions with or without brain infarcts. Early diagnosis

of antiphospholipid syndrome (APLS) is crucial because evidence for cerebral infarct or thrombosis in the presence of APLA usually indicates the need for long-term anticoagulation therapy (Cohen et al., 2010). In less than 1% of patients with APLS, a life-threatening variant, the catastrophic antiphospholipid syndrome (CAPS), occurs. CAPS is characterized by multiple organ thrombosis, mainly microvascular, often with microangiopathic hemolytic anemia (Cervera et al., 2010). Cerebral manifestations (infarcts, encephalopathy, seizures, or cerebral venous occlusions) were described in 62% of an international cohort. Small vessel cerebrovascular occlusive disease is not uncommon and may be the etiology of the encephalopathic features of the syndrome.

Pathogenesis of neuropsychiatric lupus About 40% of neuropsychiatric events in SLE can be directly attributed to active disease. The major risk factors for NPSLE events are generalized SLE disease activity or the ensuing damage, previous neurologic events, and the presence of APLA (Bertsias et al., 2010b). The pathologic mechanism for NPSLE manifestations is still not fully understood, but the main mechanism is antibody-mediated. There are two main underlying processes that can cause neurologic abnormalities in SLE: thrombotic occlusion mostly associated with APLA, and inflammation leading to neuronal apoptosis and dysfunction. In general, focal neurologic deficits are usually related to arterial or microvascular thrombosis due to APLA, whereas diffuse symptoms usually reflect autoantibody-mediated inflammatory neuronal damage. Anti-ribosomal-P antibody is found in up to 25% of SLE patients and has been associated with lupus psychosis and depression (Mahler et al., 2006). A subset of antidsDNA antibodies was found to cross-react with antibodies to N-methyl-D-aspartate receptor (NMDA-R) (Diamond, 2010). These antibodies are found in serum, CSF, and brain tissue and pose a neurotoxic effect in a mouse model (Diamond, 2010). It has been shown that cytokine-mediated blood–brain barrier integrity decrease allows these antibodies to bind to neuronal cells and cause cell apoptosis which clinically present as both cognitive and behavioral disturbances in SLE.

Diagnosis of neuropsychiatric lupus Neuropsychiatric manifestations attributable to SLE often occur as part of a generalized disease activity, although a neurologic event can be a presenting clinical feature of the disease. In a prospective study by the SLICC, 28% of newly diagnosed SLE patients experienced at least one neuropsychiatric event around the time of the disease diagnosis, although only a few were attributed to SLE (Hanly et al., 2007). Thus,

CONNECTIVE TISSUE DISORDERS 467 because there are no confirmed predictors for NPSLE hypertension, infection, or metabolic abnormalities. and there is not a single laboratory or imaging test which Symptomatic management, including antiepileptic drugs can certainly confirm SLE-related involvement of the (AEDs), antidepressants, and antipsychotic agents, nervous system, diagnosing neuropsychiatric events as should be considered for appropriate symptoms. For difa manifestation of SLE can be, and often is, a diagnostic fuse NPSLE symptoms, corticosteroids and immunosupchallenge for the rheumatologist and neurologist. Exclupressive agents are the treatment of choice. For focal sion of non-SLE conditions such as infection, metabolic events, mainly stroke or TIA, antithrombotic drugs disturbances, atherosclerotic vascular disease, and drug should be prescribed as APLA or traditional risk factors adverse effects is essential in any case of a SLE patient for atherosclerosis are probably the underlying causes. who presents with signs or symptoms suggestive of a Anticoagulation therapy might be superior to antiplatelet neurologic problem. The European League Against drugs for secondary prevention of arterial events in Rheumatism (EULAR) published recommendations patients with antiphospholipid syndrome presenting with for the management of SLE patients presenting with stroke or recurrent TIA (Bertsias and Boumpas, 2010a; neuropsychiatric manifestations using an evidenceBertsias et al., 2010b; Cohen et al., 2010). based approach followed by expert consensus Following seizures, long-term AED therapy may be con(Bertsias et al., 2010a). Accordingly, the following evalsidered. If new-onset seizures are the result of an acute uation is recommended: cerebrospinal fluid (CSF) examinflammatory brain insult as part of a concomitant SLE ination (including PCR for herpes simplex virus (HSV) flare-up, corticosteroid with or without immuneand JC virus as indicated) may help to exclude CNS suppressive drug should be considered. If seizures are infection in patients with fever or other signs and sympthought to reflect an APLA-induced arterial thrombotic toms suggestive of infection. Mild (pleocytosis, elevated event, antithrombotic therapy is the preferred mode of therprotein level) CSF abnormalities are common (40–50%) apy (Bertsias and Boumpas, 2010a; Bertsias et al., 2010b). but are not specific to the NPSLE manifestations. EEG A patient with SLE who presents with an acute constudies may help to diagnose underlying seizure disorfusional state should be treated according to the underder. Brain imaging is pivotal for the diagnosis of the lying cause. Use of haloperidol and antipsychotics is cause of the neuropsychiatric event and to rule out advised only when other interventions are ineffective. non-SLE causes. Brain MRI is the preferred imaging Corticosteroids with immunosuppressive agents, such method for detecting white matter lesions. Lesions by as cyclophosphamide, are effective in most patients, MRI may be observed in 25–75% of NPSLE patients. while in refractory cases, plasmapheresis and rituximab In patients with focal neurologic symptoms, the lesions (anti-CD20 monoclonal antibody) have been used predominate in the periventricular and subcortical white (Bertsias et al., 2010b). matter, usually in the distribution of a major cerebral Acute psychosis should be considered as blood vessel, although such lesions are not specific for corticosteroid-induced if patients are being treated with NPSLE (Bertsias and Boumpas, 2010a; Sibbitt et al., prednisone 1 mg/kg/day or more. Management involves 2010). Diffuse neurologic manifestations may be associantipsychotic and/or antidepressant drugs as indicated, ated with transient lesions in the subcortical white matter and in case of severe psychosis as part of a generalized and high-intensity signals in the gray matter (Bertsias SLE flare-up the combination of corticosteroids and and Boumpas, 2010a). immunosuppressive therapy (usually intravenous pulses of cyclophosphamide followed by oral azathioprine therapy) results in a 60–80% good response (Bertsias et al., Management 2010b). Most psychiatric events resolve within 2–4 weeks SLE is a chronic, relapsing and remitting autoimmune and only 20% of SLE patients develop chronic mild systemic disease of variable severity. The management psychosis. of SLE can be divided into remission induction and SLE myelopathy presenting as acute progressive flare-up prevention. In general, antimalarial drugs, transverse myelitis is treated with high-dose corticostemainly hydroxychloroquine, are routinely prescribed to roid and intravenous cyclophosphamide, and antithromevery SLE patient owing to their proven remissionbotic therapy should be considered in APLA-positive maintaining effects, as well as their effect in reducing myelopathy. disease-induced damage, thrombosis, and mortality In conclusion, NPSLE can present in a broad array of (Molad et al., 2002; Ruiz-Irastorza et al., 2010). Atheromanifestations alone or more commonly in the presence sclerosis risk factors should be thoroughly identified and of SLE disease activity or as a result of prothrombotic tentreated. dency related to APLA. Although commonly found in When a NPSLE event is suspected, the first step is idenSLE, only the minority of NPSLE events can be attributed tification and treatment of exacerbating factors, such as to SLE activity. Hence, a thorough evaluation should be

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performed in every patient with SLE who presents with a NPSLE manifestation to exclude non-SLE precipitating reasons and to define disease activity prior to the administration of anti-inflammatory (corticosteroid and immunosuppressive therapy) and/or antithrombotic therapy (in case of antiphospholipid syndrome).

SCLERODERMA (SYSTEMIC SCLEROSIS) Scleroderma or systemic sclerosis (SSc) or progressive systemic sclerosis (PSS) is a rare chronic widespread connective tissue disease. It is characterized by diffuse fibrosis, degenerative changes, and vascular abnormalities involving the skin, blood vessels, muscles, joints and internal organs (especially the esophagus, lower gastrointestinal (GI) tract, lung, heart, and kidney). The cause of scleroderma is unknown. Immunologic mechanisms and heredity (certain HLA subtypes) have a role in its etiology. Exposure to several chemicals and drugs (e.g., polyvinyl chloride, silica, epoxy, and aromatic hydrocarbons, bleomycin, and pentazocine) may be risk factors as they are associated with similar syndromes. Limited cutaneous scleroderma (lSSc) involves the skin distally to elbows and knees. It is also referred to as CREST syndrome (i.e. calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and teleangiectasia) and is associated with anticentromere antibodies. Diffuse cutaneous scleroderma (dSSc) is characterized by widespread skin as well as internal organ involvement and typical antibodies to topoisomerase 1 (Scl-70) and RNA polymerase. Scleroderma is about four times more common in women than in men and it usually develops between the third and fifth decades of life (Mayes, 2003). Scleroderma can overlap with other autoimmune diseases, including SLE and polymyositis. In case of an overlap of these diseases with the presence of serum antibody to ribonucleoprotein (RNP), the disorder is referred to as mixed connective tissue disease (MCTD). The most common symptoms include Raynaud’s syndrome, diffuse arthralgia, dysphagia, and heartburn. Eventually, skin tightening and contractures of the fingers develop which spread proximally and involve the trunk and face (Silver, 1991; Medsger, 2003). Death is due to complications involving the lung, heart, and kidneys (Ioannidis et al., 2005). Diagnosis is based upon the typical clinical features and the typical antinuclear antibodies.

Neurologic complications Both the PNS and CNS may be involved. Most common are myopathies and some PNS involvement, including entrapment and cranial neuropathies, and less frequent

are plexopathies, radiculopathies, and polyneuropathies (Lee et al., 1984; Hietaharju et al., 1993). CNS manifestations such as strokes, encephalopathy, seizures, dementia, and psychosis have been rarely reported. Pain is very common in SSc and was recently reported to affect 83% of the patients in a Canadian registry of 585 patients (Schieir et al., 2010). Mild pain was reported in 46% of patients, moderate in 27%, and severe in 10%. More frequent episodes of Raynaud’s phenomenon, active ulcers, worse synovitis, and GI symptoms were found to correlate with pain.

Musculoskeletal involvement Musculoskeletal involvement of SSc is a major cause of disability. Joint involvement is beyond the scope of this chapter. Yet, muscle involvement is also frequent and results in myopathy or, much less frequently, in myositis (Clements et al., 1978). Muscle biopsy may demonstrate inflammatory infiltrates in the early phase, whereas in more advanced cases fibrosis is prevalent. The ability to detect muscle involvement in the presence of disability from the skin and joint involvement was low due to concerns over harm from procedures such as electromyography or muscle biopsy. This problem has been partially resolved with new noninvasive procedures such as MR imaging, P-31 magnetic resonance spectroscopy, and near infrared spectroscopy which can provide unique quantitative data (Olsen et al., 1996). While MRI findings are not specific, myositis can be suspected by increased signal intensity on T2-weighted images in pelvic and thigh musculature, whereas muscle atrophy with fatty infiltration may be seen on T1-weighted images in chronic myositis, myopathy, or as a result of muscle disuse (Boutry et al., 2007). Recently, the dropped head syndrome was identified in patients with SSc (Rosato et al., 2009) and with scleromyositis, which combines polymyositis and SSc (Garcin et al., 2010).

Peripheral nervous system involvement Peripheral neuropathy is one of the most frequent complications of SSc. Although early case series reported a frequency of less than 5% (Leinwand et al., 1954; Gordon and Silverstein, 1970; Averbuch-Heller et al., 1992), recent studies (Poncelet and Connolly, 2003; Tagliafico et al., 2011) have shown that with newer diagnostic techniques its prevalence is much higher. Mononeuritis multiplex, trigeminal neuropathy, and entrapment neuropathies, such as carpal tunnel syndrome, are the most commonly reported. Brachial plexopathy and lumbosacral radiculopathy have also been described. The pathogenesis of peripheral nervous system involvement is not fully defined and there are currently three main hypotheses: (1) a vascular-dependent mechanism – involvement of

CONNECTIVE TISSUE DISORDERS the vasa nervorum which is supported by finding evidence of axonal degeneration; (2) a compression-dependent mechanism which is supported by findings of nerve demyelination in SSc (as compressive conditions such as carpal tunnel syndrome induce progressive demyelination with edema in the first stages of the disease and fibrosis in the late stages); (3) an autoimmune-dependent neuropathy (Nitta and Sobue, 1996). Primary nerve infiltration was also demonstrated by sural nerve biopsy in two patients with peripheral sensory motor neuropathy (Corbo et al., 1993). According to another study (Poncelet and Connolly, 2003), the presence of a nonlength-dependent (focal or multifocal) pure sensory peripheral neuropathy in patients with scleroderma who have neurologic symptoms is typical of SSc (see later). Patients suffering from SSc frequently report neuropathic symptoms early on, including numbness, paresthesias, and dysesthesias. Therefore, a thorough assessment of the peripheral nerve function was undertaken in 14 such patients, including complete neurologic examination, nerve conduction studies (NCS), and quantitative sensory testing (QST) (Poncelet and Connolly, 2003). Neurologic examination revealed reduced vibration sense in seven and reduced pinprick sensation in four patients in either the upper or lower extremities. Focal atrophy or proximal weakness was found in two and two other patients had decreased deep tendon reflexes. NCS showed reduced sensory nerve action potentials in one patient and carpal tunnel syndrome in another. QST of the upper and lower extremity revealed increased cold or vibration detection thresholds in eight of the 14 patients. These findings suggest that peripheral neuropathy occurs in patients with SSc at a higher frequency than previously appreciated. Another conclusion is that compression neuropathies cannot explain most cases, as involvement of large and small fibers in a non-length-dependent fashion was present. Contrary to this finding is the study of ultrasound (US) imaging of the peripheral nerves done recently (Tagliafico et al., 2011) in 25 SSc patients (as compared to control). With high resolution US and, additionally, MRI or CT imaging when necessary (two patients), median and ulnar nerves were evaluated bilaterally. The prevalence of sensory disturbances by clinical examination was 40%. In 10 symptomatic SSc patients, US evaluation revealed nerve abnormalities in 70% of cases. Two had carpal tunnel syndrome and five had cubital tunnel syndrome (ulnar neuropathy at the Guyon canal). In two of them, CT and MR were necessary to identify the compressed nerve at the level of the elbow due to the presence of calcifications. The results of imaging studies support the hypothesis of a vascular-dependent neuropathy in SSc as cases of diffuse nerve enlargement were not identified, nor even multifocal involvement.

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Involvement of the nervous system in lSSc is very rare yet recently a case of chronic progressive ataxic neuropathy was described in a young Japanese woman (Nobuhara et al., 2006). Marked improvement was achieved with IVIg therapy after failure of corticosteroids treatment. Cytokine analysis revealed increased levels of IL- 1b and GM-CSF both in serum and CSF.

Central nervous system involvement CNS manifestations of SSc are considered rare (Leinwand et al., 1954). When renal involvement is prominent and there is an associated hypertension, cerebrovascular events (stroke or TIA) are presumed to result from the latter (Gordon and Silverstein, 1970). Yet, cases of stroke/TIAs are described in the absence of hypertension (Averbuch-Heller et al., 1992), and a few cases of vasculitis of the brain were also reported (Pathak and Gabor, 1991). The manifestations of vasculitis also include headaches, mental status changes, and cognitive decline. Autopsy findings in two SSc patients who developed CNS manifestations (dementia, TIAs) disclosed extensive wall calcification of small arteries and arterioles in the brain (Heron et al., 1998). Sudden hearing loss has also been described, mostly as cranial (CN VIII) neuropathy. It could occur bilaterally and early in the disease course (Deroee et al., 2009). Benign paroxysmal positional vertigo was also reported to occur more frequently in patients with SSc as compared with controls (Amor-Dorado et al., 2008).

Autonomic involvement Autonomic neuropathy is present in patients with fullblown SSc (Stojanovich, 2009). It manifests itself in many ways (e.g., abnormal esophageal motility, and gastrointestinal dysfunction). By multimodal investigations of 34 such patients, autonomic dysfunction was found, to some extent, in all patients. It was characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease stages. The presence of headaches correlated significantly with these findings (Dessein et al., 1992). An abnormal autonomic nervous control of the heart was demonstrated by measuring nail fold capillaroscopy and Holter monitoring in 25 consecutive outpatient SSc patients and 25 healthy controls. Significantly decreased heart rate variability (HRV) was found in the affected group (Di Franco et al., 2007).

Treatment There is no cure for SSc and the treatment depends on the organs involved. Some immunosuppressive agents have been incorporated depending on disease severity.

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Corticosteroids are suggested in cases of myositis or other inflammatory processes including vasculitis (such as in mononeuritis multiplex) before initiating immunosuppressive therapy. However, steroids have been associated with precipitation of the scleroderma renal crisis and should, therefore, be cautiously considered for each case. For severe entrapment neuropathies, surgery is recommended.

€ SJOGREN’S SYNDROME Sj€ ogren’s syndrome (SS) is a systemic autoimmune disease that may be primary or secondary to another connective tissue disease (mainly RA, SLE, polyarteritis nodosa, or scleroderma). This syndrome is characterized by T cell (CD4þ) infiltration and destruction of salivary and lachrymal glands leading to loss of tears (keratoconjunctivitis sicca) and saliva (xerostomia). Similar mononuclear infiltrates in visceral organs or small-vessel vasculitis can produce extraglandular manifestations including bronchitis or interstitial pneumonitis, arthritis, atrophic gastritis, sclerosing cholangitis, pancreatitis, renal tubular acidosis, vaginitis, thyroiditis, myositis, vasculitis, and occasionally lymphocytic proliferation (i.e., lymphomas). It was suggested that cell-mediated autoimmunity causes the apoptosis of the ductal and acinar epithelial cells which is responsible for the glandular tissue damage (Sj€ ogren, 1933; Sisto et al., 2007). The average age of onset is the late forties, although SS occurs in all age groups in both women and men. Yet 90% of cases occur in women in the US, where it is estimated that between 1–4 million people are affected by the disease, making it the second most common autoimmune rheumatic disease. SS is diagnosed by the histologic evidence of lymphocytic infiltrates in the minor salivary glands, or when sicca symptoms present with evidence for decreased saliva and tear production in the presence of antibodies to Ro (SSA) or La (SSB) antigens. There are guidelines for the diagnosis which are based on both clinical and laboratory findings (Vitali et al., 2002).

Neurologic complications Neurologic complications are quite common in primary Sj€ogren’s syndrome and could be observed in about 20% of the patients (Alexander et al., 1982; Delalande et al., 2004). Historical aspects, dating back to Sj€ ogren himself, were reviewed a decade ago (Lafitte, 2000). Both PNS and CNS are involved. While PNS complications are more clearly defined and accepted (in about 10–20% of the patients), a considerable debate on the CNS involvement still exists as there are overlap syndromes and many of the complications were described before the establishment of firm guidelines for SS. Important also is the fact that in up

to 50% the neurologic manifestations precede the appearance of the sicca syndrome (Delalande et al., 2004). An example for the difficulties is patients with SS and CNS involvement that were mistakenly diagnosed as having multiple sclerosis (Alexander et al., 1986).

Central nervous system involvement In a French study (Delalande et al., 2004) of 82 patients with primary SS diagnosed according to the 2002 guidelines, 56 had CNS disorders, of whom 29 had spinal cord involvement (mostly myelopathies), 33 had brain involvement, and 13 had optic neuropathy. MS mimicking disease was observed in 13 patients. Also recorded were seizures in seven patients, cognitive dysfunction in nine and encephalopathy in two. Of those patients who underwent brain MRI, radiologic criteria for MS were met in 40%. Extraglandular manifestations of the disease were more common with PNS involvement and so were positive biologic markers. Aseptic meningitides and meningoencephalitides have been described in association with SS (Alexander and Alexander, 1983), yet more recently a case of subacute meningitis led to the diagnosis of SS (Rossi and Saddi, 2006), and recurrent form was also observed (Kazuyuki et al., 2007). Myelopathies are a well-known complication of SS and may take the form of acute transverse myelitis, progressive or chronic myelitis, Brown-Se´quard syndrome, neurogenic bladder, or lower motor neuron disease (De Seze et al., 2001; Williams et al., 2001).

Peripheral nervous system involvement PNS involvement is a major neurologic complication of Sj€ogren’s syndrome. It was believed to be caused by vasculitis, similar to that observed in other collagen diseases. However, studies have demonstrated that dorsal root ganglionitis with degeneration of dorsal root ganglion neurons and mononuclear cell infiltration without vasculitis were associated with the sensory ataxic form, suggesting that ganglion neurons themselves can be a target of Sj€ogren’s syndrome (Malinow et al., 1986; Griffin et al., 1990). In the French study (Delalande et al., 2004), PNS disorders were observed in 51 patients of whom 28 had symmetrical axonal sensorimotor polyneuropathies; cranial neuropathies were observed in 16, multiple mononeuropathies in seven, myositis in two, and polyradiculoneuropathy in one patient. A Japanese study of 92 patients (Mori et al., 2005) assessed the clinicopathologic features of 92 patients with primary Sj€ogren’s syndrome-associated neuropathy. It included 76 women and 16 men whose mean age was 54.7 years at disease onset. In 93% of patients

CONNECTIVE TISSUE DISORDERS the diagnosis of Sj€ ogren’s syndrome was made after the neuropathic symptoms appeared. The authors classified their patients, based on the predominant neuropathic symptoms, into seven forms of neuropathy: sensory ataxic neuropathy was found in 36 patients, painful sensory neuropathy without sensory ataxia in 18, multiple mononeuropathy in 11, multiple cranial neuropathy in five, trigeminal neuropathy in 15, autonomic neuropathy in three, and radiculoneuropathy in four patients. As expected, acute or subacute onset was seen more frequently in multiple mononeuropathy and multiple cranial neuropathy, whereas chronic progressive form was predominant in the other forms of neuropathy. Motor weakness and muscle atrophy were observed in multiple mononeuropathy, multiple cranial neuropathy, and radiculoneuropathy, whereas in the other form sensory symptoms prevail. Autonomic symptoms were often seen in all forms of neuropathies including abnormal pupils and orthostatic hypotension, which were particularly frequent in sensory ataxic, painful, trigeminal, and autonomic neuropathy. Somatosensory evoked potentials and spinal MRI were helpful in diagnosing sensory ataxic, painful, and autonomic neuropathy, whereas sural nerve biopsy findings were different with respect to the fibers involved in sensory ataxic and painful sensory neuropathies. Pathologically, signs of vasculitis were seen mainly in multiple mononeuropathy, and less so in sensory ataxic neuropathy. In an autopsy of one patient with sensory ataxic neuropathy, multifocal T cell invasion was seen in the dorsal root and sympathetic ganglion, perineurial space, and vessel walls in the nerve trunks. The authors conclude that the clinicopathologic observations suggest that sensory ataxic, painful, and perhaps trigeminal neuropathy are related to a ganglioneuronopathic process (confirming previous observations), whereas multiple mononeuropathy and multiple cranial neuropathy were more closely associated with a vasculitic process.

Muscle involvement Patients with Sj€ ogren’s syndrome may have mild muscle weakness or myalgias without having significant abnormalities of serum CK, EMG, or on muscle biopsy. If patients with Sj€ ogren’s syndrome develop significant symmetric proximal weakness, important diagnostic considerations are the concurrence of polymyositis or dermatomyositis, and the rare case of associated hypokalemic paralysis due to distal renal tubular acidosis (Pun et al., 1989).

Autonomic involvement Autonomic involvement and manifestations were already mentioned above as part of the autonomic neuropathies.

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Some 25% of patients with SS and peripheral neuropathy have tonic pupils, and evidence of autonomic dysfunction can be found in more than 80% of patients with laboratory assessment of autonomic function (Wright et al., 1999). With the use of autonomic reflex tests, parasympathetic and sympathetic dysfunction was demonstrated in SS patients (Andonopoulos et al., 1998) and objective signs of autonomic dysfunction have been reported. Since exocrine secretion is modulated by the autonomous nervous system, impaired secretion could be partly due to the interference with nervous signals to the exocrine glands. Symptoms of autonomic dysfunction were found in about 50% of patients with SS, whereas functional testing discloses abnormal results in 66% of them (Andonopoulos et al., 1998). Yet not all observations were consistent or confirmed in other studies (Stojanovich, 2009). Also, the underlining mechanisms for the above symptoms and others, such as orthostatic hypotension and urinary symptoms, are not clearly understood or appropriately studied (Stojanovich, 2009).

Treatment The management of patients with SS depends on organ involvement since there is no therapy which was shown effectively to change the disease course. In cases of severe extraglandular involvement, corticosteroid alone or in combination with immunosuppressive therapy (such as cyclophosphamide) are considered. Severe disability is more frequent in cases of CNS involvement than in cases of PNS involvement, suggesting the need for intensive and early treatment in cases of CNS involvement, yet therapeutic guidelines are absent. In cases of severe myelopathy or myelitis the treatments vary and include, besides steroids and cytotoxic drugs (mainly cyclophosphamide), intravenous immunoglobulins (IVIg) or plasmapheresis in acute stages (Williams et al., 2001; Rogers et al., 2004). The efficacy of corticosteroids is moderate and variable both for CNS manifestations and for neuropathies (axonal polyneuropathies and neuronopathies). Better efficacy was obtained with the combination of cyclophosphamide and corticosteroids in multiple mononeuropathies. In severe cases, IVIg have been used successfully in a small sample of patients with ganglionopathy.

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