Herbert B. Newton, MD, FAAN
DESCRIPTION
Rheumatoid arthritis (RA) is a chronic multisystem immune complex disease. Extra-articular manifestations occur in 10–20% of patients. Neurologic complications usually occur in patients with moderate to severe RA and can involve the central and peripheral nervous systems (CNS, PNS), including the spine. Chronic synovitis of the spine typically occurs in the cervical region, with damage to the atlantoaxial complex. Complications affecting the PNS are frequent, with carpal tunnel syndrome (CTS; compression neuropathy of the median nerve) being most common.
EPIDEMIOLOGY
Incidence/Prevalence
- RA affects 1–2% of the population. Cervical spine involvement occurs in 30–50% of all RA patients. CTS occurs in 20–65% of RA patients. Vasculitis is noted in 5–15% of all patients. Central nervous system vasculitis and RA nodules are uncommon.
- All races and ethnic groups are affected. Onset is usually between 35 and 50 years of age, but can occur at any age. There is a female predilection, accounting for 75% of cases of RA.
RISK FACTORS
Atlantoaxial subluxation (AAS) is more likely in patients with RA of 10 years or more duration, seropositivity, erosive and deforming peripheral joint disease, and male gender. Compression neuropathies correlate with the severity of local synovitis. Vasculitis is more likely to occur in patients with long-standing RA; the incidence is higher in males.
Pregnancy Considerations
A hormonal role is suspected in disease expression, because there is an increased risk of RA in nulliparous women and a possible protective effect in women that use oral contraceptives.
Genetics
There can be a genetic predisposition for RA; first-degree relatives of seropositive patients are four times more likely to develop RA than controls.
GENERAL PREVENTION
There are no preventive measures available.
PATHOPHYSIOLOGY/ETIOLOGY
RA is mediated by interaction of autoantibodies, such as rheumatoid factor (IgM or IgG class), with circulating immunoglobulins. The immune complexes are composed of IgG combined with IgM or IgG anti-IgG antibodies. Deposition of the immune complexes into the joints and soft tissues induces activation of complement and other inflammatory pathways. AAS results from rheumatoid synovial tissue-induced laxity or destruction of the transverse ligament in combination with odontoid erosion. Subaxial subluxation can occur with rheumatoid involvement of the longitudinal ligaments, vertebral endplates, apophyseal joints, and intervertebral discs. Peripheral neuropathy results from entrapment, segmental demyelination, or rheumatoid vasculitis of the small-to-medium size vessels. Nerve entrapment syndromes arise from inflamed synovial sacs and can affect the median, ulnar, and posterior tibial nerves.
COMMONLY ASSOCIATED CONDITIONS
There is a higher incidence of vasculitic complications in RA patients with Felty's syndrome (i.e., RA, splenomegaly, neutropenia, anemia, and thrombocytopenia).
HISTORY
- Spine involvement: In most cases AAS is asymptomatic, despite the radiologic appearance. Cord and nerve compression is more likely to occur if there is an atlanto-dens interval of >9 mm. Compression of the second spinal nerve roots often causes localized neck pain with radiation to the occiput and scalp. Early signs of cervical radiculopathy are numbness and paresthesias in the glove-stocking distribution. Later signs of progression to cord compromise include myelopathy, lower motor neuron injury at the level of compression, and gait difficulty. Lhermitte's sign (sudden tingling parasthesias that radiate down the spine after cervical flexion) can occur at any stage. Intradural spinal nodules can cause nerve root compression, spinal stenosis, and cord compression.
- CNS involvement: Intraparenchymal rheumatoid nodules can cause encephalopathy, seizures, and obtundation. Cerebral vasculitis can present with seizures, stroke syndromes, encephalopathy, cranial neuropathies, ataxia, and hemorrhage (intracerebral or subarachnoid).
- PNS involvement: CTS typically presents with night numbness, paresthesias, and pain in the thumb, index, and middle fingers of the affected hand. In severe cases, atrophy of the thenar muscles may be present, along with thumb weakness, and retrograde pain up the forearm. Tinel's sign is often positive—reproduction of symptoms elicited by percussion of the median nerve on the volar aspect of the wrist. Phalen's sign may also be present—flexion of the wrist for at least 1 minute, eliciting numbness, tingling, or pain in the median nerve distribution. Tarsal tunnel syndrome presents as parasthesias, pain, and burning in the toes and soles of the feet. Weakness and atrophy of the intrinsic toe muscles may occur.
- Other PNS manifestations of RA include mild and severe forms of sensorimotor polyneuropathy, as well as a mononeuritis multiplex.
PHYSICAL EXAM
Variable depending on the specific region on involvement, as noted above.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Serological testing for rheumatoid factor and other autoantibodies is necessary.
Imaging
Initial Approach
- To evaluate spinal involvement, lateral radiographs of the cervical spine (flexion and extension views) are required to demonstrate subluxation. Lateral AAS can be demonstrated on open-mouthed, anteroposterior views. MRI can further evaluate bony spinal degeneration and screen for spinal cord compression. MRI is also indicated for patients with suspected basilar invagination for whom standard radiographs are inconclusive. A dynamic flexion–extension MRI may be able to reveal subtle instability patterns (e.g., atlantoaxial instability) of the spinal column.
- MRI (with or without MR angiography) can be helpful for the diagnosis of CNS vasculitis.
Diagnostic Procedures/Other
Somatosensory evoked potentials can evaluate the functional integrity of central sensory pathways. Disease processes affecting the cervical spinal cord may produce prolongation of wave and interwave latencies recorded along these pathways. Electromyography and sensory nerve conduction studies are the most accurate method to diagnose compression neuropathies and peripheral neuropathies. Sural nerve biopsies can be helpful if the diagnosis of vasculitis is unclear.
Pathological Findings
Pathological findings include synovial inflammation, formation of invasive rheumatoid synovial tissue or pannus, and vasculitis.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is broad and includes other causes of myelopathy, cervical subluxation disorders, CNS and PNS vasculitis, entrapment neuropathies, and peripheral neuropathy. RA must be distinguished from degenerative osteoarthritis and from deforming inflammatory arthritis associated with other connective tissue disorders.
MEDICATION
First Line
Pharmacotherapy of neurological manifestations of RA consists of a combination of corticosteroids and a cytotoxic agent, such as oral cyclophosphamide or methotrexate. The corticosteroid is started at 60–100 mg/day and then tapered over several weeks. Monotherapy with one of the cytotoxic agents is then continued for long-term maintenance therapy. The efficacy of other immunosuppressive therapies such as plasmapheresis and IVIG is unknown.
ADDITIONAL TREATMENT
General Measures
- For patients with cervical spine disease, neck pain without neurologic features tends to be self-limited and usually improves. In the absence of cord compression, conservative management is appropriate with anti-inflammatory or disease modifying anti-rheumatic medications, physical therapy, and soft cervical collars.
- Rheumatoid vasculitis is a potentially life-threatening problem that requires high-dose corticosteroids in combination with a cytotoxic drug such as oral cyclophosphamide or methotrexate.
Additional Therapies
Soft cervical collars can stabilize the spine and reduce neck pain in patients with severe AAS. Local corticosteroid injections and splints may be of benefit for compression neuropathies.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Simple neck traction may be helpful in patients with severe AAS or subaxial subluxation. Physical and occupational therapy should be considered for patients with myelopathy, peripheral neuropathy, and other forms of weakness.
SURGERY/OTHER PROCEDURES
- For patients with AAS, surgical intervention with C1–2 arthrodesis stabilizes the atlantoaxial complex and usually eliminates occipital pain. The indications for surgery include basilar invagination, neurologic abnormality with spinal instability, intractable neck and head pain, vertebral artery compromise, and asymptomatic spinal cord compression on MRI.
- Surgical release of compression neuropathy may be indicated when there is a significant motor or sensory abnormality and evidence of denervation on neurophysiologic testing.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Admission is uncommon except in cases of acute neurological deterioration where the diagnosis is indeterminate or therapeutic intervention is necessary. Patients with CNS or PNS vasculitis are the most likely subgroup to require admission, usually for weakness, seizures, encephalopathy, gait dysfunction, or other acute complications.
Discharge Criteria
Variable depending on specific complication.
FOLLOW-UP RECOMMENDATIONS
Variables will be depending on the specific syndrome involved.
Patient Monitoring
Rheumatoid arthritis patients that should be screened for AAS with radiographic evaluation include those with posterior skull and/or neck pain and stiffness, and patients with long-standing erosive RA in whom radiographs have not been done within the previous 2 or 3 years. Serial neurological examinations and appropriate follow-up testing (e.g., MRI of the brain or spine, electromyography and nerve conduction testing) will be necessary.
PATIENT EDUCATION
PROGNOSIS
The best course of management is to prevent significant morbidity in RA. Aggressive immunosuppressant therapy will reduce the neurological complications of RA. The overall 5-year mortality rate of RA patients with radiographic evidence of cervical subluxations (with or without neurologic symptoms) is similar to severe RA patients without cervical involvement. The risk of developing upper cervical spinal cord compression secondary to anterior AAS is increased by male sex, anterior subluxation >9 mm, and coexistent atlantoaxial impaction. There is a higher incidence of fatality with basilar invagination. The prognosis of rheumatoid vasculitis is poor. Independent variables that best predict mortality include cutaneous vasculitis, multifocal neuropathy, and depressed C4 level.
COMPLICATIONS
Variables as noted above.
