History.
Mr. Woo was a 60-year-old ex-drinker who presented with a 5-year history of relapsing-remitting, asymmetrical tetraplegia, paresthesia, and unsteady gait.
He has a history of psoriasis and vitamin B12 deficiency on replacement.
Physical examination.
Saccades normal; no nystagmus.
Normal limb power; mild right UL pronation without drift; normal tone; generalized hyperreflexia with bilateral Hoffman sign; flexor Barbinski response; no ankle clonus.
Left limb ataxia.
Broad-based gait with normal Romberg’s.
Investigations.
Initial MRI 5 years ago for asymmetrical tetraplegia: a heterogeneous T2-hyperintense intramedullary cervical lesion spanning 2 contiguous vertebral body segments with peripheral rim enhancement and cord expansion.
Cervical cord biopsy: reactive changes and glial cell infiltration.
Serial MRI over 5 years: the cervical lesion showed interval resolution followed by progression with transient reappearance of contrast enhancement and cord expansion; new contrast-enhanced white matter lesions at the medulla, pons, cerebellar peduncles, and periventricular regions involving the corpus callosum.
LP: WCC 2 & 5 respectively; protein and glucose normal; oligoclonal band negative.
VEP: LE prolonged latency (no correlating visual symptoms). MRI orbit: unremarkable. OCT: tracing report.
anti-NMO / MOG negative (transfected cell immunofluorescence assay).
Progress.
Treated with multiple lines of immunotherapy (pulse steroids, oral steroids, MMF) with continued neurological deterioration and radiological relapses.
Thought process.
Syndrome:
- Chronic, relapsing-remitting cervical, brainstem (medulla, pons), and cerebellar syndrome.
Localization:
- Multifocal CNS involvement: cervical cord, brainstem, cerebellum, periventricular white matter (including corpus callusum).
Etiology:
- Autoimmune
- Seronegative CNS demyelinating disease
- Clinical: subacute cervical, brainstem, and cerebellar syndromes were characteristic of AQP4-NMOSD; initial presentation was relapsing (left hemiparesis followed by right hemiparesis over 1 month), and later, a more secondary progressive clinical course was described by the patient (rare in AQP4-NMOSD, a red flag); DDx poorly characterized attack history noting focal left ataxia corresponding to the new left cerebellar peduncle lesion.
- MRI: an initial non-longitudinally extensive but transverse single lesion with peripheral enhancement was less typical of AQP4-NMOSD; non-specific brainstem and cerebellar peduncle involvement, not the classical periventricular regions; subcortical periventricular white matter lesion with corpus callosum involvement may be suggestive of AQP4-NMOSD; relapsing and remitting T2 lesions with incomplete resolution, transient contrast enhancement and mass effect, followed by atrophy may be suggestive of AQP4-NMOSD; new, apparently asymptomatic brain and cord lesions (a red flag) vs symptomatic lesions not adequately characterized by the patient.
- Antibody testing: suboptimal testing (not live cell-based assay).
- Encephalomyelitis (GFAP, classically presents with encephalitis, meningitis, and myelitis; MRI: perivascular radial enhancement in 50%).
- Systemic autoimmune disease (parenchymal neurologic Behçet disease; typically 5-10 years after disease onset; oral or genital ulcers not specifically explored; most commonly involves brainstem structures and extending upwards [progression as in this case; overlap in the appearance of brainstem lesions compared with AQP4-NMOSD and MOGAD]; LETM can occur; bagel sign absent: cord T2 axial thick hyperintense rim and central hypointense core; lesions show heterogenous enhancement and hemorrhage)
- Seronegative CNS demyelinating disease
- Neoplastic
- Low-grade lymphoma (secondary progressive neurological deterioration, fleeting contrast-enhanced lesions with mass effect; diffuse large B-cell primary CNS lymphoma is commonly intraparenchymal, supratentorial, T1 / T2 hypointense, FLAIR hyperintense, DWI restriction, homogenous enhancement).
- Low-grade glioma (typically lower median age of onset (35-45); less likely multifocal lesions; predilection for the frontal lobe; cortical involvement likely; T2-FLAIR mismatch sign for astrocytoma).
- Metabolic
- Vitamin B12 deficiency (known vitamin B12 deficiency on treatment; apparently adequate serum levels, functional assays with MMA / homocysteine yet to be done; suspected “inverted V” sign at the cervical cord lesion after resolution of cord expansion and contrast enhancement, may be part of the post-inflammation atrophic process; unable to account for the contrast-enhanced lesions with mass effect and mild CSF pleocytosis).
- Genetic
- X-linked adrenomyeloneuropathy: third to fifth decade of life; progressive spastic paraparesis and peripheral neuropathy; 60% have cerebral demyelination; MRI typically shows cord atrophy without signal changes; unable to account for the contrast-enhanced lesions with mass effect.
- Alexander disease: adult-onset form; fourth to fifth decade of life; mimics MS with bulbar weakness, ataxia, sleep disturbances, autonomic dysfunction, psychiatric symptoms; slow progression, live for decades after diagnosis; MRI: white matter T2 hyperintensities starting in the frontal lobes and spreading backwards +/- basal ganglia and thalamus, periventricular contrast enhancement.
- Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: adult-onset form; slowly progressive paraplegia, spasticity, sensory ataxia, bulbar weakness; exacerbation during febrile illness or metabolic stress; MRI: symmetrical T2 hyperintensities in the white matter tracts (cerebellar peduncles, pyramidal tracts, dorsal column, medial lemniscus); elevated CSF lactate +/- serum lactate; lactate peak on MRS.
- Adult polyglucosan body disease: fourth to seventh decade of life; slowly progressive weakness, spasticity, bulbar symptoms, neurogenic bladder, neuropathy; MRI: cerebral and cerebellar atrophy, diffuse leukoencephalopathy, medullary and spinal cord atrophy without signal changes.
Learning points:
- A clear delineation of the disease progression in terms of both clinical and radiological changes over time is essential to profile the phenotype. Flexibility in thinking is important as well, since prior clinical impression was fixated on the apparent primary progressive course of the disease, which contradicted the relapsing-remitting radiological progression.
Next steps.
Repeat NMO / MOG antibody testing with CBA. GFAP antibody testing.
Serial MRI: pattern of disease progression; lactate peak on MRS (lymphoma or mitochondrial disease).
Contrast CT TAP: systemic lymphoma involvement.
Review timing of repeating LP (confirm inflammatory CSF, cytology).
Check MMA / homocysteine (exclude functional vitamin B12 deficiency).
Screen for VLCFA.