Current Neurology and Neuroscience Reports

, 14:456

Neurology of Rheumatologic Disorders


  • Amre Nouh
    • Department of Neurology, Maguire 2700 Building 105Loyola University Medical Center, Stritch School of Medicine
  • Olimpia Carbunar
    • Department of NeurologyCleveland Clinic of Florida
    • Department of Neurology, Maguire 2700 Building 105Loyola University Medical Center, Stritch School of Medicine
Neurology of Systemic Disease (J Biller, Section Editor)

DOI: 10.1007/s11910-014-0456-6

Cite this article as:
Nouh, A., Carbunar, O. & Ruland, S. Curr Neurol Neurosci Rep (2014) 14: 456. doi:10.1007/s11910-014-0456-6
Part of the following topical collections:
  1. Topical Collection on Neurology of Systemic Disease


Rheumatologic diseases encompass autoimmune and inflammatory disorders of the joints and soft tissues that often involve multiple organ systems, including the central and peripheral nervous systems. Common features include constitutional symptoms, arthralgia and arthritis, myalgia, and sicca symptoms. Neurological manifestations may present in patients with preexisting rheumatologic diagnoses, occur concurrently with systemic signs and symptoms, or precede systemic manifestations by months to years. Rheumatic disorders presenting as neurological syndromes may pose diagnostic challenges. Advances in immunosuppressive treatment of rheumatologic disease have expanded the treatment armamentarium. However, serious neurotoxic effects have been reported with both old and newer agents. Familiarity with neurological manifestations of rheumatologic diseases, diagnosis, and potential nervous system consequences of treatment is important for rapid diagnosis and appropriate intervention. This article briefly reviews the diverse neurological manifestations and key clinical features of rheumatic disorders and the potential neurological complications of agents commonly used for treatment.


Connective tissue diseaseSystemic lupus erythematosusNeuropsychiatric lupusAntiphospholipid antibody syndromeRheumatoid arthritisSjögren’s syndromeVasculitisGiant cell arteritisTakayasu’s arteritisImmune complex vasculitisAntineutrophil-cytoplasmic-antibody-associated vasculitisBehçet’s diseaseStrokeMononeuritis multiplexNeuropathyCranial neuropathyMyelopathyInflammatory myositisDermatomyositisPolymyositisInclusion body myositisSarcoidosisNeurosarcoidosisIgG4-related disordersNeurotoxicity


Rheumatologic diseases encompass autoimmune and inflammatory disorders of the joints and soft tissues that often involve multiple organ systems. The meninges, brain, spinal cord, cranial and peripheral nerves, and muscle may be involved owing to either the underlying disease process or its treatments (Fig. 1). Innate and adaptive immunity disturbances may mediate the immunopathogenesis. Common and disease-specific genetic risk loci have been identified in genome-wide association studies; however, environmental triggers and hormonal factors likely contribute to clinical disease expression [1]. Common features include constitutional symptoms, arthralgia and arthritis, myalgia, and sicca symptoms (keratoconjunctivitis and xerostomia). Pulmonary and renal involvement are common; however, neurological manifestations may be the presenting feature of rheumatologic disease, which may delay diagnosis for many months [2••]. Enhanced classification criteria and increasing discovery of autoantibodies may facilitate timely diagnosis. The evolution of pharmacologic and biologic immunosuppression has expanded treatment strategies to ameliorate morbidity and mortality in patients with rheumatic disorders; however, these treatments also carry a risk of adverse neurological effects. Therefore, familiarity with neurological manifestations of rheumatologic diseases, diagnosis, and potential nervous system consequences of treatment is paramount. This article reviews the clinical, neurological, and systemic features of rheumatic disorders with an emphasis on more recent developments in diagnosis and treatment implications.
Fig. 1

Nervous system involvement in rheumatologic disease. ANCA antineutrophil cytoplasmic antibody, APLa antiphospholipid antibody, AS ankylosis spondylitis, BD Behçet’s disease, Cryo essential cryoglobulinemic vasculitis, CS Cogan’s syndrome, CVT cerebral venous thrombosis, DM dermatomyositis, EGPA eosinophilic granulomatosis with polyangiitis, GCA giant cell arteritis, GPA granulomatosis with polyangiitis, IBM inclusion body myositis, ICH intracerebral hemorrhage, IGA IgA vasculitis (Henoch–Schönlein purpura), IMNM immune-mediated necrotizing myopathy, IVIG intravenous immunoglobulin, KA Kawasaki’s arteritis, MPA microscopic polyangiitis, NMO neuromyelitis optica, NS neurosarcoidosis, PACNS primary angiitis of the central nervous system, PAN polyarteritis nodosa, PD Paget’s disease, PM polymyositis, PRES posterior reversible encephalopathy syndrome, PSS primary systemic sclerosis, RA rheumatoid arthritis, SA spondylitic arthropathies, SAH subarachnoid hemorrhage, SLE systemic lupus erythematosus, SS Sjögren’s syndrome, TA Takayasu’s arteritis, TIA transient ischemic attack

Connective Tissue Diseases

Systemic Lupus Erythematosus

Patients with systemic lupus erythematosus (SLE) have widespread systemic involvement, including prominent arthritic manifestations, cutaneous features, visceral involvement, and frequent neurological consequences [3]. The incidence of neuropsychiatric SLE (NPSLE) is unknown; however, half of SLE patients will experience NPSLE, and central nervous system (CNS) manifestations may be the initial presenting feature in up to 25 % of patients [4]. The American College of Rheumatology defines 19 neuropsychiatric manifestations involving the CNS and peripheral nervous system (PNS) [5]. Less than 40 % of NPLSE manifestations are directly related to disease activity, with the remainder related to systemic complications or treatment [6].

The main mechanism of CNS injury is brain ischemia. Premature atherosclerosis, small vessel vasculopathy, antibody-mediated thrombosis, and, rarely, vasculitis can occur [7]. Lupus cardiomyopathy or valvular heart disease such as Libman–Sacks endocarditis may lead to embolism [8]. Intracerebral or subarachnoid hemorrhages and cerebral venous thrombosis (CVT) occur less commonly [6]. Antiphospholipid antibodies (APL), including anticardiolipin, lupus anticoagulant, and β2-glycoproteins, are present in approximately 40 % of SLE patients and can lead to arterial or venous thrombosis. Antithrombotic medications should be considered in patients with cerebral ischemia and APL [6, 9, 10].

Headaches occur in over half of SLE patients [4]. Migraines are reported in a third; however, this frequency is similar to that in the general population [11]. Other headache types include tension, cluster, nonspecific intractable, and idiopathic intracranial hypertension. Secondary causes such as aseptic meningitis, ischemic and hemorrhagic stroke, and CVT should be considered. “Lupus headache,” defined as a persistent, severe, intractable, nonnarcotic responsive headache, has been reported in 1.5 % of SLE patients [11]. Association with disease activity or APL has not been established [11, 12]. After exclusion of secondary causes, headaches are treated symptomatically and improve with time [11].

Seizures occur in 11-20 % of SLE patients [13, 14] and are recurrent in up to 15 % of SLE patients [15]. Generalized tonic–clonic and complex partial seizures are the commonest types and can occur without obvious CNS disease. SLE disease activity, lupus nephritis, and presence of APL have been associated with seizures [6, 13, 14]. Interictal EEG abnormalities may predict seizure recurrence [13]. Comprehensive evaluation for seizure cause should be undertaken to evaluate the patient for CNS infection, CVT, metabolic disturbances, treatment side effects, and disease unrelated to SLE. An SLE-like syndrome can occur with carbamazepine and lamotrigine. Valproic acid, levetiracetam, and clobazam may be better antiepileptic drug choices [15].

Cognitive dysfunction is reported in a third of SLE patients [16]. Dementia occurs less commonly than mild or moderate cognitive dysfunction. The impairment patterns are diverse owing to the heterogeneity of neuropsychiatric involvement and the underlying mechanism of CNS dysfunction [17]. APL have been reported as a risk factor for cognitive dysfunction. MRI findings do not correlate well with the cognitive dysfunction [6, 17]. Formal neuropsychological testing should be considered.

Mood disorders are present in 10-20 % of SLE patients, and psychosis is present in less than 5 % of SLE patients [6]. Lupus psychosis may present with paranoia and auditory or visual hallucinations, which may relapse, making the distinction from schizophrenia challenging. Chronic psychosis may be disabling. Depression is common with direct CNS involvement [16]. Evaluation should include delirium, medication adverse effects, and structural causes. Major depression and psychosis may respond to immunosuppressive therapy.

Clinical and radiographic demyelinating disease in SLE patients may present as focal neurological deficits, optic neuritis, or transverse myelitis and is commonly associated with APL [18]. The term “lupus sclerosis” has been used to describe these syndromes [16]. Transverse myelopathy occurs in 1-2 % of SLE patients and is associated with APL. The T5–T8 segments are typically involved [19]. Cerebrospinal fluid (CSF) abnormalities include mild lymphocytic pleocytosis, mild proteinuria, hypoglycorrhachia, infrequent oligoclonal bands, and abnormal IL-6 levels. Low C3 and C4 levels have been associated with disease activity [6]. Improvement after oral anticoagulation has been observed with SLE APL-related syndromes [18].

Movement disorders are rare with SLE. Chorea is the commonest, followed by ataxia and parkinsonism. MRI findings are inconsistent in patients with chorea. Basal ganglia or thalamic T2 hyperintensities are seen in only half of patients with parkinsonism [20]. Movement disorders may respond to steroids, intravenous immunoglobulin (IVIG), and plasma exchange. Low-dose antidopaminergic agents may help chorea, and parkinsonism may respond to dopaminergic agents in some patients [20].

PNS manifestations include peripheral neuropathy, plexopathy, cranial neuropathy, myopathy, and neuromuscular junction disease. As many studies have not required electrodiagnostic evidence for neuropathy diagnosis, the 30 % reported incidence may be an overestimation [14]. Peripheral neuropathy can present as mononeuritis multiplex due to vasculitic involvement of the vasa nervorum, as an acute inflammatory demyelinating polyradiculopathy, or as a chronic sensorimotor demyelinating polyneuropathy [6]. Patients with lupus nephritis and APL are at higher risk of developing peripheral neuropathy [21].

Rheumatoid Arthritis

Rheumatoid arthritis causes destruction of joints and bones, leading to severe disability. Extra-articular manifestations are common; however, manifestations involving the CNS or PNS occur in less than 1 % of the population [22]. Atlantoaxial sublaxation, extradural pannus formation, vertebral collapse, rheumatoid nodules, and epidural lipomatosis may lead to spinal stenosis causing myelopathy, lower cranial neuropathy including cranial nerves IX, X, and XII [23], or nerve root compression in patients with long-standing rheumatoid arthritis [24]. Cerebral manifestations include headaches, seizures, and encephalopathy due to lymphocytic and fibrinoid nodular deposits in the dura and leptomeninges leading to chronic pachymeningitis and cranial neuropathy [25, 26]. Mononeuritis, sensorimotor polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and autonomic neuropathy can occur owing to immune complex deposition in the vasa nervorum. Optic neuritis, entrapment neuropathies, including carpal tunnel syndrome, and myopathy have also been reported [22, 27]. Cerebral vasculitis is rare. Treatment includes corticosteroids, cyclophosphamide, and anti-TNF-α agents.

Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic lymphoid inflammation of the lacrimal and salivary glands causing the sicca complex. Neurological manifestations are diverse. As sicca symptoms can be mild or absent and immunological abnormalities of other extraglandular manifestations may be lacking, diagnosis should be considered in any unexplained neurological presentation.

Neurological manifestations of SS include transverse myelitis with or without positive neuromyelitis optica antibodies as part of neuromyelitis optica spectrum disorders [28], optic neuritis [29], myositis, cranial neuropathies (trigeminal neuropathies and less likely cranial nerves VII and VIII), and a wide spectrum of peripheral neuropathies. Peripheral neuropathies have been described in 22-27 % of SS patients [30, 31]. CNS manifestations have been reported in 0.3-48 % of SS patients [32, 33]. These include aseptic meningitis, demyelination, vasculitis, acute cerebellitis, seizures, and cognitive impairment [34]. Since the sicca syndrome and the anti-Ro/SSA and anti-La/SSB antibodies can be found in classic multiple sclerosis, distinguishing multiple sclerosis from SS may be difficult [35]. The presence of extraglandular manifestations and antibodies against α-fodrin, more frequently detectable in primary syndromes, may be useful [35]. Fewer than four oligoclonal bands in CSF favors SS over multiple sclerosis [36, 37]. Correct diagnosis has therapeutic implications, since interferon-β is ineffective in neuro-SS [38].

Several forms of peripheral nerve involvement have been described, the commonest being the length-dependent sensorimotor polyneuropathy, mononeuritis multiplex, small fiber neuropathy, and a pure sensory neuronopathy. Nerve root involvement or chronic polyradiculoneuropathy is rare [29]. Muscle stretch reflexes are typically absent; however, the masseter (or jaw jerk) reflex is present as the cell bodies of the afferent limb are protected within the CNS in the mesencephalic nucleus [39].

Sensory neuronopathy is an asymmetric non-length-dependent neuropathy, usually affecting arms more than legs. Patients may have severe proprioceptive loss leading to pseudoathetosis. The levels of anti-Ro/SSA and anti-La/SSB are usually elevated, but not invariably [40]. The presence of antineuronal antibodies has been associated with SS and sensory neuropathy [41]. Minor salivary gland or lip biopsy showing lymphocytic invasion of salivary glands has a sensitivity of 70-83 % and is confirmatory but not mandatory for the diagnosis and the findings may be positive even in the absence of xerostomia [40].

Motor neuron syndromes have been described infrequently [42, 43]. Differentiating them from ALS is important as patients with SS may respond to immunosuppression [44]. SS has been associated with myositis [45]. Proximal weakness with high creatine kinase (CK) concentration is the main feature, and muscle biopsy confirms the diagnosis with histological features similar to those of polymyositis. Prednisone, 1 mg/kg/day, is the mainstay of treatment [46].

In general, treatment of SS is aimed at controlling the sicca symptoms, when present. Neurological complications are an indication for immunosuppressive medication.

Scleroderma (Primary Systemic Sclerosis)

Systemic manifestations of primary systemic sclerosis include progressive fibrosis of the skin, lung, gastrointestinal tract, kidney, and nervous system. Neurological manifestations occur in 19-40 % of patients with scleroderma [47, 48] and are associated with anti-Scl-70 (anti-topoisomerase I) and anti-U1-RNP antibodies [49].

Distal axonal sensorimotor peripheral neuropathy occurs in 57 % of those with neurological involvement and responds poorly to treatment. Other peripheral nerve involvement includes entrapment neuropathies, (especially median), brachial plexopathy, and mononeuritis multiplex. Cranial neuropathy, most frequently a trigeminal sensory neuropathy, and less commonly neuropathy of cranial nerves VII and IX can also develop. Myositis has been reported in 15-17 % of cases. Onset can be in childhood or in adulthood, and males are more commonly affected. Proximal weakness is typically mild, and CK levels are high, but less than ten times normal [50]. Treatment requires corticosteroids, methotrexate, or cyclosporine. Scleroderma rarely involves the CNS, but cerebritis has been reported [51].

IgG4-Related Disorders

Initially described in patients with autoimmune pancreatitis, IgG4-related disorders have been reported to involve the salivary glands, lung, kidney, lacrimal gland, retroperitoneum, aorta, prostate, breast, thyroid, pituitary, lymph nodes, and nervous system. Neurological manifestations include inflammation of the cranial and spinal pachymeninges and leptomeninges causing headache, reversible cognitive deterioration, compressive cranial neuropathy, or myelopathy [52]. Painful sensorimotor neuropathy has been reported [53]. Nervous system involvement may occur independently of other organ systems. Histopathology demonstrates lymphoplasmacytic inflammation and fibrosis in affected tissues. Immunohistochemistry demonstrates elevated serum IgG4 levels or increased levels of IgG4 plasma cells. CSF pleocytosis and elevated protein level may be present, but not invariably. Neurological symptoms may respond to steroid treatment.

Systemic Vasculitis

Inflammation-mediated vascular injury is the common denominator for central and peripheral neurological manifestations of systemic vasculitis. The vasculitides are classified by predominant vessel size (Table 1). However, vasculitis of all categories can affect a vessel of any size and may present as a manifestation of CTD such as rheumatoid arthritis, SLE, and sarcoidosis or conditions such as Cogan’s syndrome and Behçet’s disease. Primary angiitis of the CNS is a single-organ vasculitis requiring exclusion of systemic and secondary causes. Multiple infarctions on MRI and inflammatory CSF may suggest CNS vasculitis. Angiographic findings suggesting vasculitis include arterial stenosis, occlusion, dilatation, and beading [55, 56•]. Vasculitis can involve vessels beyond the resolution of conventional angiography, requiring brain and meningeal biopsy for diagnosis.
Table 1

Major vasculitides of systemic and rheumatologic disease by vessel size [24, 54••, 55, 56•, 5759, 60•, 6172]


Large vessel

Medium vessel

Small vessel

Variable vessel

Single organ


Immune complexb














Age more than 50 years, commoner among Caucasians of European descent; temporal headaches; scalp tenderness; jaw claudication; AION; amaurosis fugax, less commonly TIA/stroke; mononeuritis multiplex

Typical age 15–40 years; commoner in women than in men; Asian ancestry; constitutional symptoms; limb claudication; hypertension; asymmetric pulse and BP in arms; carotid tenderness; subclavian steal syndrome, ischemic stroke/TIA, or ICH

Constitutional symptoms; rash; arthralgia; abdominal pain; peripheral neuropathies commoner than CNS (ischemic stroke, ICH, diffuse encephalopathy, seizures, SAH)

Infants, children, and young adults; fever (at least 5 days); rash; cervical lymphadenopathy; constitutional symptoms; angina with exercise; sudden death; MERS; aseptic meningitis; facial palsy; seizures; rarely stroke

Early renal and pulmonary involvement (alveolitis, glomerulonephritis); mononeuritis multiplex; polyneuropathy; rarely stroke or ICH

Prominent upper and lower respiratory tract involvement such as nasal ulceration, epistaxis, sinusitis, “saddle nose,” cough, and pulmonary hemorrhage; mononeuritis multiplex commoner than cerebrovascular events; ocular involvement such as retinal or optic nerve ischemia, keratitis, uveitis, and, orbital pseudotumor; seizures; cranial neuropathy

Asthma; rhinitis; recurrent pneumonia; weight loss; heart failure; palpable purpura; cranial neuropathy; mononeuritis; encephalopathy; stroke; visual loss; chorea; renal involvement uncommon

Children, peak incidence at 5 years old; palpable purpura and renal involvement prominent; GI colic; arthralgia; headache; encephalopathy; focal deficits; peripheral neuropathy

Mean age 50 years; arthralgia; purpura; nephritis; polyneuropathy; small fiber neuropathy; RLS; ischemic stroke/TIA uncommon; ICH

Commoner in Middle Eastern men; mucocutaneous and genital ulcers; uveitis; retinal vasculitis; arthritis; gastroenteritis; headache; focal neurological deficits; brainstem meningoencephalitis; myelopathy; CVST, cranial neuropathy; peripheral neuropathy; myopathy

Commonest in young Caucasian adults; interstitial keratitis and audiovestibular symptoms (e.g., tinnitus, vertigo, hearing loss) typically within 2 years of onset; aortic insufficiency; arthralgia; headache; TIA and ischemic stroke; GI symptoms

Men more commonly affected; mean age 50 years; history of headaches; insidious onset cognitive impairment usually precedes cerebrovascular events; infrequently cranial neuropathy; ICH

Clinical signs and diagnosis

Nodular, tender temporal artery; optic disc edema acutely present; ESR >50 mm/h; CRP level typically elevated; CRP >2.45 mg/dl strongly correlates with positive temporal artery biopsy; skip lesions may occur; granulomatous arteritis and multinucleated giant cells on biopsy; aorta may be involved

Subclavian or aortic bruit; possible aortic valve regurgitation and coronary involvement; elevated ESR; microcytic anemia; radiological evidence of subclavian, renal or other large aortic branch stenosis or aneurysmal dilatation of renal artery; consider FDG-PET of aorta and subclavian arteries

Elevated ESR and CRP level; axonal neuropathy with asymmetric involvement; visceral aneurysms; abnormal urinary sediment; may be associated with chronic HBV infection; muscle and nerve biopsy show vasculitic changes

Coronary aneurysm and occlusive disease; CSF pleocytosis in 1/3 of cases during acute phase

Serum C-ANCA commoner than P-ANCA; elevated ESR and CRP level; UA can show protein, sediment and casts; CT of chest, EMG/NCV, and renal or nerve biopsy may be necessary

Serum C-ANCA positive; elevated ESR and CRP level; leukocytosis; thrombocytosis; UA can show protein, sediment and casts; CT of chest and sinuses, EMG/NCV, echocardiogram, and renal or nerve biopsy may be necessary

Serum P-ANCA positive; marked eosinophilia; elevated ESR and CRP level; anemia; CT of chest, EMG/NCV, echocardiogram, and nerve biopsy may be necessary

Increased serum IgA level; mild leukocytosis; elevated ESR and CRP level; thrombocytosis; skin or renal biopsy may be useful

Serum cryoglobulins present; low C3 and C4 levels; evaluate for HCV; EMG/NCV showing axonal polyneuropathy

Positive pathergy test; elevated ESR; HLA-B51/B27 type; thrombophilia screen; CSF pleocytosis and protein level elevation; absent CSF oligoclonal bands; MRI of brain and spine

Exclude other causes; negative syphilis serological test; labyrinthine T1 hyperintensity on MRI; elevated ESR and CRP level

Deep subcortical white matter hyperintensities on MRI; characteristic vasculitic findings on angiography; CSF lymphocytic pleocytosis and elevated protein level, oligoclonal bands, and increased IgG index less common; exclude other causes of secondary vasculitis


Prednisone, 40–60 mg daily, on clinical suspicion and prior to further testing (continue for 2–4 weeks); Methylprednisolone, 1,000 mg intravenously daily for 3 days, for impending visual loss; reduce daily dose by 10 % every 1–2 weeks

Prednisone, 40–60 mg daily; cyclophosphamide, methotrexate, azathioprine; angioplasty/stenting, surgical revascularization; antithrombotics for ischemic stroke prevention

Corticosteroids and cytotoxic drugs (e.g., cyclophosphamide); treatment of HBV if present; symptomatic management of neurological complications

IVIG within first 10 days of illness; aspirin; consider steroids or cytotoxic agents in patients with refractory disease

Corticosteroids and cyclophosphamide are first-line treatment; consider azathioprine, methotrexate, leflunomide, and rituximab; trimethoprim-sulfamethoxazole may be adjunct therapy for GPA

Corticosteroids and cyclophosphamide are first-line treatment; consider azathioprine, methotrexate, leflunomide, and rituximab

Symptomatic treatment; steroids for arthritis, GI pain, and renal involvement; consider azathioprine or cyclophosphamide

Consider corticosteroids, cyclophosphamide, rituximab, and PLEX

Methylprednisolone, 1,000 mg daily intravenously, immediately followed by taper of orally administered prednisone; consider infliximab, azathioprine, mycophenolate mofetil, and use of cyclosporine A in patients with uveitis ; anticoagulation for CVST

Corticosteroids are first-line treatment; consider cyclophosphamide, azathioprine, and TNF-α blockers

Corticosteroids and cytotoxic agents such as cyclophosphamide are first-line treatment; management of ischemic complications; progressive and fatal if left untreated


Aortic/thoracic aneurysm late complication, consider evaluation; treatment for 1–2 years; up to 50 % of patients may have spontaneous exacerbations within 2 years

Serial monitoring of stenotic vessels; cardiac evaluation for coronary involvement, aortic insufficiency, and heart failure; manage stroke risk factors including hypertension

Combined treatment usually necessary; relapses less common in HBV-related PAN

Consider in children younger than 5 years old with persistent fevers after exclusion of other causes; early use of IVIG is associated with decreased incidence of symptomatic coronary involvement

Symptomatic treatment; steroids for arthritis, GI pain, and renal involvement; consider azathioprine or cyclophosphamide

Renal involvement associated with significantly worse outcome; low C-ANCA level observed in inactive disease or focal involvement

Prodrome of rhinitis and increasing asthma severity may precede systemic involvement and eosinophilia by 2–20 years and may be associated with a higher risk of cardiomyopathy

Excellent prognosis; morbidity related to severity of renal involvement

Response of neuropathy to interferon therapy is variable, relapse may occur; may be associated with HCV, or may overlap with other CTD

Course typically subacute progressive; relapses associated with poor prognosis and morbidity

Topically administered atropine and corticosteroids for ocular involvement; surgical repair may be necessary for aortic insufficiency

Brain and meningeal biopsy typically needed to confirm diagnosis and exclude other causes; skip lesions and patchy involvement accounts for a sampling error between 37 and 48 %

AION anterior ischemic optic neuropathy, ANCA antineutrophil cytoplasmic antibody, BD Behçet’s disease, BP blood pressure, C-ANCA cytoplasmic antineutrophil cytoplasmic antibody, CNS central nervous system, CRP C-reactive protein, Cryo essential cryoglobulinemic vasculitis, CS Cogan’s syndrome, CSF cerebrospinal fluid, CTD connective tissue disease, CVST cerebral venous sinus thrombosis, EGPA eosinophilic granulomatosis with polyangiitis, EMG electromyography, ESR erythrocyte sedimentation rate, FDG-PET18 F-deoxyglucose PET, GCA giant cell arteritis, GI gastrointestinal, GPA granulomatosis with polyangiitis, HBV hepatitis B virus, HCV hepatitis C virus, ICH intracerebral hemorrhage, IgA IgA vasculitis (Henoch–Schönlein purpura), IVIG intravenous immunoglobulin, KA Kawasaki’s arteritis, MPA microscopic polyangiitis, MERS mild encephalitis/encephalopathy with a reversible splenial lesion, NCV nerve conduction velocities, PACNS primary angiitis of the central nervous system, PAN polyarteritis nodosa, P-ANCA perinuclear antineutrophil cytoplasmic antibody, PLEX plasma exchange, RLS restless leg syndrome, SAH subarachnoid hemorrhage, TA Takayasu’s arteritis, TIA transient ischemic attack, UA urine analysis

aNecrotizing vasculitides

bHypersensitivity vasculitides

Behçet’s disease is a multisystem inflammatory process of unknown origin with prominent mucocutaneous and ocular features. It is commonest among young to middle-aged men of Middle Eastern or Asian descent. Neurological involvement is reported in nearly half of patients and occurs within 3–6 years of disease onset. Headache is common and may occur independently of overt neurological involvement. The commonest parenchymal manifestation is meningoencephalitis affecting the upper brainstem and thalamus, presenting with an array of focal deficits and brainstem syndromes. Seizures, stroke-like syndromes, cognitive and behavioral changes, spinal cord syndromes, and optic neuropathies have been reported. Spinal cord or optic nerve involvement predicts a poor prognosis. The commonest nonparenchymal manifestations are CVT and intracranial hypertension. PNS manifestations are less common. Acute manifestations respond well to corticosteroid therapy. A third of patients will have residual neurological impairments and will require long-term immunosuppression [57, 58].

Cogan’s syndrome is a rare autoimmune vasculitic disease that occurs most commonly among young Caucasian adults. It is characterized by nonsyphilitic interstitial keratitis followed by audiovestibular dysfunction with hearing loss. The interval between the onset of ocular and audiovestibular manifestations is typically less than 2 years, but can be longer. Occasionally, the audiovestibular symptoms can occur first. Hearing loss is usually bilateral and progresses over 1-3 months, resulting in deafness in 60 % of cases. Atypical ocular manifestations include scleritis, iritis, uveitis, conjunctivitis, and papilledema. Constitutional symptoms are common. Systemic manifestations include gastrointestinal tract ulcerations, congestive heart failure, aortic insufficiency, splenomegaly, lymphadenopathy, and skin rash. Treatment involves high-dose corticosteroids. Prognosis is variable and is predicted by the degree of hearing loss, systemic involvement, and time until treatment initiation. Other immunosuppressive therapies have been attempted with variable success [59, 60•].

Vasculitis can be due to nonrheumatic disorders. Common infectious causes include hepatitis B virus associated polyarteritis nodosa, hepatitis C virus associated cryoglobulinemia, varicella–zoster virus, human immunodeficiency virus, cytomegalovirus, parvovirus B19, neurosyphilis, neuroborreliosis, and mycoplasma pneumoniae. Fungal and parasitic vasculitis are less common in developed countries, but may be seen in immunocompromised patients and travelers to developing countries [73]. Antimicrobials, vaccines, cytotoxic agents, and other drugs have been associated with vasculitis. Hydralazine-associated microscopic polyangiitis has been described. Drugs may be associated with immune complex deposition or antineutrophil cytoplasmic antibody positivity. Furthermore, vasculitis can be associated with hematologic, lymphoproliferative, and solid organ malignancies [54••].

Idiopathic Inflammatory Myositis

There are four distinct idiopathic inflammatory myopathies: polymyositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) (Table 2). These myopathies can occur in isolation, in association with malignancy, or as an overlapping syndrome with CTD.
Table 2

Idiopathic inflammatory myositis [7479]







>20 years

Juvenile or adult onset

>18 years

>50 years


Commoner in females than in males when associated with CTD

Commoner in female than in males

Commoner in males than in females

Predilection of weakness

Symmetric; proximal weakness commoner than distal weakness

Symmetric; proximal leg weakness commoner than arm weakness, neck flexors more commonly involved than extensors

Symmetric; proximal weakness commoner than distal weakness

Asymmetric finger flexors and knee extensor weakness; atrophy of the quadriceps and forearm flexors

Other clinical features

Muscle pain and tenderness; dysphagia in 1/3 of patients

Gottron’s papules; heliotrope rash; shawl sign; V sign and holster sign; dysphagia in 30 % of patients, subcutaneous calcifications in children


Dysphagia in 40 % of patients

Associated manifestations

Cardiac (CHF, inflammatory cardiomyopathy, conduction abnormalities); ILD in 10 % of patients; polyarthritis in 45 %

Cardiac (conduction defects, arrhythmias); ILD in 20 % of patients; GI (dysphagia, delayed gastric emptying); arthralgia; vasculopathy


Associated CTD

SLE; Sjögren’s syndrome; phospholipid antibody syndrome in 30 % of patients


Scleroderma; mixed CTD

SLE, scleroderma, or sarcoidosis in 15 % of patients


CK level typically more than 5 times normal; ANA positive, up to 40 % of patients

CK level elevated in 90 % of patients; ANA positive, 24–60 % of patients; positive MSA (anti Jo-1)

CK level markedly elevated, more than 10 times normal; ANA positivity

CK level elevated but less than 10 times normal; ANA can be positive

Associated malignancy

Mild increased risk

Increased risk of adenocarcinoma (lung, breast, ovarian, nasopharyngeal) and lymphoma in adults

GI adenocarcinomas, and small cell/non-small-cell lung carcinomas


EMG/NCS findings

NCS usually normal findings; EMG shows increased spontaneous activity (positive waves and fibrillations); myopathic MUP; early recruitment; with treatment fibrillations decrease or disappear

NCS can show a mild sensory or sensorimotor neuropathy; EMG shows increased spontaneous activity; MUP can be myopathic, normal, or large and long with polyphasia


Perivascular, perimysial, or endomysial inflammation surrounding and invading nonnecrotic muscle fibers

Prominent perifascicular atrophy; predominantly perimysial inflammation

Many necrotic muscle fibers; MAC deposition on small blood vessels; pipestem capillaries on EM

Endomysial inflammation; atrophic fibers; rimmed vacuoles


Lifelong immunosuppression (corticosteroids, azathioprine, methotrexate, and/or cyclosporine)

Responds well to immunosuppression (corticosteroids, methotrexate, and cyclophosphamide in refractory cases); IVIG

Difficult to treat; immunosuppression (corticosteroids plus a second-line drug); IVIG

Not responsive to treatment

ANA antinuclear antibody, CHF congestive heart failure, CK creatine kinase, EM electron microscopy, IBM inclusion body myositis, ILD interstitial lung disease, IMNM immune-mediated necrotizing myopathy, MAC membrane attack complex, MSA muscle-specific antibodies, MUP motor unit action potential, NCS nerve conductions study, SLE systemic lupus erythematosus

Polymyositis usually presents after the age of 20 years, and is commoner in women than in men. Muscle pain and tenderness occur commonly, but the major symptom is symmetric proximal weakness. One third of patients have dysphagia. Polymyositis can be associated with a CTD such as SLE, SS, or scleroderma. Other manifestations include myocarditis, interstitial lung disease (ILD) in 10 % of patients [74], and polyarthritis in up to 45 % of patients. CK concentration is usually elevated at least fivefold. Histopathology shows endomysial infiltrates composed of CD8+ T cells and macrophages invading the nonnecrotic muscle cells expressing MHC-1 antigen [75]. Polymyositis usually responds to immunosuppression and may require lifelong treatment.

Dermatomyositis can affect children, representing more than 90 % of immune myopathies in this group. The typical presentation is symmetric proximal weakness with classic skin manifestations. Skin lesions may be subtle, and include purplish discoloration over the eyelids (heliotrope rash), an erythematous rash over the knuckles (Gottron’s papules), and photosensitivity over the face, neck and chest (V sign), shoulders and upper back (shawl sign), hips (holster sign), or extensor surface of the elbows and knees (Gottron’s sign). Dysphagia occurs in 30 % of patients. Subcutaneous calcifications occur in children more commonly than in adults. Malignancy is present in 6-45 % of adults with dermatomyositis but not children [76] and does not correlate with rash severity or weakness. The CK level is elevated in over 90 % of patients [77]; however, it does not correlate with the severity of weakness. Antinuclear antibodies are detected in 20-60 % of patients and more commonly with overlapping syndromes. Myositis-specific antibodies such as anti-Mi-2, anti-Mas, and anti-Jo are found in a minority of patients. Anti-Jo antibodies are associated with ILD and inflammatory myopathies in 20 % of patients. The presence of anti-Jo antibodies predicts a poor treatment response and prognosis. Histopathology demonstrates prominent perifascicular atrophy and predominantly perimysial inflammation. Cancer treatment may result in improvement of weakness. Poor prognostic factors include older age, associated ILD, cardiac disease, and late treatment. Without malignancy, prognosis is generally favorable.

IBM presents with insidious asymmetric proximal and distal weakness after the age of 50 years. Quadriceps, forearm flexor, and ankle dorsiflexor atrophy is pathognomonic. Dysphagia can develop in 40 % of patients, leading to weight loss or aspiration. Myocarditis, ILD, and malignancy are uncommon with IBM. Up to 15 % of patients may have underlying SLE, SS, scleroderma, or sarcoidosis [78]. CK levels are usually normal. Myositis-specific antibodies are absent, but antinuclear antibodies are present in 20 % of patients when IBM is associated with other autoimmune diseases. HLA-D3 phenotype has been associated with IBM [79]. Congo red staining using polarized light reveals amyloid deposition in vacuolated muscle fibers on biopsied specimens. IBM does not usually respond to steroids, although a trial of prednisone is reasonable while excluding chronic polymyositis when the CK level is normal. Additionally, IBM does not respond well to IVIG or other immunosuppressant agents, including methotrexate and etanercept. Intensive physical therapy and symptomatic management is the mainstay of treatment [80, 81].

Despite lack of inflammation, IMNM is usually categorized as an inflammatory myopathy. Patients present with either acute or insidious proximal weakness and myalgia. CTD and malignancy (paraneoplastic necrotizing myopathy) may be associated with IMNM. The most commonly associated malignancies are gastrointestinal adenocarcinoma, small cell lung carcinoma, and non-small-cell lung carcinoma. CK level is markedly elevated. Necrotic muscle fibers are seen on biopsy and are seen as thickened, hyalinized (pipestem) capillaries on electron microscopy.

EMG cannot differentiate between polymyositis, dermatomyositis, and IMNM. Increased insertional activity and myopathic motor units (small duration and amplitude and polyphasic) action potentials are usually present. Involvement of both proximal and distal muscles on EMG with intermixed myopathic, normal, or neurogenic motor unit action potentials suggests IBM. Large polyphasic potentials can erroneously lead to misinterpretation as motor neuron disease.

All inflammatory myopathies except IBM respond to corticosteroids. IMNM is more difficult to treat than polymyositis or dermatomyositis but usually responds to a corticosteroid plus a second-line agent. IVIG may be beneficial.


Sarcoidosis is a noncaseating granulomatous disease that has predilection for the lungs, spleen, lymph nodes, eyes, skin, and nervous system. Neurological manifestations include basal meningitis, hydrocephalus, vasculitis, encephalopathy and dementia, parenchymal brain lesions, cranial neuropathy, myelopathy, radiculopathy, neuropathy, and myopathy. CNS involvement usually occurs in the early phases of the disease, whereas PNS and muscle disease are seen in late stages [82]. Neurological manifestations can be the presenting feature of sarcoidosis in up to 74 % of patients, and isolated neurosarcoidosis is seen in 10-17 % of patients [83]. Additionally, neurosarcoidosis can have a relapsing–remitting course.

The commonest CNS manifestations in sarcoidosis are related to meningeal, parameningeal, cranial nerve, hypothalamic, and pituitary involvement [84]. Basal meningitis is caused by granulomatous infiltration or compression of adjacent structures [82]. Optic nerves are frequently affected [85]. Unilateral or bilateral facial nerve involvement is also common, followed by involvement of cranial nerves VIII, IX, and X. Hypothalamic and pituitary involvement is characteristic of neurosarcoidosis, with the posterior part of the pituitary commonly affected. Polydipsia and polyuria due to diabetes insipidus may be the presenting symptom. Focal granulomatous infiltration has a predilection for the fourth ventricle, causing hydrocephalus [86]. Sarcoidosis can present as a myelopathy with focal enlargement of the spinal cord with gadolinium enhancement on MRI.

PNS involvement includes polyradiculopathy, mimicking Guillain–Barré syndrome, and multiple mononeuropathies. Sensory more than motor peripheral polyneuropathy and small fiber neuropathy have also been encountered.

MRI may show nodular leptomeningeal enhancement around the brainstem and cranial nerve roots. CSF may show pleocytosis and increased protein levels. Use of CSF angiotensin-converting enzyme (ACE) level is controversial [85]. Over half of patients with neurosarcoidosis have high CSF ACE levels; however, high concentrations can also be seen with infections and malignancies [87]. Serum ACE level sensitivity is 24–76 %. Serum IL-2 receptor level has been found to be more useful than ACE level for monitoring disease activity [88].

If the diagnosis is uncertain, tissue biopsy is indicated. Extraneural biopsy from clinically affected organs is preferable, as it may be safer. 18 F-Deoxyglucose PET may be useful in identifying extraneural biopsy sites [89••]. Muscle and nerve biopsy, including an epidermal specimen with quantitative nerve terminal analysis when small fiber sensory neuropathy is present, can be easily performed.

Granulomas may affect muscle in more than 50 % of patients, with sarcoidosis causing acute myositis, palpable nodular myopathy, or chronic myopathy. Chronic myopathy is most common, with slowly progressive weakness and normal CK level. Only 1-2 % of patients present with symptomatic muscle disease. Muscle MRI can be useful; however, muscle biopsy may be required [90].

Prednisone (1 mg/kg) is recommended for treatment of neurosarcoidosis. In severe cases, a short course of intravenously administered methylprednisolone may be useful. Although corticosteroids suppress inflammation, symptoms may recur on tapering prednisone below 10 mg/day. Steroid-sparing agents such as methotrexate, azathioprine, cyclosporine, cyclophosphamide, and infliximab have been used [89].


Ankylosing spondylosis is a severe spondyloarthritis due to inflammatory enthesopathy of the axial joints. Extra-articular effects include uveitis, gastrointestinal, cardiopulmonary, dermatological, and renal involvement. Neurological manifestations are rare [91]. Spinal stenosis and myelopathy due to atlantoaxial subluxation, posterior longitudinal ligament ossification, and occult vertebral collapse have been reported. Cauda equina syndrome has been reported [92].

Paget’s disease of the bone is a pathologic process whereby normal bony architecture is replaced by vascular connective tissue and osseous dysplasia. Neurological manifestations occur owing to compression of adjacent neural or neurovascular structures. Deafness occurs in up to 50 % of patients owing to auditory nerve compression, cochlear invasion, or middle ear ossification. Vestibular and olfactory nerves, spinal cord, and spinal nerve roots are frequently involved. Basilar invagination may cause headaches, cerebellar and brainstem dysfunction, cognitive impairment, seizures, and cranial neuropathy owing to direct compression or hydrocephalus. Neurovascular compromise may cause vertebrobasilar insufficiency, ischemic myelopathy, and cauda equina syndrome [93].

Neurological Complications of Immunosuppressive Therapies

Disease-modifying therapies for patients with rheumatic disorders include NSAID and immunosuppression with corticosteroids, chemotherapeutic medications, and biologics. Many of these agents result in serious neurological complications. A complete review of neurotoxicity from these treatments is beyond the scope of this article.

Immunosuppressed patients are predisposed to infection from opportunistic organisms, including bacteria, fungi, and viruses, including cytomegalovirus and varicella–zoster virus. Progressive multifocal leukoencephalopathy (PML) due to the ubiquitous JC virus has been reported in patients treated with the biologics natalizumab, rituximab, and efalizumab [94, 95•, 96]. PML has also been reported in patients with SLE and other rheumatic diseases in the absence of exposure to biologics [97]. PML typically causes asymmetric posterior cerebral demyelination that is infrequently enhanced on MRI with gadolinium. CSF may demonstrate mild pleocytosis or elevated protein level but is usually normal. The optic nerves and spinal cord are spared, which may help distinguish PML from other causes, including SLE [98]. This distinction may be challenging but important as it impacts treatment. CNS demyelination and optic neuritis have been reported in patients receiving anti-TNF-α agents including infliximab, etanercept, and adalimumab [99, 100].

Several agents, particularly those also used to prevent rejection in patients with solid organ transplants such as cyclosporine and tacrolimus, have been associated with posterior reversible encephalopathy syndrome (PRES). PRES commonly presents with headache, visual changes, and seizures. Neuroimaging typically shows symmetric T2 hyperintensity in the posterior cerebrum and cerebellum without restricted diffusion or contrast enhancement. PRES usually resolves within several days after discontinuation of the offending agent(s). Cyclosporine, mycophenolate mofetil, and tacrolimus have also been associated with tremor and incoordination [101].

Stroke has been reported to occur in patients with vascular risk factors receiving IVIG for the first time [102]. Other CNS side effects include psychosis associated with agents such as corticosteroids, antimalarials, and dapsone. Aseptic meningitis may be related to NSAID overuse and sulfasalazine [101].

Neurotoxicity may also affect the PNS. Neuropathy has been reported from many chemotherapeutic agents, and myopathy has been associated with long-term corticosteroid use, antimalarials, colchicine, cyclosporine, and penicillamine. Antimalarials may cause retinopathy and ototoxicity [101, 103]. Penicillamine may induce myasthenia gravis [104], optic neuritis, polymyositis, and dermatomyositis [105].


Diagnosis of neurological complications in patients with established rheumatologic diagnoses is usually not difficult; however, diagnosis of a rheumatic disorder in a patient with a neurological manifestation as the presenting feature may be challenging. Additionally, distinguishing neurotoxicity of rheumatologic treatments from manifestations of the rheumatic disease being treated or another cause may be problematic. Efficient diagnosis and treatment should be a multidisciplinary collaborative effort that includes expertise in rheumatology and rehabilitation among other fields.


We thank Rania Nouh for providing us with the illustration for this review.

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Conflict of Interest

Amre Nouh, Olimpia Carbunar, and Sean Ruland declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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© Springer Science+Business Media New York 2014