Clinical Approach to Myelopathy Diagnosis

1.The Concepts of Myelopathy and Myelitis

Myelopathy

Any pathologic process that leads to spinal cord dysfunction.

Etiologic factors associated with myelopathies comprise two major groups of disorders:

1.Inflammatory myelopathies, or myelitis, which are associated with inflammation is the primary pathogenic driver of spinal cord injury

2.Non-inflammatory myelopathies, in which pathologic processes of the spinal cord, those are not related to inflammation (myelopathy but not myelitis)

Fig 1. The diagnostic spectrum of myelopathies comprises a broad group of clinical conditions associated with diverse pathogenic mechanisms categorized as inflammatory and noninflammatory.

2.The Diagnosis Spectrum of Myelopathies

In an extensive study of 1193 patients diagnosed with transverse myelitis, 65% of cases were associated with inflammatory myelopathies, and 35% were related to noninflammatory pathologies.

(Murphy OC, et al. Identification of specific causes of myelopathy in a large cohort of patients initially diagnosed with transverse myelitis. J Neurol Sci 2022; 442:120425)

Based on this classification. after structural causes are excluded, immune-mediated mechanisms appear to cause myelopathy frequently.

Fig 2. Overview of the spectrum of myelopathies initially diagnosed as transverse myelitis, indicating the final etiologic diagnosis based on a single-center cohort of 1193 patients.

What have we learned from that study?

It is important to determine the etiological diagnosis of myelitis (due to diverse causes).

No everything that hyperintense in the spinal cord is transverse myelitis (TM).

Myelitis (inflammation)the heterogenous group of myelopathies with different etiologies.

Almost 30% of cases diagnosed as TM are misdiagnosed.
Vascular myelopathies are frequently misdiagnosed as TM.

3.Clinical Approach to the Patient with Myelopathy

3.1. Clinical History

3.1.1. Symptoms recognition:

Bilateral greater than unilateral sensory and/or motor symptoms (weakness, numbness, tingling, dysesthesias such as perception of the chest or abdominal “tight banding” sensation such as abdominal tightness)
The distribution and pattern of weakness in both upper and lower extremities
Bladder, bowel, and/or sexual dysfunction
The presence of flaccid or spastic muscle tone (more stiffness in the legs) and symmetry or asymmetry of weakness distribution
Neck and/or back pain in association with neurologic symptoms, particularly if the patient had preceding trauma or if pain is exacerbated by neck flexion or extension (Lhermitte sign)
Sensory symptoms distribution and sensory level across the trunk (often more reliable as a symptom than a sign) and (positive as well as negative sensory symptoms)
Neurogenic claudication (suggests cauda equina pathology rather than a lower cord lesion)
Sensory ataxia (can also occur with peripheral nervous system disorders)
Dyspnea when lying flat (C3-C5 lesion)
The +/- of radicular or peripheral nerve symptoms
The +/- of autonomic dysfunction symptoms
The +/- of transitory recrudescence of symptoms caused by heat, fever, or exercise (Uhthoff sign)

3.1.2. Temporal Profile of Symptom Presentation

hyperacute (≤6 hours from onset to nadir) — > spinal cord stroke, hemorrhage, trauma,
acute (6 to 48 hours) — > viral infections (acute flaccid paralysis)
subacute (2 to 21 days) — > Autoimmune-associated and demyelinating myelopathies, space occupying lesions (epidural abscess)
chronic evolving (>21 days) — > sarcoidosis-associated, dural AVF, metabolic diseases, hereditary spastic paraparesis, motor neuron disease
relapsing-remitting profiles — > multiple sclerosis and NMOSD

Fig. 3 Distribution of temporal profile of symptom evolution in patients with inflammatory and noninflammatory myelopathies.

3.1.3. Triggering Factors of Myelopathy
Identifying potential triggering factors or preceding symptoms may help to identify specific etiologies

e.g., systemic illness, environmental risk factors, traveling history, exposure to infected people, seasonal infection, and virus circulation, intense exercising, extreme physical activities, use of recreational drugs, dietary restrictions, detailed comorbid medical history.

3.2. Comprehensive physical and neurological examination

Weakness pattern (paraparesis or quadriparesis or monoparesis)
Muscle tone — > flaccid or spastic
Reflexes — > hypo-or hyper, plantar responses, clonus, other pathological reflexes
Cranial nerves — > optic nerve and other CNs
Root or cauda equina involvement?
Meningeal signs +/-?
Gait disturbances (stiff legs, circumduction, scissoring, sensory ataxia with positive for Romberg sign
CNS involvement
Signs of systemic infections

4. LABORATORY APPROACH IN THE ASSESSMENT OF MYELOPATHY

4.1. Biomarkers in Autoimmune Inflammatory Myelopathies

Blood and CSF laboratory studies are critical for establishing an accurate diagnosis of inflammatory myelopathy, not only for determining the role of inflammation as a pathogenic mechanism but also for providing a specific diagnosis in some types of myelitis.

Testing of the autoantibodies should be on serologic studies rather than CSF because such autoantibodies are less frequent in CSF samples.

Other serologic studies for identifying systemic rheumatologic disorders should obtain in selected conditions with myelitis.

4.2. Common laboratory investigation for clinically suspicious of myelitis

Serum

Autoimmunity: Anti-AQP4 (aquaporin 4), MOG
Rheumatology: ANA, SS-A, SS-B, ANCA, ACL
Infections: PCR for West Nile Virus, Lymes, Syphilis, TB, Flavivirus, HIV, HTLV-1, and others
Metabolic: B12, Zinc, Copper, Methylmalonic acid, Plasma and urine amino acids and others
Vascular risks: Lipid panel, Lipoprotein A, Apolipoprotein B, and coagulation panel and others
Genetic disorders: very long chain fatty acid, long chain fatty acid, and others

CSF analysis

Assessment of CSF is one of the most valuable diagnostic tools available to differentiate inflammatory and noninflammatory myelopathies.

The absence of inflammatory changes in the CSF may direct the clinician to consider noninflammatory etiologies when evaluating myelopathies.

Most autoimmune inflammatory myelopathies are associated with lymphocytic pleocytosis

Neutrophilic pleocytosis can be seen in myelopathies associated with neuromyelitis optica, rheumatologic disorders such as Behçet disease, or granulomatous diseases such as sarcoid-associated myelopathy.

Oligoclonal bands are not specific to demyelinating disorders because oligoclonal bands can be present in autoimmune, paraneoplastic, and infectious or postinfectious neurologic disorders.

The search for infection to be based on the patient’s clinical profile and epidemiologic and medical risk factors.

5. Diagnostic Neuroimaging in the Evaluation of Myelopathy

Diagnostic imaging studies evaluate lesion features, magnitude, and extension of pathology within the spinal cord (e.g., spinal cord MRI), structural abnormalities in the spine (e.g., CT of the spine), or vascular abnormalities of the blood supply to the spinal cord (CT angiography [CTA] or spinal angiography).

5.1. MRI

Cervical, thoracic, and lumbar spine MRI with and without gadolinium is used:

to characterize the spinal, vertebral, disk, and spinal cord pathologies contributing to inflammatory and noninflammatory myelopathies.
to characterize number and topography of lesions, which facilitates the identification of different types of myelopathies.
to review the relationship of the spinal cord, nerve roots, and cauda equina with the spine vertebral bodies and disks.

Contrast-enhancing spinal cord studies provide:

to exclude intrinsic T1 hyperintensities, such as those caused by blood products, fat accumulation, or residual lesions.
to specify enhancement of focal and longitudinally extensive lesions (in inflammatory type) and their appearance such as homogeneity (focal, patchy, or ring-enhancing).
to search for leptomeninges or extra-axial structures, such as nerve roots and the dura mater, involvement.

The use of diffusion-weighted (DW) spinal cord imaging is limited by artifacts and distortions, and its use is still unreliable.

5.2. CT

Spine CT and CT myelography are used when MRI is contraindicated because of metallic implants and medical devices or there is a need for emergency assessment of the spine and vertebral body structures in the

setting of trauma, spondylotic myelopathy, metastatic disease, or structural myelopathies.

to evaluate the relationship between vertebral bodies and disk structures with the spinal cord, spinal nerve roots, and blood vessels.
to assess extra-axial spinal lesions, compression produced by epidural hematomas, abscesses, ossification of the posterior longitudinal ligament and ligamentum flavum, disk calcifications, hypertrophy of facet joints, and marginal osteophytes.
CT myelography is for review of the spinal canal and the relationship of the cord with extra-axial spinal or dural structures.

5.3. Spine Angiography

Spine angiography is the best approach to evaluate abnormalities of the vascular supply to the spinal cord.

CTA and magnetic resonance angiography (MRA) are widely used imaging techniques in the evaluation of vascular anatomy.

Spine MRA preassessment of patients with suspected dural AVFs and AVMs helps minimize procedure time and radiation exposure by quick identification of specific areas of interest.

They have limitations in identifying vascular pathology and associated vascular myelopathies especially for the vascular supply of the thoracolumbar region

Spinal digital subtraction angiography (DSA) is the standard diagnostic approach:

for evaluating the spinal cord’s vascular anatomy and assessing abnormalities such as dural AVFs and spinal AVMs.
for the identification and characterization of these vascular abnormalities and providing paths for interventional endovascular treatments or planning for surgical interventions.

6. An integrative approach to diagnosis of myelopathy

The clinician should integrate the clinical history, the epidemiologic and risk factor information, the laboratory testing, biomarkers, and neuroimaging results to achieve a precise diagnosis.

6.1. Inflammatory Myelopathies

Inflammatory myelopathies constitute the most frequently occurring myelopathies and have assorted immune-mediated disease mechanisms associated with them.

The mechanisms of immune-mediated disease include:

demyelinating disease associated with multiple sclerosis
autoimmune myelopathies associated with specific antibodies against neural antigens (e.g., NMO, MOG-associated disorders, paraneoplastic disorders)
autoimmune myelopathies related to systemic autoimmune or rheumatologic diseases (e.g., Sjögren syndrome, systemic lupus erythematous)
infection-associated myelopathies
other inflammatory myelopathies caused by the use of medications that target immune pathways that trigger autoimmune responses against the spinal cord such as immune checkpoint inhibitors used in cancer treatment or tumor necrosis factor inhibitors in the treatment of rheumatologic disorders

6.2. Noninflammatory Myelopathies

Common etiological groups of noninflammatory myelopathies are (1) vascular (2) structural and (3) metabolic.

The correct distinction between myelitis and noninflammatory myelopathies is important because their misdiagnosis frequently leads to unnecessary and potentially harmful immunologic therapies.

Previous studies showed that approximately 20% to 25% of cases of “transverse myelitis” were associated with vascular etiologies, and almost 10% were structural myelopathies.

Vascular myelopathies

Vascular myelopathies comprise two subgroups of spinal cord disorders: Acute and Chronic

An acute group associated with acute ischemic injury produced by spinal cord strokes

A bimodal age distribution characterizes the epidemiology of spinal cord strokes seen in young and older adults who are presenting as hyperacute onset.
Clinical predictors for acute ischemic spinal cord stroke diagnosis include a hyperacute temporal profile, new onset of back pain, flaccid weakness, and extensive longitudinal lesions on MRI.
Spinal cord imaging showing a lesion involving specific vascular distribution, a spinal cord watershed area, or selective involvement of the anterior horns of the cord is highly suggestive of acute vascular injury or ischemic stroke.

Another with chronic, evolving vascular malformations such as dural AVFs and AVMs.

Patients with dural AVF and AVM present with chronic onset more frequently male older than 50 years.
Clinical predictors of a diagnosis of chronic evolving vascular myelopathies associated with dural AVF and AVM include older age, male sex, chronic evolution of symptoms, bladder, or bowel dysfunction, worsening symptoms with exercise, flaccid weakness, and involvement of the conus medullaris.
Imaging features such as venous congestion, venous hypertension, and extensive longitudinal lesions in men older than 50 years are frequently associated with chronic vascular abnormalities such as dural AVFs and AVMs.

Structural myelopathies

Structural causes of myelopathy are frequently associated with

cervical spondylosis
disk herniations
spinal cord syrinx

Less frequent conditions are, epidural lipomatosis, Chiari malformation with cord compression, dorsal arachnoid web, and spinal cord herniation.

Clinical predictors for an accurate diagnosis of spondylotic myelopathy include

age,
male sex,
chronic evolution of symptoms
presence of central signal intensity abnormalities in axial views of the cervical spinal cord MRI
associated extra-axial compression by ossification of the posterior longitudinal ligament and ligamentum flavum, disk calcification, hypertrophy of facet joints, and marginal osteophytes

Acute-onset structural myelopathies related to cord compression are associated with extradural hematomas and epidural abscesses.

Metabolic myelopathies

Common causes include vitamin B12 deficiency producing subacute combined degeneration, copper deficiency, and mitochondrial disorders.

History clues in the assessment of metabolic myelopathies

vegetarian diet
previous gastrointestinal surgery including bariatric surgery
recreational use of nitrous oxide
chronic use of medications such as metformin, histamine receptor 2 antagonists (H2 blockers) and proton pump inhibitors

Common laboratory test for suspected metabolic myelopathies:

vitamin B12 concentration
methylmalonic acid
homocysteine
copper
zinc
vitamin E
plasma and urine amino acids

7. Summary

Myelopathies comprise a broad group of clinical conditions associated with diverse pathogenic mechanisms categorized as inflammatory and noninflammatory.

A comprehensive diagnostic approach in myelopathies should include the clinical history and neurologic assessment combined with the use of neuroimaging techniques and biomarkers of disease such as immune biomarkers in blood and CSF analysis all of which will provide a precise etiologic diagnosis to facilitate effective treatment leading to better outcomes as well as for prevention, neurologic rehabilitation, and functional recovery.

Fig. 4 Summary of the strategic approach for establishing a precise etiologic diagnosis of myelopathies

References

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