Neuropsychiatric Manifestations of Rheumatic Diseases in the Elderly
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Neuropsychiatric (NP) syndromes in rheumatic disorders in the elderly represent a field of medicine situated at the crossroads of neurology, psychiatry, rheumatology, immunology, and geriatrics. NP symptoms highly prevalent in rheumatic conditions, are a major source of disability and diminished quality of life, and potentially represent the target of treatment interventions that stand to significantly decrease the suffering they generate. The NP manifestations in rheumatic diseases in the elderly may be focal or generalized or a secondary consequence of the primary disease. A focal cerebral event may result in (1) a stroke-like presentation with an acute neurologic deficit, (2) a headache due to hemorrhage (e.g., subarachnoid hemorrhage in vasculitis) or temporal arteritis, (3) focal seizures, (4) optic neuropathy or cranial neuropathies due to compression by granulomatous lesions. A generalized event may result in cognitive dysfunction, headaches, or seizures. The spinal cord may be involved with resulting paraparesis, bowel or bladder dysfunction, or sensory disturbances. A common peripheral nervous system involvement is peripheral neuropathy, with symptoms of numbness, sensory paresthesias, weakness, or gait imbalance; nevertheless neuropathy may be multifocal and asymmetric. The presence of comorbid conditions and treatment adverse events including infections associated with immunosuppressive treatment or biologic therapy may compound the sign and symptoms of the NP syndromes of the underlying disease.
KeywordsAging brain Neuropsychiatric manifestations Rheumatic disorders
The advances in the past few years have furthered our understanding of both the normal aging and the pathogenic immune system functioning within the central nervous system (CNS), and indicated that the neural immune interaction in the elderly seems to be altered to some extent [1, 2, 3]. There is an increased inflammatory activity that accompanies normal brain aging; local glial cell activation, upregulation of cytokines, and transcriptional alterations of inflammatory factors as well as blood brain barrier age-related changes are well-documented components of this complex process that contribute to CNS autoimmune and chronic inflammatory diseases.
Neuropsychiatric manifestations of rheumatic diseases
Central nervous system
•Transient ischemic attacks
•Stroke (ischemic or hemorrhagic)
•Visual disturbances/optic neuropathy
•Movement disorders (chorea, athetosis, ballism, hemidystonia)
•Psychiatric symptoms (depression, mania, hallucinations, and psychoses)
•Myelopathy (acute or chronic)
•Optic neuritis/visual disturbances/Devic’s syndrome
•Multiple sclerosis–like syndromes
Peripheral nervous system
•Brachial or lumbosacral plexopathies
•Autoimmune neuropathy (acute/chronic inflammatory demyelinating polyradiculopathy)
Inflammatory idiopathic myopathies
•Inclusion body myositis
In this chapter, specific rheumatic disorders such as systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), systemic vasculitis, and rheumatoid arthritis (RA) are explored in relation to NP manifestations with emphasis on clinical presentation, diagnostic approach and therapy.
Systemic Lupus Erythematosus
Systemic lupus erythematosus is an autoimmune disease characterized by multisystem involvement with highly variable clinical manifestations. Women of child-bearing age are most often affected; however, approximately 12–20% of cases occur in older patients. Many studies suggest that the clinical and serological features of lupus in the elderly differ from those in the younger patients [4, 5, 6, 7, 8, 9, 10, 11] (see Chap. 13 ). While NP manifestations, including headache and cognitive impairment have been reported to be more frequent in the elderly with lupus, epileptic seizures, psychosis, and polyneuropathy are less frequent . Ischemic strokes account for approximately 20% of neurologic events in SLE, and are often associated with an antibody-associated hypercoagulable state, cardiogenic embolism, hypertension, and dyslipidemia. Cerebral hemorrhage (intracerebral or subarachnoid) may also occur possibly related to arterial dissection.
The prevalence in the elderly SLE of psychiatric syndromes of acute confusional state and mood disorders, though common in the elderly, is not determined. With the anticipated increase in longevity in the general population and in SLE patients, the impact of NP damage, including dementia is predicted to increase in the years to come. These findings probably reflect the contribution exerted by the burden of disease, comorbid conditions and treatment complications.
The pathogenic mechanism of NPSLE is still unknown, but likely to be multifactorial, involving autoantibodies, cytokines production, and microangiopathy . The histopathological changes seen in NPSLE are characterized by microvascular infarcts, perivascular microglia, vascular necrosis and scarce perivascular infiltrate. Rarely vasculitis is seen .
Although the classification criteria for SLE and nomenclature of NPSLE are established in most cases predominantly in younger patients, such criteria may be inaccurate in the elderly, for whom the differential diagnosis may be broader and difficult to ascertain . The attribution of comorbid medical conditions needs to be carefully considered in the interpretations of specific NP signs and symptoms. A decline in organ function associated with normal aging, including cognitive function such as attention, information processing, and working memory, or abnormalities reflected on structural neuroimaging, or gait and imbalance disorders or myopathy in the setting of sarcopenia of aging make the diagnosis of NPSLE more difficult to establish .
There are no specific autoantibodies associated with NPSLE, and thus, the diagnosis should be based on the clinical signs and symptoms rather than laboratory testing. The prevalence of many autoantibodies, including anticardiolipin antibodies, increases among healthy elderly persons, reflecting alteration of B cell homeostasis and regulation associated with age . The reported incidence of antiribosomal P protein antibodies among patients with SLE is quite variable (10–40%), with lower incidence rates in the elderly and African–American populations (unpublished data from Maryland lupus cohort), and higher incidence rates in children and Asian populations. While antiribosomal P protein antibodies have been associated with lupus psychosis and depression by some authors [16, 17], this association has not been confirmed by others [18, 19].
Abnormalities on brain magnetic resonance imaging (MRI) including, cerebral atrophy, infarcts, or subcortical hyperintensity in patients with NPSLE are common findings in the aging brains, but may be associated with antiphospholipid antibodies (aPL) as well . Fluid-attenuated inversion recovery imaging in NPSLE has obvious advantages and is more sensitive than routine MRI in diagnosing cerebral lesions.
Optimal management of NPSLE in the elderly is empiric because of a lack of randomized controlled studies. However, the approach to treatment is similar, regardless of the age of the patient. SLE in the elderly has been reported to be milder and more responsive to treatment than in younger patients. With mild NPSLE manifestations, such as headache and seizures, hydroxychloroquine therapy and low doses of glucocorticoids may be adequate. However, with moderate to severe NPSLE disease including acute nonthrombotic CNS manifestations, higher doses of glucocorticoids and use of immunosuppressive therapy, such as methotrexate, azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil may be needed. Plasmapheresis may be added for patients with severe illness refractory to conventional treatment. Intrathecal methotrexate and dexamethasone have been also reported to be beneficial in some patients.
NPSLE patients with severe organ involvement and/or patients who have had an inadequate response to glucocorticoids, or have a resistant disease, or catastrophic antiphospholipid syndrome generally do poorly and may require high dose chemotherapy followed by autologous stem cell transplantation or monoclonal anti B lymphocyte antibodies. Despite the promising reports of uncontrolled studies in the use of the chimeric anti CD 20 monoclonal antibody agent, rituximab, a placebo-controlled randomized trial in 257 patients with active SLE (EXPLORER trial), which included those with neuropsychiatric syndromes, noted no significant difference in outcomes between the groups that received prednisone and two infusion of rituximab versus prednisone and placebo infusion.  Then again, the case reports of a possible association with the use of rituximab, and fatal progressive multifocal leukoencephalopathy due to reactivation of latent viral infections including JC virus (a type of polyomavirus) require caution as advised by the U.S. Food and Drug Administration (FDA).
Psychotropic agents, antidepressant medications, and varied psychotherapeutic interventions may be required in certain patients.
Guidelines for primary stroke prevention of patients with aPL are not available, because the literature on asymptomatic (no history of thrombotic events) aPL-positive patients is limited. Recent studies report that aPL do not seem to be a strong risk factor for recurrent stroke or transient ischemic attacks (TIA), nor do they predict a differential response to aspirin or warfarin therapy, and thus, aspirin therapy is recommended in the elderly SLE patients with or without aPL antibodies [22, 23]. Secondary prevention with high-level oral anticoagulation is still the most commonly used treatment for aPL-positive patients who have experienced strokes, particularly those with left-sided cardiac valve lesions and persistent high titers of IgG anti-cardiolipin antibodies.
Sjögren’s syndrome is a chronic autoimmune disorder of the exocrine glands of unknown etiology [24, 25]. The clinical manifestation range from autoimmune exocrinopathy to extraglandular (systemic) involvement, and is associated with autoantibody responses against the Ro (SSA) and La (SSB) ribonucleoproteins. In addition, SS may be primary or secondary to another connective tissue disease (mainly SLE, RA, or systemic sclerosis). The prevalence of this syndrome in the geriatric population has been reported to be between 2 and 11% of all cases, and mostly involve women  (see Chap. 27). Late-onset SS is associated with lower prevalence of ocular tests and anti-Ro (SSA) antibodies.
The chronic inflammatory process involves primarily the exocrine glands and is characterized by a particular pattern of mononuclear infiltration resulting in destruction of salivary and lachrymal glands and leading to xerostomia and xerophthalmia . Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can give extraglandular manifestations affecting the lungs, kidneys, blood vessels, and muscles, and is gradually progressive and uncommonly undergoes transformation to lymphoma.
Neurologic involvement has been reported in primary SS since its initial clinical description by Sjögren in 1935. Though the exact prevalence remains controversial, neurologic symptoms can affect the PNS and the CNS [28, 29, 30]. The main types of PNS involvement, which is reported in 10–20% of SS patients includes sensory–motor axonal polyneuropathy, pure sensory axonal neuropathy, sensory neuropathy, and multiple mononeuropathy. A long-term, insidious course is typically observed.
In addition to the high frequency of cognitive impairment of subcortical type, most of CNS involvement is frequently focal disease with multiple ischemic infarcts, or cranial nerve palsies (trigeminal neuropathy and optic neuritis). Anti-Ro (SSA) antibody has been associated with more severe CNS disease and abnormal angiographic findings. Spinal cord involvement can be acute and at times severe with acute transverse myelitis, or chronic with progressive myelopathy. Some older patients with SS have CNS symptoms that mimic relapsing-remitting multiple sclerosis and may have white matter changes on brain MRI compatible of demyelinating syndrome . However, the localization of the lesions in the corpus callosum and basal ganglia lesions, with markedly lower prevalence of oligoclonal bands and association of PNS involvement and extra-glandular features may help in the diagnosis.
Affective and personality disorders, memory disturbances with frontal lobe abnormalities and mild cognitive dysfunction are frequent, and are associated with fatigue and large brain ventricular volumes . Anxiety and depression with high levels of introverted hostility are reported by SS patients, including paranoid ideation, somatization, and obsessive compulsiveness. Alteration in pain sensation has been postulated to be related to active inhibition of the parasympathetic system in the periaqueductal gray area of the limbic system.
The pathophysiologic mechanism of NP involvement in SS is still unclear, but likely to differ according to clinical features. Demyelinating, vascular (ischemic, cryoglobulinemia, or vasculitis), inflammatory etiologies (mononuclear cell infiltration in the CNS), immunologically-mediated CNS vascular damage, or direct role of SSA and anti-neuronal antibodies, have been suggested. Necrotizing vasculitis has been detected on nerve biopsy in patients with multiple mononeuropathies. Lymphocytic infiltration of dorsal ganglia is also described.
A precise definition of primary SS resting on “revised” or “international” criteria has been accepted by most experts . Though nonspecific, the neurological involvement is usually highlighted by gadolinium-enhanced MRI of the brain (T2-weighted) with fluid-attenuated inversion recovery (FLAIR) displaying an increased diffuse leptomeningeal enhancement . The clinician should be aware, however, that the test results may vary depending on the age of the patient and the type of SS (primary or secondary). Differential diagnosis includes adverse effects of drugs, sarcoidosis, lipoproteinemias, age-related atrophy, lymphomas, amyloidosis, and infection. Newer techniques, such as magnetic spectroscopy and magnetization transfer imaging to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in SS. Cerebrospinal fluid (CSF) analysis with moderate pleocytosis of polymorphonuclear leukocytes and increased protein and at times immunoglobulin levels are reported.
Despite progress in the understanding of the broad clinicopathological spectrum of SS, its treatment remains largely empirical and symptomatic . The efficacy of corticosteroids seems to be variable in cases with CNS manifestations and in axonal polyneuropathies. Cyclophosphamide is particularly effective in cases of myelopathy, with improvement or stabilization of disability. However, other immunosuppressive treatments (methotrexate, azathioprine, chlorambucil) have been tried with variable efficacy. Intravenous immunoglobulin, reported to be an effective treatment for ataxic sensory neuropathy, may be considered in the setting of acutely worsening CNS symptoms. Plasmapheresis may be needed with ganglionopathy or in sensory–motor neuropathy of cryoglobulins. Antitumor necrosis factor (TNF) alpha inhibitors or B-cell depleting therapies may find a new indication in SS. Induction of oral tolerance and gene-transfer modalities remain experimental therapies with promising results.
Systemic vasculitis occurs in a heterogeneous group of primary disorders or can be a manifestation of infection, an adverse drug reaction, malignancy or a connective tissue disease. NP symptoms related to systemic vasculitis should be suspected in the elderly patients with atypical cerebrovascular events, especially when polymyalgia rheumatica, inflammatory arthritis, palpable purpura, glomerulonephritis or multiple mononeuropathies are also present.
The classification of vasculitis affecting the nervous system
1.Systemic vasculitis disorders
•Giant cell arteritis
•Necrotizing arteritis of the polyarteritis type
•Systemic granulomatous vasculitis
•Diverse connective tissue disorders
•Viral, spirochete, fungal, and retroviral infection
4.Granulomatous angiitis of the brain
5.Isolated peripheral nerve vasculitis
Giant Cell Arteritis
Giant cell arteritis (GCA), also called temporal arteritis, is the most common form of systemic vasculitis seen in humans, occurring almost exclusively in people older than 50 years [38, 39] (see Chap. 21). It is characterized by granulomatous inflammation/arteritis of the aorta and its major branches and has a predilection to affect the extracranial branches of the carotid artery, and rare involvement of the intracranial vessels. Transmural inflammation of the arteries induces luminal occlusion through intimal hyperplasia. Patients with GCA will typically present with headache, jaw or tongue claudication, scalp tenderness, constitutional features, or fever. Systemic inflammation, characteristic of polymyalgia rheumatica, a syndrome of musculoskeletal pain and stiffness in the neck, shoulders and hips, often occurs with GCA, but can occur independently.
Neurologic complications of GCA are not uncommon, in particular, vision loss caused by optic nerve ischemia from arteritis involving vessels of the ocular circulation . Cranial nerve palsies, in particular oculomotor, related to aneurysm formation may occur, yet involvement of PNS are more frequent than cerebral ischemia or neuro-ophthalmological complications . Severe PNS involvement has an affinity to the midcervical nerve roots and the brachial nerve plexus. Ischemic strokes have been reported to occur in 3–4% of patients, often within days of steroid therapy initiation.
Findings on physical examination in GCA include nodularity, tenderness, or absent pulsations of the temporal arteries or other involved vessels. An elevated erythrocyte sedimentation rate (ESR) occurs in greater than 80% of patients, and when seen together with compatible clinical features, suggests the diagnosis of GCA. Temporal artery biopsy is confirmatory in 50–80% of cases with the demonstration of a panmural mononuclear cell infiltration that can be granulomatous with histiocytes and giant cells.
Glucocorticoids prevent visual complications in GCA and bring about a rapid improvement in clinical symptoms. The initial dosage of prednisone is recommended at 40–60 mg daily, yet in patients who present with acute visual loss, methylprednisolone 1 g/day for 3 days can be considered. No cytotoxic or biologic agent has been found to be effective, although novel therapeutic approaches remain under active investigation. Current evidence suggests that low dose aspirin reduces cranial ischemic complications in GCA and should be considered in all patients who do not have contraindications .
Polyarteritis nodosa (PAN) is defined by the presence necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules  (see Chap. 18). Using this definition, PAN is believed to be very uncommon, but it remains an important multisystem illness that can present acutely in older patients. The most common clinical manifestations of PAN include hypertension, fever, musculoskeletal symptoms, and vasculitis involving the nerve, gastrointestinal tract, heart, and non-glomerular renal vessels. Involvement of PNS is seen in 50–75% of patients, usually as asymmetric sensory and motor neuropathy due to ischemia of peripheral nerves. The most common stroke subtypes in PAN are lacunar stroke syndromes occurring within 8 months of disease onset . These strokes are postulated to be secondary to thrombotic microangiopathy rather than to active vasculitis. Acute myelopathy with paraparesis has been associated with PAN.
The diagnosis of PAN is made on the basis of biopsy or arteriography that shows microaneurysms, stenoses, or a beaded pattern with areas of arterial narrowing and dilation. Biopsies of clinically involved areas such as the peripheral nerve or testicle reveal necrotizing inflammation involving the medium-sized or small arteries with abundant neutrophils, fibrinoid changes, and disruption of the internal elastic lamina. Laboratory findings reflect an acute inflammatory process with anemia, leukocytosis, thrombocytosis, and an increased ESR. Antineutrophil cytoplasmic antibodies (ANCA) are uncommon.
Patients with immediately life-threatening disease affecting the CNS should be treated with daily cyclophosphamide and glucocorticoids. In patients with mild disease and no major organ dysfunction, glucocorticoids alone can be considered as initial therapy with immunosuppressive therapy being added in patients who continue to have evidence of active disease or who are unable to taper prednisone. In PAN-like vasculitis associated with hepatitis B, hepatitis C or the human immunodeficiency virus, antiviral therapy should be considered.
ANCA Associated Vasculitis
Vasculitis involving the small vessels clinically manifests in a variety of ways that can include cutaneous vasculitis, alveolar hemorrhage, and glomerulonephritis  (see Chap. 18). Small vessel vasculitis is a prominent feature of three important forms of primary systemic vasculitis: Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg–Strauss syndrome (CSS). Although these disease entities possess unique features, they are grouped together as they share similar involvement of the small vessels, glomerular histology, and the frequent association with ANCA.
Neurologic involvement occurs in approximately 34% of patients with WG, with mononeuropathy multiplex and cranial neuropathies being the most common manifestations [46, 47]. These complications may result from compression or infarction due to granulomatous invasion or as a result of focal vasculitis. Sural nerve biopsy specimens have shown findings consistent with vasculitis or axonopathy. Though the CNS may be involved in 2–8% of WG patients, lesions arising within the brain parenchyma itself are rare, and confirmed vasculitis of the CNS radiologically is rare. Stroke and seizures are the most frequent clinical manifestations. Other NP manifestations include headaches, confusion, or transient neurologic events, such as paresthesia, blackouts, or visual loss. Pachymeningitis may also occur in the setting of early WG active disease, and disease activity can be monitored by ANCA titers in the cerebrospinal fluid (CSF), which may disappear after treatment. Mononeuritis multiplex occur in up to 58% of MPA patients, and in up to 78% of CSS patients. In CSS, granulomatous disease may erode through the nasopharynx and lead to basilar meningitis, dural venous thrombosis, or optic neuropathy. Asymptomatic anterior ischemic optic neuropathy in the setting of systemic disease may also occur.
The diagnosis of ANCA associated vasculitis is usually based on the presence of characteristic histologic findings in a clinically compatible setting. To date, widely accepted diagnostic criteria for ANCA associated vasculitis have not been developed. Surgically obtained biopsies of abnormal renal and non-renal tissues (pulmonary parenchyma and upper airways) yield diagnostic changes of granulomatous inflammation in a substantial number of patients. The diagnosis based on neuroimaging is limited because of poor sensitivity of routine angiography of the involved small vessels (50–300 μ(mu)m in diameter). However, granulomatous disease may infiltrate the dura of the brain and spinal cord, resulting in contrast-enhancing lesions by MRI.
Treatment of ANCA associated vasculitis is based on the classification of patients into categories of either limited or severe disease. Limited disease, with no immediate threat to function of a vital organ or life of the patient responds favorably to corticosteroids. Severe disease with CNS or peripheral nerves or vasculitis neuropathy requires the use of cytotoxic drugs, such as induction with cyclophosphamide, followed by remission maintenance therapy with either methotrexate, or azathioprine. Intrathecal methotrexate and glucocorticoids treatment is helpful in patients with pachymeningitis. There are no sufficient data to judge on the role of other therapies such as plasmapharesis, intravenous immunoglobulin, mychophenolate mofetil, and leflunomide. Biological treatment with etanercept was found not to be effective in the maintenance of remission in patients with WG. Rituximab and other strategies for B cell depletion are to be considered as an alternative to cytotoxic immunosuppressive medication, in particular in those with refractory disease. In the elderly, caution must be taken as serious infections and increased risk of malignancy are associated with prolonged immunosuppressive therapy.
Primary Angiitis of the Central Nervous System
Primary angiitis of the CNS is an idiopathic, recurrent vasculitis confined to the CNS and spinal cord . The angiitis is multifocal and segmental in distribution and involves the small leptomeningeal and intracerebral arteries. The disease predominantly affects males and most patients are young or middle aged, although older patients are also affected. The most common symptom is headache. Various neurological presentations are seen, including, recurrent TIA, ischemic strokes, paraparesis, ataxia, seizures, aphasia, and visual field defects. Cognitive dysfunction or fluctuating levels of consciousness are not uncommon.
The diagnosis of CNS angiitis requires evidence of vasculitis on biopsy or angiographic findings suggestive of vasculitis in the setting of other compelling features including neuroimaging and CSF pleocytosis, which is abnormal in 80–90% of cases. Because of the focal and segmental distribution of primary angiitis, the sensitivity of meningeal and brain biopsy may not be greater than 65%. A negative biopsy does not exclude the diagnosis of angiitis, but may be essential to exclude other disorders that mimic CNS angiitis including, cerebral vasospasm, CNS infection, arterial thromboembolism, intravascular lymphomatosis, and atherosclerosis.
The prognosis is potentially fatal; however, it may be altered by aggressive immunosuppressive therapy with high doses of glucocorticoids and cyclophosphamide. No controlled treatment trials are available, and optimal duration of therapy is unknown.
RA is a chronic systemic autoimmune inflammatory disease with an overall prevalence that steadily increases to 5% in women by the age of 70 (see Chap. 14). Neurologic complications occur in moderate to severe RA as a result of the disease’s erosive effects on joints and bones or related to the disease itself (e.g., compressive rheumatoid nodules, rheumatoid vasculitis) [49, 50]. Peripheral entrapment neuropathy, mononeuritis mutiplex, and atlantoaxial subluxation occur in as many as 70% of patients with advanced RA. Those with disease duration of more than years and onset before the age of 50 are particularly at risk. Myelopathy may also result from compression by extradural rheumatoid nodules or by epidural lipomatosis, which frequently occurs as a result of long-term glucocorticoid administration. The degenerative changes in the cervical spine may also compress the vertebral arteries, resulting in vertebrobasilar insufficiency. CNS vasculitis is rare and may present with seizures, dementia, hemiparesis, cranial nerve palsy, blindness, hemispheric dysfunction, cerebellar ataxia, or dysphasia. The management of neurological syndromes in RA with may require the use of immunosuppressive including cyclophosphamide and biologic therapies.
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