Concurrent MS and Amyotrophic Lateral Sclerosis
Concurrent MS and Amyotrophic Lateral Sclerosis
A 37 year old man presented with a left VIth cranial nerve palsy and nystagmus that improved on a brief course of steroids. A diagnosis of possible MS was entertained. Two years later, he experienced a subacute episode of bilateral leg weakness that was steroid responsive, prior to which he had a several month history of gradual decline in cognition, decreased visual acuity, widespread fasciculations with asymmetric upper limb weakness, and bilateral appendicular and truncal ataxia. The subsequent 12 months were notable for the evolution of debilitating lethargy and fatigue, and progressive dysarthria and dysphagia. He died of respiratory compromise at the age of 40.
Formalin-fixed paraffin-embedded sections of pre-frontal and sub-frontal cortex, hippocampus, cerebellum, pons, low and high cervical and thoracic, lumbar and sacral spinal cord were stained with Luxol Fast Blue and Cresyl Violet (LBCV), Palmgren silver, Proteolipid protein (PLP), CD68 (PG-M1), CD3, and TDP-43 antibodies (Figure 1). Using the LCBV stain, anterior horn cells (AHC) were identified quantified and compared to counts from two age- and sex-matched controls using established methods.
(Enlarge Image)
Figure 1.
Neuropathological features of concurrent MS and ALS. Left hemispheric leukocortical (within box) and periventricular lesions (arrow) (A). PLP staining of leukocortical plaque in A (inlay) demonstrating demyelination spanning grey and white matter (B), PG-M1 staining showing macrophage infiltration and microglia activation (C), and perivascular cuffing with cells resembling lymphocytes (D) within same lesion. Gross (E) and PLP-stained section (F) of pons (with cerebellum) demonstrating periventricular and parenchymal demyelination. PLP-stained section of demyelinated lesion in dorsal column of cervical spinal cord (arrow) (G) with diffuse microglia activation extending beyond lesional borders (PG-M1 staining) (H). Gross view of thinned and discolored ventral roots of lower cervical cord from case (I) compared to control (J). LBCV section of lumbar cord demonstrating significant loss of anterior horn cells in the case (K) compared to control (L). TDP-43 staining demonstrating intracytoplasmic neuronal inclusions in anterior horn cells in lumbar spinal cord (arrowheads) in case (M) compared to nuclear neuronal staining of the same area in a control (N).
Pathological confirmation of MS was supported by evidence of multiple discrete areas of inflammatory demyelination in prototypic locations, including cortex (subpial, leukocortical), periventricular region, corpus callosum (Figure 1A, B), pons (Figures 1E, F), cerebellar peduncle, and lateral and posterior columns of the spinal cord (Figure 1G). Microscopically, lesions were characterized by infiltration of macrophages in the epicenter of acute lesions and the border of chronic active lesions (Figure 1C); perivascular lymphocytic cuffing was noted in both (Figure 1D). Lesions of all stages of demyelinating activity were observed, with acute lesions being predominant. An extensive demyelinating lesion involving all layers of the hippocampus was the likely substrate for the patient's significant cognitive difficulty during life. Axonal density appeared to be mildly reduced in plaques when compared to surrounding normal appearing white matter. Meningeal inflammation with monocytic infiltrates was observed often without underlying subpial demyelination. No evidence of TDP-43 inclusions were noted in any of the MS lesions studied.
There were several classic features of ALS pathology in areas distinct from MS plaques. Ventral nerve roots were discoloured and selectively thinned (Figure 1I), and a marked reduction (approximately 75%) of anterior horn cells at multiple serial lumbosacral cord levels when compared to controls was observed (Figure 1K, L). Microglial activation was noted in i) layer V of the motor cortex (where Betz cells were sighted), and ii) at various levels of the spinal cord (Figure 1H). Corticospinal tract axonal loss appeared to be size selective, with large fibres particularly affected - a finding previously noted in ALS, and opposite to that found in MS (where small fibres are preferentially lost). Anterior horn cells in both cervical and lumbar cord demonstrated intracytoplasmic TDP-43 positive inclusions (Figure 1M), with no evidence of such inclusions in the cortical and deep gray matter regions examined. FUS staining was negative in all areas studied.
Case Presentation
A 37 year old man presented with a left VIth cranial nerve palsy and nystagmus that improved on a brief course of steroids. A diagnosis of possible MS was entertained. Two years later, he experienced a subacute episode of bilateral leg weakness that was steroid responsive, prior to which he had a several month history of gradual decline in cognition, decreased visual acuity, widespread fasciculations with asymmetric upper limb weakness, and bilateral appendicular and truncal ataxia. The subsequent 12 months were notable for the evolution of debilitating lethargy and fatigue, and progressive dysarthria and dysphagia. He died of respiratory compromise at the age of 40.
Pathology
Formalin-fixed paraffin-embedded sections of pre-frontal and sub-frontal cortex, hippocampus, cerebellum, pons, low and high cervical and thoracic, lumbar and sacral spinal cord were stained with Luxol Fast Blue and Cresyl Violet (LBCV), Palmgren silver, Proteolipid protein (PLP), CD68 (PG-M1), CD3, and TDP-43 antibodies (Figure 1). Using the LCBV stain, anterior horn cells (AHC) were identified quantified and compared to counts from two age- and sex-matched controls using established methods.
(Enlarge Image)
Figure 1.
Neuropathological features of concurrent MS and ALS. Left hemispheric leukocortical (within box) and periventricular lesions (arrow) (A). PLP staining of leukocortical plaque in A (inlay) demonstrating demyelination spanning grey and white matter (B), PG-M1 staining showing macrophage infiltration and microglia activation (C), and perivascular cuffing with cells resembling lymphocytes (D) within same lesion. Gross (E) and PLP-stained section (F) of pons (with cerebellum) demonstrating periventricular and parenchymal demyelination. PLP-stained section of demyelinated lesion in dorsal column of cervical spinal cord (arrow) (G) with diffuse microglia activation extending beyond lesional borders (PG-M1 staining) (H). Gross view of thinned and discolored ventral roots of lower cervical cord from case (I) compared to control (J). LBCV section of lumbar cord demonstrating significant loss of anterior horn cells in the case (K) compared to control (L). TDP-43 staining demonstrating intracytoplasmic neuronal inclusions in anterior horn cells in lumbar spinal cord (arrowheads) in case (M) compared to nuclear neuronal staining of the same area in a control (N).
Pathological confirmation of MS was supported by evidence of multiple discrete areas of inflammatory demyelination in prototypic locations, including cortex (subpial, leukocortical), periventricular region, corpus callosum (Figure 1A, B), pons (Figures 1E, F), cerebellar peduncle, and lateral and posterior columns of the spinal cord (Figure 1G). Microscopically, lesions were characterized by infiltration of macrophages in the epicenter of acute lesions and the border of chronic active lesions (Figure 1C); perivascular lymphocytic cuffing was noted in both (Figure 1D). Lesions of all stages of demyelinating activity were observed, with acute lesions being predominant. An extensive demyelinating lesion involving all layers of the hippocampus was the likely substrate for the patient's significant cognitive difficulty during life. Axonal density appeared to be mildly reduced in plaques when compared to surrounding normal appearing white matter. Meningeal inflammation with monocytic infiltrates was observed often without underlying subpial demyelination. No evidence of TDP-43 inclusions were noted in any of the MS lesions studied.
There were several classic features of ALS pathology in areas distinct from MS plaques. Ventral nerve roots were discoloured and selectively thinned (Figure 1I), and a marked reduction (approximately 75%) of anterior horn cells at multiple serial lumbosacral cord levels when compared to controls was observed (Figure 1K, L). Microglial activation was noted in i) layer V of the motor cortex (where Betz cells were sighted), and ii) at various levels of the spinal cord (Figure 1H). Corticospinal tract axonal loss appeared to be size selective, with large fibres particularly affected - a finding previously noted in ALS, and opposite to that found in MS (where small fibres are preferentially lost). Anterior horn cells in both cervical and lumbar cord demonstrated intracytoplasmic TDP-43 positive inclusions (Figure 1M), with no evidence of such inclusions in the cortical and deep gray matter regions examined. FUS staining was negative in all areas studied.