Neurorheumatology



Neurorheumatology


Sharmik Bhattacharyya

Tamara B. Kaplan

Nagogopal Venna



Wide spectrum of primarily autoimmune systemic d/os that can affect the CNS, PNS, & autonomic nervous systems. Expression depends on genetic & environmental factors. Neurologic si/sx can be 1° or 2° (e.g., to effects related to other organs or to Rx). Neurologic involvement → significant morbidity, may indicate ↑ dz activity. Sometimes neurologic si/sx = presenting manifestations of systemic rheumatologic dz.































Clinical Sx Suggesting Systemic Rheumatologic Dz


Constitutional

Fever, fatigue, malaise, wt loss, anorexia


Glandular

Dry eyes or mouth


Musculoskeletal

Joint pain or swelling, myalgias, prolonged morning stiffness


Renal

Proteinuria, urinary cellular casts


Vascular

Unexplained thrombosis or thromboembolism; Raynaud’s, livedo reticularis


Cutaneous

Malar or discoid rash, photosensitivity, psoriasis, oral or genital ulcers, petechiae, subcutaneous nodules, alopecia, erythema nodosum


Ocular

Uveitis, scleritis, conjunctivitis



ORDERING RHEUMATOLOGICAL LABORATORY MARKERS

Labs alone insufficient for diagnosis & MUST be guided by clinical suspicion. Screen w/sensitive markers before ordering panels.





























Guide to Rheumatologic Dx & Tests by Syndrome


Syndrome

Brief Immunological DDx & Initial Testing


Ischemic stroke (Infarct)

DDx: SLE, APLS, vasculitis, sarcoidosis, Behçet disease


Lab: ESR, CRP, C3/C4, ANA (further serologic testing if positive), lupus anticoagulant, anti-cardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM, ANCA, lumbar puncture (cell count w/diff, protein, glucose), ACE (serum & CSF)


Myelitis

DDx: Multiple sclerosis, NMO, SLE, Sjögren syndrome, paraneoplastic, vasculitis, sarcoidosis, Behçet disease (see other sections for infxn, neoplastic, vascular, & degenerative etiologies)


Lab: NMO-IgG, anti-Ro/La, ESR, CRP, ANA, ANCA, ACE, lumbar puncture, (cell count w/diff, protein, glucose, oligoclonal bands, ACE). Paraneoplastic panel if malignancy, CSF inflammatory, or initial workup negative


Meningitis

DDx: IgG4 related disease, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, SLE (rare)


Lab: IgG subsets, RF, anti-CCP, anti-Ro/La, ANA, ESR, CRP, serum & CSF ACE


Encephalopathy

DDx: SLE, Sjögren syndrome, APLS, multiple sclerosis, NMO, Hashimoto encephalopathy, vasculitis, paraneoplastic, neuronal surface antibody, sarcoidosis (large ddx guided by imaging & hx)


Lab: ESR, CRP, ANA, anti-Ro/La, lupus anticoagulant, anti-cardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM, ANCA, lumbar puncture (cell count w/diff, protein, glucose, oligoclonal bands), anti-TPO, anti-thyroglobulin, NMO-IgG (if suggestive imaging). If evidence of malignancy or CSF inflammatory, consider sending for paraneoplastic antibodies. If appropriate syndrome, test for neuronal cell surface antibodies (see Neuro-Oncology chapter).


Neuropathy

DDx: Can accompany many rheumatologic disorders & tx. SLE, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, vasculitis, scleroderma


Lab: ESR, CRP, ANA, RF, anti-CCP, anti-Ro/LA, serum ACE, ANCA, cryoglobulin, HBV sAg, HCV Ab, anti-Scl70, anti-centromere (further testing guided by EMG/NCS results)



DIFFUSE CONNECTIVE TISSUE DISEASES


SYSTEMIC LUPUS ERYTHEMATOSUS

Neurol Clin 2002;20:151; Continuum 2008;14:94; Lancet 2007;369:587.

Epid: Prev ˜40-50/100,000; more common: (1) F > M, (2) Asian, African, Latino ancestry, (3) young adults. Dx of SLE (Arth Rheum 1982;25:1271 & 1997;40:1725): 11 criteria of American College of Rheumatology (ACR); require ≥4. Criteria used in research; pt may have SLE w/o ≥4 criteria.

Dz Activity: ↑ ESR, CRP. ↓ C3, C4, CH50. ↑ anti-dsDNA titers. Other tests organ specific.


































ACR Criteria for Dx of SLE


System

Criteria


Cutaneous/dermatologic

1. Malar rash (fixed erythema over malar eminences)


2. Discoid rash (red raised patches w/scaling & follicular plugging)


3. Photosensitivity (skin rash from unusual reaction to sunlight)


4. Oral ulcers (oral or nasopharyngeal, usually painless)


Musculoskeletal

5. Arthritis (nonerosive of ≥2 peripheral joints)


Cardiopulmonary

6. Serositis (pleuritis or pericarditis)


Renal

7. Persistent proteinuria (>0.5 g/day or 3+) or urinary cellular casts


Neuro/psych

8. Seizures or psychosis (no other cause identified)


Hematologic

9. Hemolytic anemia (w/reticulocytosis) or leukopenia (<4,000/mm3) or lymphopenia (<1,500/mm3) or thrombo-cytopenia (<100 k/mm3 w/o offending drug present)


Immunologic/serologic

10. ⊕ anti-dsDNA or anti-Sm or antiphospholipid ab (elevated IgG/IgM anticardiolipin, LA, IgG/IgM β2-glycoprotein I)


11. ⊕ ANA (in the absence of drugs a/w drug-induced lupus)



Neuropsychiatric SLE (NPSLE): NPSLE replaces terms “CNS lupus,” “neurolupus,” & “lupus cerebritis.” Can present before or after clinical dx of SLE, including quiescent periods. Nineteen proposed CNS/PNS syndromes to provide standardized nomenclature but not specific to SLE. Other causes need to be excluded first.

NPSLE syndromes (19 described; dx criteria, exclusions, associations, w/u on ACR website [http://www.rheumatology.org/publications/ar/1999/aprilappendix.asp]).

Central Manifestations: Acute confusional state, anxiety disorder, aseptic meningitis, cerebrovascular disease, Cognitive disorder, demyelinating syndrome, headache, mood disorder, movement disorder, myelopathy, psychosis, seizure disorder

Peripheral Manifestations: Autonomic neuropathy, cranial neuropathy, Guillain-Barre syndrome (AIDP), mononeuropathy, myasthenia gravis, plexopathy, polyneuropathy








































Specific ACR Neuropsychiatric SLE Syndromes


Syndrome

Notes


Cerebrovascular Dz

Cause 20%-30% of deaths in SLE. ˜65% of pts w/stroke & SLE have anti-phospholipid antibodies. Can be small vessel, large arterial territory, or venous sinus thrombosis. Dx: MRI, IgG/IgM anti-cardiolipin, IgG/IgM, anti-β2-glycoprotein I, lupus anticoagulant, TTE (marantic endocarditis), vessel imaging (MRA/CTA/angiogram). Tx: Thrombolysis (if acute), anticoagulation (INR 2-3) for APLS, efficacy of new anticoagulants unclear, aggressive risk factor control like obesity, HTN, HLD, DM (a/w steroids).


Seizure

Can be provoked (uremia, acute infarct) or occur in isolation. Generalized or focal. Hx of stroke & anti-phospholipid Ab risk factors. ˜88% of sz are single episode. Dx: MRI, EEG. Tx: AED only if recurrent sz, MRI/EEG abnl.


Mood disorder

Depression (unclear if related to disease or reaction)


Psychosis

A/w SLE systemic dz activity. Steroid often contributing factor. Tx: Antipsychotics. Immune suppression for other SLE dz activity.


Cognitive disorder

Prevalent; mild to severe impairment in majority on testing.


Acute movement disorders

Hemichorea, generalized chorea w/or w/o APL & w/or without basal ganglia infarctions


Myelopathy

Often longitudinal (>3 vertebral segments). Can be a/w neuromyelitis optica IgG (NMO-IgG/anti-aquaporin 4 Ab) or seronegative aggressive necrotic myelopathy. Dx: LP (pleocytosis lymphocytic or neutrophilic, ↑protein, glucose can be low), MRI spine, serum NMO IgG. Tx: Steroid pulse, rituximab (esp if NMO IgG +), plasmapheresis, IVIg. Arthritis Rheum 2009;60:3378.


Neuropathy

Variable. Typically axonal length dependent. Usually polyneuropathy, can also be multiple mononeuropathy, cranial (esp isolated trigeminal) or small fiber neuropathy. Dx: EMG/NCS, Tx: No trials. Steroids, IVIg, plasma exchange, or rituximab all reported.


Headache

Common. In isolation, does not correlate w/dz activity or flare. Tx: symptomatic. Brain 2004;127:1200.



RHEUMATOID ARTHRITIS

Neurol Clin 2002;20:151; Continuum 2008;14:120.

Epid: Prevalence ˜1/100; F > M; > w/↑ age.

Dx of rheumatoid arthritis (RA): Different criteria exist. Best known (“1987 ACR criteria”) gives 7 criteria; need 4 criteria for dx; Se 91%-94%, Sp 89% w/≥4 criteria for established disease (Arth Rheum 1988;31:315). These criteria not sensitive for early disease; updated criteria exist for early disease (Ann Rheum Dis 2010;69:1580).


























1987 ACR Criteria for Dx of RA


System Involved

Criteria


Musculoskeletal

1. Morning stiffness, ≥1 h × 6 wk


2. Arthritis ≥3 joints (PIP, MCP, wrist, elbow, knee, ankle, or MTP) simultaneously × 6 wk; observed by physician


3. Arthritis ≥1 hand joint (PIP, MCP, or wrist) × 6 wk


4. Symmetric joint arthritis × 6 wk


Cutaneous/derm

5. Rheumatoid (SQ) nodules observed by physician


Immunologic/serologic

6. ⊕ RF (Se 67%, Sp 79%). [anti-citrullinated peptide antibody has Se 67% & Sp 96%; part of newer criteria]


Radiographic

7. Typical Δ on PA hand/wrist radiographs c/w RA (erosions or periarticular decalcification)



Neurologic manifestations of RA

1. Cervical spine dz (tends to spare rest of vertebral column) in 25%-70% of pts w/advanced RA.

Atlantoaxial subluxation: Dislocation of atlas horizontally from the axis. Sx: asymptomatic → pain in neck & occiput → cord compression & myelopathy (often mild spastic quadriparesis, atrophy/sensory loss in hands/upper cervical dermatomes).

Cranial settling: Vertical upward migration of dens into foramen magnum. Sx: Dysfxn of pons/medulla w/drop attacks, sudden death; lower cranial neuropathies including trigeminal neuropathy & myelopathy.

Subaxial subluxation: Involvement of facets below C1/C2; radiographic “staircase spine.” Sx: Asymptomatic → dermatomal pain → myelopathy. Dx: Plain XR w/flexion/extension views. Cautions: r/o C-spine dz prior to intubation. Avoid maneuvers such as Dix-Hallpike in RA pts.

Rx: Cervical spine dz present in ˜70% of MRI but sx less frequent; unclear how to treat radiographic dz; cervical spine decompression in symptomatic dz.

2. Neuropathy

Compression or entrapment from synovitis/pannus/joint deformity; common in median, ulnar, peroneal, post tibial nerves. Rx: Mild → conservative, severe → consider surgery.

Vasculitic usu severe RA w/↑ ESR & ⊕RF; commonly mononeuritis multiplex or distal sensory; Rx: immunomodulation.

3. Myopathy: Consider in pts w/proximal wkns. Multiple causes: disuse, steroids, vasculitic; ˜5% polymyositis or dermatomyositis.

4. CNS dz: Meningitis [rare; (Neurology 2007;68:1079)]; Likely direct inflammation of CNS, usually in long-standing RF⊕ dz. Rare pachymeningitis W/u: LP (r/o infxn, DDx inflam CSF), MRI, consider meningeal bx. Rx: No RCT or consensus on optimal Rx, ? immunomodulation.


SJÖGREN SYNDROME

Semin Neurol 2014;34:425; Continuum 2008;14:120.

Epid: Prev: ˜0.6%. F:M – 10:1, average age at dx: 55 Can be 1° or 2° (w/other autoimmune dz; most common RA). 2/2 lymphocytic infiltration of salivary/lacrimal glands (large ddx).

Dx of Sjögren syndrome (SS): six criteria (Am. Europ. Consensus Group (AECG); Ann Rheum Dis 2002;61:554).

1°: 4/6 criteria (must incl. # 4 or 6) OR 3/4 objective crit. (#’s 3-6); Se 96%, Sp 94%.

2°: Presence of autoimmune dz + crit: # 1 or 2 & any 2 of #s. 3-5; Exclusions: H/o head/neck XRT, hep C, AIDS, lymphoma, sarcoidosis, GVHD, anticholinergic use (w/in t1/2 × 4).



















AECG Criteria for Dx of SS


System

Criteria


Cutaneous/glandular

1. Daily, bothersome dry eyes × 3 mo, recurrent sensation of sand/gravel in eyes, or use tear substitute >3×/day.


2. Daily dry mouth × 3 mo, recurrent/persistent salivary gland swelling, or frequent liquids to aid swallowing dry food.


3. ⊕Schirmer test or Rose Bengal score.


4. Minor salivary gland focal lymphocytic sialoadenitis on histopath (focus score ≥1).


5. ↓ whole salivary flow, diffuse sialectasias on parotid sialography, or abnormal salivary scintigraphy.


Serologic

6. ⊕ anti-Ro (SSA) or La (SSB)



Neurologic manifestations of SS

1. PNS: Most common findings: symmetric sensorimotor polyneuropathy & cranial neuropathy. No definite findings to distinguish from neuropathies of other causes.

Rx: No

RCT or consensus on optimal Rx for pts w/neuropathy & SS; IVIg often used for painful neuropathy while corticosteroids used for multiple mononeuropathies.


Other immune modulating agents like rituximab, infliximab, or plasmapheresis also used.

2. CNS: Longitudinal TM often w/⊕ NMO-IgG; W/u, Rx: same as for NMO (see Chapter 18). Also a/w recurrent meningoencephalitis (Neurology 1983;33:593).












































Peripheral Neuropathies Described in SS


Suspected pathology

Type/Sx

Also consider


Dorsal sensory root ganglionitis (lymphocytic infiltration)

Sensory ataxia: distal paresthesias → severe joint position/vibration loss

Paraneoplastic (SCLC, anti-Hu)

Trigeminal sensory: CN V distribution numbness; uni- or b/l

Mass lesion, MS, infarct

Autonomic: Adie pupils, orthostatic hypotension, hypohydrosis


Vasculitis

M. Multiplex: Sensory or motor dysfxn. in separate peripheral nerves

Lyme, hepatitis, TB, HIV, sarcoid, GCA, carcinomatous, mass lesion

Multiple cranial neuropathies


Small-fiber

Sensory w/o ataxia: painful distal dysesthesias & pain/temp loss


Demyelinating

Sensorimotor polyneuropathy. Dist > proximal

AIDP, myelopathy


(Adapted from Continuum 2008;14:124; Orig. data: Brain 2005;128:2518.)



SCLERODERMA (SCL)

Neurol Clin 2002;20:151.

Epidemiology (Primer Rheum Dis 1997;263). Rare; Incidence ˜17-19 cases/million/yr (some reports: up to ˜400 cases/million/yr). F > M; more common in middle age. ↑risk w/certain chemical (e.g., silica dust) & possibly virus exposures (homologous regions to those of auto-g in feline sarcoma virus, CMV, HIV, HSV-1, EBV).

Dx of Scl: One major & three minor criteria defined by ACR; must meet one major or two minor for dx. Se 97%, Sp 98% w/criteria (Arth Rheum 1980;23:581).



















ACR Criteria for Dx of Scleroderma


System

Criteria


Dermatologic

Major: Thickening/tightening/induration of skin on fingers extending prox. to MCP/MTPs

Minor:


1. Sclerodactyly—as above, but limited to fingers


2. Digit pitting/loss of finger pad (2/2 ischemia/prolonged Raynaud’s)


3. Bibasilar pulmonary fibrosis

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Aug 17, 2016 | Posted by in NEUROLOGY | Comments Off on Neurorheumatology

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