Pathology of Motor Neuron Disorders 

Motor neuron disorders (MNDs) are a clinically and pathologically heterogeneous group of neurologic diseases, characterized by progressive degeneration of motor neurons, and they include both sporadic and hereditary diseases. There are 2 sets of motor neurons that can be affected: (1) the upper motor neurons (UMNs), which originate from the primary motor cortex of the cerebrum (precentral gyrus) and possess long axons forming corticospinal and corticobulbar tracts, and (2) the lower motor neurons (LMNs), which originate in the brainstem (cranial nerve [CN] motor nuclei) and spinal cord (anterior horn cells) and directly innervate skeletal muscles. Motor neuron disorders (MNDs) can be classified into those affecting primarily the UMNs, LMNs, or both, and the nomenclature is used accordingly. The patient's symptoms vary depending on which set of motor neurons is involved.

In this review, the following conditions will be discussed:

• Amyotrophic lateral sclerosis (ALS)
• Primary lateral sclerosis (PLS)
• Hereditary spastic paraparesis (HSP)
• Progressive bulbar palsy (PBP), including hereditary forms
• Spinal muscular atrophy (SMA)
• X-linked spinobulbar muscular atrophy (SBMA; Kennedy disease)
• Postpolio syndrome (PPS)

Amyotrophic lateral sclerosis

ALS, also known as Lou Gehrig disease, is the most common neurodegenerative disease of adult onset involving the motor neuron system. It is a fatal disorder and is characterized by progressive skeletal muscle weakness and wasting/atrophy (ie, amyotrophy), spasticity, and fasciculations as a result of degeneration of the UMNs and LMNs, culminating in respiratory paralysis. There are 3 types of ALS: sporadic, familial, and Western Pacific ALS with/without Parkinsonism-dementia complex (ALS/PDC).

The majority of ALS cases are sporadic, and only 5-10% of cases are considered to be familial. Approximately 20% of cases of familial ALS are due to a mutation in the Cu/Zn superoxide dismutase 1 (SOD1) gene. Western Pacific ALS occurs on the islands of Guam (Guam ALS), on the Kii peninsula of Japan, and in Western New Guinea. It is now clear that a subset of ALS cases shows features of frontotemporal lobar degeneration (FTLD) (ie, FTLD-MND/ALS).

Primary lateral sclerosis

PLS is a rare, idiopathic, neurodegenerative disorder that primarily involves the UMNs, resulting in progressive spinobulbar spasticity. Because substantial numbers of cases initially diagnosed as PLS would be reclassified as ALS as the disease progresses, Pringle et al suggest a disease duration of at least 3 years is required to render this diagnosis clinically.^[1] There is still debate regarding whether PLS is a distinct pathologic entity or whether it represents one end of a clinical spectrum of ALS.

Hereditary spastic paraparesis

HSP, also known as familial spastic paraplegias or Strumpell-Lorrain disease, is a clinically and genetically heterogeneous group of hereditary disorders that are characterized by slowly progressive spastic paraparesis. This condition is classified clinically as either a "pure" ("uncomplicated") or "complicated" form, depending on whether the paraparesis exists in isolation, or with other major clinical features. There is significant overlap in clinical characteristics between "pure" HSP and PLS.^[2] Genetically, HSPs are classified by the mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and are subdivided by chromosomal locus or causative gene. "Pure" autosomal dominant HSP is the most common form.

Progressive bulbar palsy

PBP is a progressive degenerative disorder of the motor nuclei in the medulla (specifically involving the glossopharyngeal, vagus, and hypoglossal nerves) that produces atrophy and fasciculations of the lingual muscles, dysarthria, and dysphagia. In adults, because most of the cases presenting with these "pure" bulbar symptoms represent "bulbar-onset" ALS and eventually develop widespread symptoms typically seen in ALS, some authors consider this disorder to be a subset of ALS.

Infantile PBP is a rare disorder that occurs in children and presents as the following 2 phenotypically associated forms: Brown-Vialetto-Van Laere syndrome (pontobulbar palsy with deafness) and Fazio-Londe disease. Brown-Vialetto-Van Laere syndrome is characterized by bilateral sensorineural deafness that is followed by CN VII, CN IX, and CN XII palsies, whereas Fazio-Londe disease causes progressive bulbar palsy without deafness. Both of these disorders are genetically heterogeneous.

Spinal muscular atrophy

SMA comprises a large group of genetically determined neuromuscular disorders that are characterized by progressive degeneration of spinal LMNs (ie, alpha motor neurons in the anterior horns) accompanied by amyotrophy, with no evidence of sensory or pyramidal tract involvement. This condition is genetically heterogeneous with autosomal recessive (most common), autosomal dominant, and X-linked recessive modes of inheritance.

The International SMA Consortium defined the following 4 clinical groups, depending on the age of onset and achieved motor abilities^[3] : type I SMA (acute form, Werdnig-Hoffmann disease), type II SMA (intermediate form), type III SMA (juvenile form, Kugelberg-Welander disease), and type IV SMA (adult form).

X-linked spinobulbar muscular atrophy (Kennedy disease)

First described in 1968 by Kennedy et al,^[4] X-linked spinobulbar muscular atrophy is an adult-onset, X-linked recessive trinucleotide, polyglutamine disorder that is caused by expansion of a polymorphic CAG tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12.^[5]

This disorder is characterized by slowly progressive weakness of bulbar and limb muscles, associated with endocrinologic disturbances (androgen insensitivity). Because of X-linked transmission, this disorder almost exclusively affects males but is transmitted by female carriers.

Postpolio syndrome

PPS is a clinical diagnosis and essentially one of exclusion, characterized by late-onset muscle weakness and fatigue in skeletal or bulbar muscles, unrelated to any known cause, in individuals with a previous history of an acute attack of paralytic poliomyelitis.^[6] Survivors of the polio epidemics that occurred worldwide in the mid 20^th century constitute a population at risk of presenting PPS.

Amyotrophic lateral sclerosis

ALS develops with a uniform frequency in major Western countries with an annual incidence rate of around 2 per 100,000 population.^[7] The estimated prevalence rate is 5 per 100,000 in the United States; approximately 30,000 Americans currently have the disease. Analysis of the most recent epidemiologic data suggests that smoking may be an established risk factor for sporadic ALS.^[8] The peak age of onset is between 55 and 75 years. Men are affected more frequently than women; however, this sex discrepancy is not as pronounced in familial cases.

Primary lateral sclerosis

The incidence of PLS is difficult to determine because of its rare occurrence, as well as the presence of a significant overlap with ALS.

Hereditary spastic paraparesis

The prevalence of HSP varies with different studies due to marked differences in the classifications used and their included diagnoses. In Ireland, the prevalence of "pure" autosomal dominant HSP is 1.17/100,000 population,^[9] whereas in southeast Norway, the HSP prevalence was estimated to be 7.4/100,000 population (pure autosomal dominant HSP, 4.5/100,000; complex autosomal dominant HSP, 1.0/100,000; and autosomal recessive HSP, 1.3/100,000).^[10]

Progressive bulbar palsy

The prevalence of adult-onset PBP is difficult to determine, as there is a significant overlap with "bulbar-onset" ALS.

For infantile PBP, approximately 60 cases of Brown-Vialetto-Van Laere syndrome have been reported to date, and around one half of those cases were sporadic.^[11] The male-to-female ratio is approximately 1:3 in reported cases. Fewer than 40 cases of Fazio-Londe disease have been reported to date.

Spinal muscular atrophy

SMA is considered to be the second most common autosomal recessive disease in humans after cystic fibrosis. An overall incidence of SMA is frequently cited to be around 1 in 6000 to 1 in 10,000 live births, and the carrier frequency is as high as 1 in 40.^[12]

X-linked spinobulbar muscular atrophy (Kennedy disease)

Amongst the hereditary motor neuron diseases (MNDs), this disorder has one of the lowest prevalence rates, with approximately 1/40,000 male population. SBMA is more common among Japanese and Scandinavian men due to a founder effect.^[13] In the Vasa region of Western Finland, the prevalence of this condition is reportedly greater than that of ALS, with a prevalence of 13/85,000 amongst the male population.^[14]

Postpolio syndrome

The prevalence of PPS has been reported to vary from around 30% to 85%, depending on the population being studied and the diagnostic classification used.^{[15, 16, 17]} According to a cross-sectional survey in Kitakyushu, Japan, the prevalence of PPS is 18.0/100,000 population (24.1 polio survivors per 100,000 population).^[16]

Amyotrophic lateral sclerosis

The etiology of sporadic ALS remains uncertain, however, ALS is considered to be a multifactorial disease that is triggered by a complex interaction of internal factors (eg, genetic susceptibility to different neuronal insults, immunologic alterations) and external factors (environmental, etc). The key theories proposed to date for the pathogenesis include glutamate-induced excitotoxicity, oxidative injury, altered mitochondrial function, cytoskeleton alterations, axonal transport dysregulation, neuroinflammation, immunomodulation, and autoimmunity.^[18]

Of these, the leading theory is excitotoxicity induced by glutamate, the major excitatory neurotransmitter, which may disrupt intracellular calcium homeostasis, resulting in motor neuron death. Riluzole, a glutamate-release inhibitor, is licensed for the slowing of ALS progression, and randomized controlled trials have demonstrated a relatively mild effect, with a small, positive effect on bulbar and limb function but not on muscle strength.^[19] The most recently supported hypothesis suggests that mitochondrial dysfunction acts with oxidative stress to cause abnormal neurodegeneration via calcium-mediated motor neuron injury.^[20] As external/environmental factors, neurotoxicants such as various metals, chemicals, and foods are proposed.

Primary lateral sclerosis

The etiology of PLS is unknown, but it may involve a similar etiopathogenesis as that proposed for ALS.

Hereditary spastic paraparesis

More than 40 genetic loci ascribed to the different HSP types have been identified; however, a clear genetic basis for most HSP types remains uncertain.

Progressive bulbar palsy

The etiopathogenesis of Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease remains elusive.

Spinal muscular atrophy

SMA (types I, II, and III) is caused by alterations in the survival motor neuron gene (SMN). This gene becomes active in the healthy, mature fetus and functions in the stabilization of the neuronal population. In the absence of SMN, there is continued programmed cell death.

X-linked spinobulbar muscular atrophy (Kennedy disease)

SBMA is caused by an expansion of a polymorphic tandem CAG repeat in the first exon of the androgen-receptor gene located on chromosome Xq11-q12, which encodes a polyglutamine stretch that may be a substrate for cysteine protease cell death executioners, the caspases.

Postpolio syndrome

The etiology of PPS remains controversial; however, the most widely accepted hypothesis is that of distal degeneration of greatly enlarged motor units that developed through terminal axonal sprouting for the reinnervation of denervated fibers during recovery following acute poliomyelitis. The motor units undergo a continuous remodeling process with denervation and reinnervation, followed by an eventual loss of this balanced process, resulting in permanent denervation.^{[21, 22]}

Other hypotheses include immunologic mechanisms (autoimmune/related to persistent poliovirus infection), the normal aging process, overuse myopathy, and disuse.^[23] The latter 3 processes are likely contributing factors.

Amyotrophic lateral sclerosis

The incidence of ALS increases with age, until it peaks around 75 years. In familial ALS, the onset is a decade earlier. Otherwise, familial and sporadic cases are clinically indistinguishable, and thus, a detailed family history and genetic studies are very important in discriminating between these 2 forms.

Approximately two thirds of patients with ALS initially present with focal muscle weakness in the upper or lower limbs (classic "Charcot" ALS), and approximately one fourth of patients presents with dysarthria, followed by progressive dysphagia (bulbar-onset ALS). In ALS with SOD1 mutations, extremity onset, particularly in the legs, is much more common than bulbar onset. About 5% of cases present with respiratory weakness without significant limb or bulbar symptoms.^[24] The "flail arm" and "flail leg" variants are initially localized forms with predominantly lower motor neuron (LMN) symptoms.^[25] These are characterized by progressive weakness and severe wasting of the upper and lower limbs, bilaterally.

Regardless of the body part that is first affected by ALS disease, weakness and atrophy spread to other parts of body with varying degrees of upper motor neuron (UMN) symptoms (eg, spasticity) and eventually involve the muscles of all 4 extremities and the trunk, as well as bulbar muscles. Rectal and bladder sphincters and oculomotor muscles are usually spared. Sensory examination is usually unremarkable.

Approximately 5% of patients with ALS develop dementia of the frontotemporal type, characterized by behavioral changes with or without language dysfunction.

Primary lateral sclerosis

The age of PLS disease onset is usually between ages 40 and 60 years, with spasticity in the legs accompanied by hyperactive deep tendon reflexes, clonus, and Babinski sign. Patients with spastic dysarthria as an initial symptom of PLS are also described. In contrast to ALS, the LMNs remain intact and thus, no amyotrophy is observed.

Rare cases frontotemporal dementia with PLS have been reported.^[26]

Hereditary spastic paraparesis

In "pure" HSP, the age of disease onset varies from infancy to the eighth decade,^[27] and the disease severity varies, both reflecting marked interfamilial variation. The essential clinical findings are slowly progressive and often include severe spasticity, hyperreflexia, and weakness in a pyramidal distribution, noticeably in both lower limbs, with extensor plantar responses.

Most patients with HSP present with difficulty walking or gait disturbance. In those with childhood onset, a delay in walking is not uncommon. Upper limb involvement is usually mild. Interestingly, up to 25% of affected patients are asymptomatic.^[28] Sensory impairment is seen in 10-65% of cases and usually consists of diminished vibration sense and, less often, diminished joint-position sense in the lower extremities.^[28] Urinary sphincter dysfunction occurs in up to 50% of patients, whereas anal sphincter involvement is unusual.^[28] Important negative clinical findings include no cranial nerve (CN) involvement and no corticobulbar tract involvement.

In "complicated" HSP, spasticity is accompanied by a variety of conditions that are related to central and peripheral nervous system involvement, including muscle amyotrophy, optic atrophy, pigmentary retinopathy, mental retardation, extrapyramidal disease, ataxic syndrome, dementia, deafness, ichthyosis, peripheral neuropathy, and epilepsy.^[28]

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome typically presents with progressive sensorineural hearing loss in most cases. The age of onset of the initial symptoms reportedly varies from infancy to the third decade of life.^[11] This is usually followed by other symptoms, including abnormalities of lower CNs VII-XII and LMN signs in the limbs, with an interval of several years. This interval has been reported to be shorter in males (mean, approximately 5 y) than in females (almost 11 y).^[11] Abnormalities of CNs II-VI occur much less frequently.

Fazio-Londe disease manifests itself in childhood with rapidly progressive weakness of the tongue, face, and pharyngeal muscles, as well as progressive upper limb weakness. No hearing impairment is seen.

Spinal muscular atrophy

The clinical picture of SMA is highly variable and represents a continuum. The age of disease onset varies from before birth to adulthood. The International SMA Consortium defined the following 4 clinical groups (types I-IV) depending on the age of onset and achieved motor functions^[3] :

• Type I SMA (Werdnig-Hoffmann disease): This type is the most severe form of SMA. The patients present with profound hypotonia and generalized weakness ("floppy infant") and never achieve the ability to sit. By definition, all patients present before age 6 months (with onset sometimes from the prenatal period). The diaphragm and the extraocular muscles tend to be spared (in contrast to "SMA plus " types and severe congenital SMA).^[29] No cardiac muscle involvement is seen. Creatine kinase is normal.
• Type II SMA: The onset of disease is before the age of 18 months. It may overlap with that of type I SMA, but the median age of onset is generally later than in type I SMA. The clinical course of type II SMA is marked by periods of apparent arrest in clinical progression. Patients are able to sit independently, but they are never able to walk unaided. Spine deformities and contractures of all major joints often develop.
• Type III SMA (Kugelberg-Welander disease): This is a mild form of childhood and juvenile SMA. By definition, the disease onset is usually after the age of 18 months but may show a wide range in age of onset up to the third decade of life. The patients gain the ability to walk without support. Spine deformities and contractures are frequent complications.
• Type IV SMA: This is an adult-onset type (age >30 y) and represents the mildest form within the spectrum of SMA phenotypes. The patients present with pronounced proximal weakness, and the clinical picture is very similar to that of a limb-girdle muscular atrophy.

X-linked spinobulbar muscular atrophy (Kennedy disease)

SBMA is clinically characterized by adult-onset limb and bulbar weakness, muscular atrophy, and fasciculation, with frequent occurrence of endocrine disturbances such as gynecomastia, testicular atrophy, hypercholesterolemia, and diabetes mellitus. Asymptomatic patients are also present. One clinical study reported that the mean age at first onset of muscle weakness was 41 years, and the most common presenting symptom was muscle cramps followed by tremors and leg weakness.^[30] Also reported was that muscle strength and function correlated directly with serum testosterone levels.^[30]

Postpolio syndrome

Most patients with PPS present with new, slowly progressive muscle weakness, frequently accompanied by muscle pain (myalgias) and fatigue, which can occur in muscles both previously affected and unaffected. This condition can also affect respiratory and bulbar muscles.

Amyotrophic lateral sclerosis

In the spinal cord, the anterior nerve roots are gray and thin/atrophic compared with the posterior sensory roots, as seen in the image below; this is more pronounced in the cervical and lumbar enlargements. The hypoglossal nerves are also affected. The bilateral pyramids in the medulla oblongata may be flattened. The brain is usually unremarkable; however, the precentral gyrus (primary motor cortex) may be atrophic, especially in severe cases. In ALS cases with accompanying dementia, the brain may exhibit frontal (and temporal) lobe atrophy.

At autopsy, widespread muscle atrophy and wasting affecting the proximal and distal extremities, tongue, intercostal muscles, and diaphragm are noted. The skeletal muscle is grossly pale. Given the loss of muscle bulk through atrophy, rigor mortis is usually absent in advanced stages of ALS disease.

Primary lateral sclerosis

No valid autopsy findings of "pure" PLS, excluding upper motor neuron (UMN) – dominant ALS cases, have been reported to date. However, theoretically, neither atrophy of the anterior nerve roots nor widespread muscle atrophy/wasting is seen.

Hereditary spastic paraparesis

Given the few autopsy cases reported and the rarity of this condition, no characteristic gross pathology for HSP has been described.

Progressive bulbar palsy

Given the few autopsy cases reported and the rarity of this condition, no characteristic gross pathology has been described.

Spinal muscular atrophy

In type I SMA, atrophy of the anterior spinal nerve roots is seen in the spinal cord, whereas the posterior nerve roots are normal.^[31] However, spinal cords in this affected age group are so small that the evaluation is often difficult. The brain is unremarkable. No detailed gross neuropathologic findings have been reported in type II or III SMA.

X-linked spinobulbar muscular atrophy (Kennedy disease)

Although detailed microscopic descriptions have been reported in several autopsy cases of SBMA, no gross neuropathologic findings are described.

Postpolio syndrome

The spinal cord in PPS shows atrophic anterior nerve roots and normal dorsal roots.^[32] The brain is unremarkable. Skeletal muscle atrophy of varying degree is noted.

Amyotrophic lateral sclerosis

The cardinal histologic change seen in ALS is loss of both upper (UMNs) and lower motor neurons (LMNs) with associated astrogliosis. In the LMN system, there is loss/degeneration of the anterior horn cells (especially the large neurons) with anterior nerve root atrophy, as well as of the brainstem motor nuclei (eg, cranial nerve [CN] XII, motor VII, and motor V) (see the following images).

However, the brain stem nuclei controlling eye movements (CNs III, IV, and VI), the Clarke column (see the first image below), as well as the Onufrowicz nucleus (see the second image below) in the sacral spinal cord (involved in maintenance of micturition and defecatory continence) are largely spared until late in ALS disease.

The anterior horns show variable astrogliosis depending on the stage of the disease, and the surviving motor neurons usually show chromatolysis and cytoplasmic shrinkage with abundant lipofuscin granules in the soma (see the first image below). Axonal spheroids are frequently observed (see the second image below).

Neuronophagia and perivascular lymphocytic cuffing is occasionally seen in ALS. In the UMN system, the motor cortex is affected and shows loss/degeneration of neurons with astrogliosis mainly in the third and fifth layers (cell bodies of Betz cells) (see the first image below), a feature that is more apparent in cases of longer duration. Superficial cortical spongiosis may also be seen (see the second image below).

Other histologic findings reported in the precentral gyrus in ALS patients include clusters of astrocytes in the upper cortical layers (layers II and III), an increase in size and number of subcortical white matter astrocytes, and astrocytosis in the gray-white matter junction (see the following image).^[33]

The cytopathology of the affected motor neurons in ALS is characterized by Bunina bodies; skeinlike inclusions; round, hyaline inclusions/Lewy body–like hyaline inclusions; and basophilic inclusions.

Bunina bodies are currently considered to be a specific histologic hallmark of ALS and can be observed in frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) and Guamanian ALS. In contrast, these findings have not been reported in patients with SOD1 -mutated familial ALS.

Bunina bodies are small, eosinophilic (hematoxylin and eosin [H&E] stain), and blue (Luxol fast blue stain) granular perikaryal inclusions in the remaining LMNs, appearing either singly or in a group, and sometimes arranged in small beaded chains (see the following image). They average 2-5 µm in diameter, and the number varies in each neuron.

Bunina bodies (BBs) are seen predominantly in the somata and occasionally in the dendrites; however, they have not been found within the axoplasm.^[34] Bunina bodies are seen more frequently in the lumbar than in the cervical and thoracic cords, are primarily distributed in the motor nuclei of the spinal cord and brainstem, but are rarely found in Betz cells, neurons of the oculomotor nuclei, and the Onufrowicz nuclei.^[35]

Ultrastructurally, Bunina bodies are composed of electron-dense amorphous material containing tubules or vesicular structures, with a few central clear areas containing cytoplasmic components.^[35] Although their morphologic structure is well known, their origin and nature remain unknown.

Skeinlike inclusions (SLIs) are intracytoplasmic filamentous structures and are found as aggregates of threadlike structures, as seen in the images below. They are usually detected with immunohistochemical stains (see Immunohistochemistry below), whereas, with H&E stain, skeinlike inclusions are barely visible or are sometimes detected as faintly eosinophilic linear or curvilinear structures.^[34] Skeinlike inclusions are made of bundles of filaments 15-20 nm thick. It is reported that skeinlike inclusions are significantly related to neuronal loss, especially in the spinal cord.^[36]

Round hyaline inclusions (RHIs) are round, eosinophilic, hyaline structures in the remaining anterior horn neurons, and some of them consist of cores and halos and are called Lewy body–like hyaline inclusions (LBHIs). LBHIs are indistinguishable from the Lewy bodies seen in Parkinson disease when stained with H&E. Their size varies from small to as large as >20 µm in diameter.^[37] The somata usually contain a single inclusion. Of note is that there is confusion surrounding the definition of these 2 very similar inclusions, and both terms are often used interchangeably.

Basophilic inclusions (BIs) are irregularly-shaped neuronal, cytoplasmic, light basophilic inclusions, initially described in patients with sporadic juvenile ALS. They are stained light red by methyl green-pyronin, suggesting an RNA component in the inclusions. Basophilic inclusions are seen not only in the residual large anterior horn cells but also in the small anterior horn cells and neurons in the intermediolateral nuclei.^[38] Generally, Bunina bodies and skeinlike inclusions are not found in cases with basophilic inclusions.

Widespread neuronal loss and degeneration can be seen with basophilic inclusions in areas including the cerebral cortex, basal ganglia, and thalamus; thus, cases of ALS with basophilic inclusions are considered to be within the spectrum of the most recently recognized entity, basophilic inclusion body disease (BIBD).^[39]

In ALS, there is characteristic degeneration of the descending motor tracts (ie, anterior and lateral corticospinal tracts). The corticospinal tract degeneration is most evident in the lower spinal segments, supporting the "dying back" hypothesis. The posterior columns and spinocerebellar tracts are usually spared in the spinal cord. Some forms of familial ALS are known to show posterior column involvement.^[33] In the degenerated tracts, there is loss of large myelinated fibers, which can be highlighted with myelin stains (eg, Luxol fast blue), in association with infiltration of foamy macrophages and variable astrogliosis.

In FTLD-MND/ALS, spongiosis (microvacuolation) is observed in the frontal and temporal cortices, in addition to ALS features.

The striated muscles show neurogenic atrophy, characterized by clumps of pyknotic nuclei, small and large group atrophy, scattered angulated atrophic fibers, and fiber type grouping, as demonstrated in the following images.

In the late stage of ALS disease, especially at autopsy, the muscles usually show marked atrophy with interstitial fibrosis and fatty infiltration, as shown in the image below.

Primary lateral sclerosis

Degeneration in PLS is confined to UMNs, including their descending motor tracts (see the following images). No loss/degeneration of LMNs or gliosis is seen in the spinal anterior horns. No Bunina bodies are identified.

Hereditary spastic paraparesis

The most severely affected pathways in pure HSP are the crossed and uncrossed corticospinal tracts to the lower limbs and the fasciculus gracilis fibers from the lower limbs. The primary neuropathologic feature of pure HSP is axonal degeneration that is maximal in the terminal portions of the corticospinal tracts (descending tracts) and, to a lesser extent, of the dorsal column fibers (ascending tracts), suggesting a process of "dying back." Demyelination and gliosis can accompany the axonal loss. About 50% of HSP cases show spinocerebellar tract involvement.^[28] Dorsal root ganglia, posterior roots, and peripheral nerves are unremarkable, as are the anterior horn cells.

Progressive bulbar palsy

Pathologic description of PBP is available in a few reported cases of Brown-Vialetto-Van Laere syndrome, which show neuronal injury and loss of neurons in the III, V, VI and lower cranial nerve (VII-XII) nuclei.^[11]

Spinal muscular atrophy

Autopsy findings of SMA have mostly been reported from patients with SMA type I. The cardinal histologic feature of SMA type I is the paucity of motor neurons in the spinal cord and brainstem, with the few surviving motor neurons characterized by ballooning and chromatolysis.^[40] In SMA type I, chromatolytic neurons tend to be markedly ballooned, spheroidal, and contain as yet ill-defined material inside, which is in contrast to those seen in other MNDs (eg, ALS).^[41]

Chou and Wang described the following histopathologic tetrad of SMA type I: (1) central chromatolysis; (2) empty-cell beds; (3) migratory (heterotopic) motor neurons; and (4) glial bundles of spinal roots.^[41] Empty-cell beds are empty (glial) shells or spaces that are still enclosed by the usual fiber network left by the previous occupants, motor neurons. These are easily visible with special stains (Bodian, etc). Migratory motor neurons are seen along the distal pathways of their axons in the anterior spinal roots. Outgrowth of birefringent glial bundles parallel to the spinal root axons is frequently seen in the anterior spinal nerve roots (proximal portion), which is apparent with polarizing microscopy.

Other reported findings, especially in individuals with longer survival periods, include involvement of the dorsal root ganglia (with nodules of Nageotte), Clarke column, and lateral thalamic nucleus, with neuronal chromatolysis and ballooning.^{[40, 42]}

An autopsy report on 2 patients with clinicogenetically confirmed SMA type II described severe reduction of motor neurons and gliosis in the spinal cord and brainstem.^[42] However, in contrast to SMA type I, the Clark and lateral thalamic nuclei were spared, and ballooned and chromatolytic neurons were rarely seen. Additional findings were reduced Betz cells and large myelinated fibers in the lateral funiculus.^[42]

The main histologic findings of SMA type III is a marked neuronal loss in the anterior horns throughout the length of the spinal cord. The only autopsy report of a patient with clinicogenetically confirmed SMA type III demonstrated inconspicuous empty-cell bed formation, a small number of "migratory" (heterotopic) motor neurons, and prominent glial bundles in spinal roots in addition to the typical changes in the spinal anterior horns.^[43] Chromatolytic motor neurons were not as enlarged, were small in number, and were observed only in the anterior horn. Changes other than those in motor neurons included moderate loss of myelinated fibers in the fasciculus gracilis and marked loss of neurons with severe gliosis in the dentate nucleus.

The histopathologic features of muscle biopsies in SMA types I and II are essentially identical, not allowing their distinction on muscle pathology alone. The characteristic features include atrophy affecting both type 1 and type 2 fibers, with type I fiber hypertrophy, and (in non-early onset cases) fiber type grouping (see the images below). The atrophic fibers are usually round in shape, in contrast to other forms of neurogenic atrophy such as ALS. Excess endomysial connective tissue is not seen.

The muscle pathology in SMA type III is variable, ranging from minimal changes to small and/or large group atrophy with fiber type grouping. Fatty infiltration of variable degree is noted. Hypertrophic type I fibers can be seen. A concomitant myopathic pattern can also be present.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The cardinal histopathologic feature of SBMA is loss of neurons in the anterior horns and motor nuclei in the spinal cord and brainstem. Motor nuclei of CNs III, IV, and VI are spared. Sensory neurons in the dorsal root ganglia are less severely affected, and large myelinated fibers demonstrate a distally accentuated sensory axonopathy in the peripheral nervous system.^{[44, 45]} The neurons in the Onufrowicz nuclei, intermediolateral columns, and Clarke columns of the spinal cord are generally well preserved, as seen in ALS.^[45] Muscle biopsy shows neurogenic atrophy of varying degree.

Postpolio syndrome

In PPS, the spinal cord demonstrates active chronic inflammation with perivascular lymphoplasmacytic infiltrate in the anterior horns and leptomeninges.^[46] The cord gray matter is gliotic with axonal spheroids seen in the anterior horns. No degenerative changes are noted in the lateral columns, in contrast to ALS. These features are not specific to PPS, as similar changes are seen in patients with stable postpoliomyelitis deficits.^[46]

Miller reported focal, perivascular, intraparenchymal, chronic inflammatory infiltrates composed mostly of B cells with rare macrophages and no T cells in the spinal cord, suggesting an autoimmune etiology of the disease.^[32] He also reported loss of neurons with profound gliosis and scattered axonal spheroids in the anterior horns, moderate Wallerian degeneration in the lateral columns, and an entirely unremarkable brain, specifically the internal capsule and precentral gyri.^[32] Muscle biopsy showed neurogenic changes with secondary myopathic features of varying degree.

Amyotrophic lateral sclerosis

The immunohistochemical profile of pathologic structures seen in ALS is shown in Table 1. Ubiquitin immunohistochemical staining is very useful to highlight neuronal cytoplasmic inclusions, which are a highly sensitive and specific marker for ALS. Of note is that the Bunina body, one of the pathognomonic features of ALS, is immunonegative for ubiquitin but immunoreactive for cystatin C.

The transactive response (TAR)-DNA–binding protein with a molecular weight of 43-kDa (TDP-43) has been identified as a major component of frontotemporal lobar degeneration (FTLD) with ubiquitin-only immunoreactive inclusions (FTLD-U). TDP-43 immunoreactivity is reported to be consistently co-localized with ubiquitinated inclusions observed in sporadic ALS (see the following image) and Guam ALS.^{[47, 48]} However, in the vast majority of cases with familial ALS with SOD1 mutation, TDP-43 immunoreactive inclusions are absent despite the presence of ubiquitin immunoreactive inclusions.^{[47, 48]}

In addition to the neuronal cytoplasmic inclusions, TDP-43 immunoreactive and variably ubiquitin immunoreactive glial (probably oligodendroglial) cytoplasmic inclusions are identified within the anterior horns and close to the white matter in the spinal cord in sporadic ALS cases.^[48] Basophilic inclusions are occasionally ubiquitin immunoreactive; however, they have recently been found to be labeled with antibody against fused-in-sarcoma (FUS) protein.^[49]

In Guamanian ALS with/without Parkinsonism-dementia complex (ALS/PDC), widespread tau-immunoreactive neurofibrillary tangles, especially in the isocortices and hippocampal formation, are known to be a characteristic feature.

In FTLD-MND/ALS, ubiquitin and TDP-43 immunoreactive, tau-negative inclusions and neurites are observed in the upper layers of the frontal cortex and the dentate fascia of the hippocampus in the brain.

As a sensitive method to detect degeneration of white matter tracts, CD68 is very useful to highlight macrophages within the degenerated tracts, especially in early degeneration, as seen in the image below.

The table below outlines the immunohistochemical profile of pathologic structures seen in ALS.

Table 1. Immunohistochemical Findings of Pathologic Structures Seen in ALS (Open Table in a new window)

Primary lateral sclerosis

No characteristic immunohistochemistry findings are noted in PLS. When ubiquitin immunoreactive inclusions are identified in the lower motor neurons (LMNs), ALS may be much more likely than PLS. No data on TDP-43 immunohistochemistry findings have been reported to date.

Hereditary spastic paraparesis

No characteristic immunohistochemistry findings are noted in HSP.

Progressive bulbar palsy

No characteristic immunohistochemistry findings are noted in Brown-Vialetto-Van Laere syndrome or Fazio-Londe disease.

Spinal muscular atrophy

In SMA type I, phosphorylated neurofilament protein (pNFP) and ubiquitin immunostains preferentially label the peripheral perikarya and proximal neurites, as well as the center of the ballooned neurons, respectively^{[40, 41, 42]} ; however, these features were not found in reported cases of SMA type II.^[42] Glial bundles invading into the proximal portions of the anterior spinal roots are highlighted with glial fibrillary acidic protein (GFAP) immunostain. No data on TDP-43 immunohistochemistry findings have been reported to date.

X-linked spinobulbar muscular atrophy (Kennedy disease)

As a pathologic hallmark of most polyglutamine-mediated neurodegenerative diseases, nuclear inclusions (NIs) containing the mutant androgen receptors are present in the residual motor neurons in the spinal cord and brainstem, as well as in the skin, testis, and some other visceral organs in SBMA.^[45] These nuclear inclusions are detected by antibodies recognizing a small portion of the N-terminus of the androgen-receptor protein and the expanded polyglutamine tract (immunohistochemistry IC2 antibody). No ubiquitin immunoreactive cytoplasmic inclusions that are seen in ALS are noted in SBMA. No data on TDP-43 immunohistochemistry findings have been reported to date. Abnormal pNFP expression in the somata is not seen.

Postpolio syndrome

No characteristic immunohistochemistry findings are noted in PPS. No ubiquitin immunoreactive inclusions are identified in the LMNs in PPS.

Amyotrophic lateral sclerosis

Most forms of ALS are sporadic and considered to be multifactorial diseases, but about 10% of patients have an inherited familial form of the disease with a clear family history. In many instances, however, the disease does not transmit in a typical dominant or recessive manner.^[50] Dominant causative mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene on chromosome 21q22.11 are seen in approximately 20% of familial ALS cases (genetic nomenclature: ALS1) and about 1% of sporadic cases. SOD1 mutations, which can occur at almost any position in the gene, result in a toxic gain-of-function pathology. The loss of the normal function of SOD1 is not the cause of ALS.^[50] However, no consensus on the exact mechanisms as to how SOD1 mutations lead to selective premature death of motor neurons has yet emerged.

Homozygous loss-of-function mutations in the ALSIN gene on chromosome 2q33, encoding the protein alsin, produce either an autosomal recessive juvenile onset ALS or a juvenile-onset upper motor neuron (UMN) – predominant ALS (genetic nomenclature: ALS2).^[51]

Mutations in TAR-DNA binding protein (TARDBP) gene, which codes for TDP-43, on chromosome 1 (1p36.22) have been identified in patients with both familial and sporadic ALS. A total of 30 different mutations are now known in 22 unrelated families (about 3% of familial ALS cases) and in 29 sporadic cases of ALS (about 1.5% of sporadic cases).^[52] All TARDBP mutations exhibit an autosomal dominant pattern of inheritance.

In recent years, mutations in FUS/TLS (translocation in liposarcoma) have been identified. These mutations were reportedly detected in approximately 4% of familial ALS (about 0.4% of all ALS cases).^[52] Both TDP-43 and FUS/TLS are DNA/RNA-binding proteins with striking structural and functional similarities, implicating alterations in RNA processing as a pathogenesis of ALS.

Primary lateral sclerosis

PLS is typically sporadic with no family history; however, rare familial forms are seen. Mutations in the ALSIN (ALS2) gene on chromosome 2q33 cause juvenile PLS, which may overlap with the juvenile-onset UMN-predominant ALS. This condition is inherited in an autosomal recessive pattern.

In recent years, a unique locus (chromosome 4ptel-4p16.1) for an autosomal dominant form of adult-onset PLS in a large French-Canadian family was mapped.^[53]

Hereditary spastic paraparesis

HSP comprises a large clinically and genetically heterogeneous group of inherited neurologic disorders and is transmitted as an autosomal dominant, autosomal recessive, or rarely, X-linked recessive trait. Of these, autosomal dominant inheritance accounts for 70-80% of all HSP cases and is the most commonly associated with pure forms of HSP. Autosomal recessive HSPs are less common but exhibit greater phenotypic variability.

Forty-five gene loci have been identified, of which 20 have been identified as causative genes.^[54] Of autosomal dominant HSP cases, about 40% are linked to the spastic paraplegia 4 (SPG4) locus on chromosome 2p21-p22. More than 150 mutations are scattered along the coding regions of the gene SPAST, encoding spastin,^[54] and have been implicated in the causation of varying types of DNA modification^{[55, 56]} Approximately 10% are due to mutations in ATL1, encoding for atlastin, with an early-onset pure phenotype (SPG3A).^{[54, 56]}

Of autosomal recessive HSP cases, it is reported that SPG11 (SPG11, spatacsin) is the most frequent form, followed by SPG15 (ZFYVE26, spastizin).^[57] Clinically, both forms are characterized by complicated HSP, cognitive deficits, thin corpus callosum (seemingly the best phenotypic predictor for these 2 forms of HSP), peripheral neuropathy, and mild cerebellar ataxia.^[58]

Progressive bulbar palsy

Around 50% of all reported cases of Brown-Vialetto-Van Laere syndrome are sporadic. The majority of familial cases have demonstrated an autosomal recessive inheritance.^[11] There are no known molecular alterations.

Spinal muscular atrophy

The classic form of SMA (types I, II, and III) is an autosomal recessive motor neuron disorder (MND). All forms of SMA are associated with a locus on chromosome 5q13 that harbors the survival motor neuron gene (SMN1), and they are all caused by loss-of-function mutations or deletions of SMN1.

The SMN gene product is ubiquitously expressed, but it is detected at especially high levels in neuronal cells. This entity is a part of nuclear germ structures rich in heterogeneous nuclear ribonucleoproteins (hnRNPs). Some researchers have suggested that the SMN protein, as part of a large complex, plays a role in the assembly and regeneration of spliceosomal complexes.

The SMN gene exists in 2 copies, SMN1 and SMN2, which differ by only a single nucleotide in exon 7. The vast majority of the functional SMN protein is produced by SMN1, whereas SMN2 undergoes an alternative splicing pathway, producing primarily a transcript lacking exon 7 (SMN∆7) as the consequence of a single nucleotide transition (ie, C to T transition at position +6 of exon 7; c.840C>T). SMN∆7 is an unstable protein and is not functionally equivalent to full-length SMA. About 10% of the mRNA transcript from SMN2 is spliced into the full-length transcript that codes for the fully functional SMN protein. Thus, the major factor influencing the severity of SMA phenotype (ie, SMA types I-III) is the number of SMN2 copies, which usually varies between 1 and 4 and rarely reaches up to 8.^[59] The underlying mechanism generating an increased number of SMN2 copies and a reduction or absence of SMN1 is gene conversion.^[59]

Among 5q13-linked SMA patients, 96% of types I-III SMA patients show homozygous absence of SMN1 exon 7 and 8 or exon 7 only because of deletions of SMN1 or gene conversion of SMN1 into SMN2.^[59] Based on the relatively uniform mutational spectrum seen in types I-III SMA patients, a fast and reliable polymerase chain reaction (PCR)-based testing is available. As a diagnostic test, SMN1 -targeted mutation analysis is used to detect deletion of exons 7 and 8 of SMN1. As for SMA carrier testing, SMN gene dosage analysis, determining the number of SMN1 gene copies, is used for highly accurate carrier detection.

X-linked spinobulbar muscular atrophy (Kennedy disease)

SBMA is an adult-onset, X-linked recessive disorder. Female carriers of the mutation are usually clinically unaffected. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the exon 1 of the androgen receptor gene on chromosome Xq11-12. The CAG repeat ranges in size from 11 to 35 in normal individuals, but it ranges from 40 to 62 in SBMA patients.^[44] Expanded CAG-repeat size is inversely correlated with age at onset and has a slight tendency to further expansion in successive generations (ie, anticipation).^[5] Molecular genetic testing for the CAG trinucleotide repeat expansion is available on a clinical basis.

The pathogenesis of this polyglutamine disorder is still unclear; however, there are strong indications that aggregation of the mutant androgen receptors within the nucleus or cytoplasm of motor neurons and visceral cells results in disruption of cellular functions in SBMA patients.^[5]

Postpolio syndrome

There are no known molecular alterations or significant genetic findings in this condition.

Amyotrophic lateral sclerosis

ALS is typically relentless in progression, with 50% of patients surviving for less than 3 years after diagnosis, whereas approximately 20% of patients survive for 5-10 years.^[60] Patients with ALS invariably develop respiratory weakness, and most die from pulmonary complications.

Primary lateral sclerosis

In contrast to ALS, clinically "pure" PLS, defined by isolated upper motor neuron (UMN) signs 4 years after symptom onset, is a syndrome of slow progression with high levels of independence for years or decades.^[61] UMN-dominant ALS (ie, predominantly UMN disease with minor lower motor neuron [LMN] signs) presents with disability similar to ALS but slower progression.^[61]

Hereditary spastic paraparesis

HSP is a disease that is compatible with a normal life expectancy, with most patients dying in old age from coincidental diseases.^[28]

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome reportedly shows a variable clinical course, with less than 40% of reported cases demonstrating survival for 10 or more years after the initial symptoms.^[11] Abrupt deterioration of the condition has also been reported in approximately one sixth of patients.

Spinal muscular atrophy

The mortality and/or morbidity rates of SMA are inversely correlated with the age at onset. In type I SMA, because bulbar and respiratory muscles become affected rapidly, two thirds of patients expire within the first 2 years. In type II SMA, survival into adolescence or adulthood is common. In type III SMA, the life expectancy is close to that of the normal population.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The life span of individuals with SBMA is not thought to be reduced.

Postpolio syndrome

PPS is a slowly progressive disease that is rarely fatal. However, patients with PPS commonly develop new disabilities that cause significant morbidity, such as orthopedic complications (progressive instability of joints, osteoporosis, fractures, osteoarthrosis, scoliosis, spondylosis, etc), respiratory insufficiency (progressive nocturnal hypoventilation), and neurologic complications related to skeletal deformity and to the use of medical supporting devices (eg, peripheral neuropathy).

Amyotrophic lateral sclerosis

There are several conditions that should be considered in the differential diagnosis of ALS, and they include the following:

• Neurodegenerative disorders, such as primary lateral sclerosis, hereditary spastic paraparesis, spinal muscular atrophy, X-linked spinobulbar muscular atrophy
• Peripheral neuropathy, such as multifocal motor neuropathy, an acquired immune-mediated demyelinating neuropathy with frequently elevated anti-GM1 antibody titers that usually responds to treatment with intravenous immunoglobulin
• Myopathy, including inclusion body myositis, which has a characteristic wasting and weakness of deep finger flexors and quadriceps femoris, with typical rimmed vacuoles in muscle biopsy
• Postpolio syndrome
• Monomeric amyotrophy, also known as Hirayama disease, a structural cervical cord disorder due to dynamic compression of the cord that is seen only at neck flexion with forward displacement of the posterior dura. Young males in the second and third decades of life are mainly affected, the onset is insidious, and predominantly unilateral upper extremity weakness and atrophy with no sensory or upper motor neuron (UMN) symptoms occurs.^[62]
• Conditions listed in the PLS differential diagnosis, below

Primary lateral sclerosis

The major differential diagnosis for PLS is UMN-dominant ALS. According to Pringle et al, disease duration of at least 3 years is required to render this diagnosis^[1] ; similarly, Gordon et al reported that clinically "pure" PLS can be defined by isolated UMN signs 4 years after symptom onset.^[61] Differentiation between PLS and UMN-dominant ALS has reported prognostic significance.^[61]

Other diseases that cause a slowly progressive pyramidal and/or pseudobulbar syndrome should be considered in the differential diagnosis of PLS and include the following:

• Structural spinal cord disorders (compressive lesions at the foramen magnum or cervical spinal cord), such as cervical spondylotic myelopathy, Arnold-Chiari malformation, tumors
• "Pure" hereditary spastic paraparesis
• Metabolic disorders, such as subacute combined degeneration of the cord (vitamin B12 deficiency)
• Viral infections, such as tropical spastic paraparesis (human T-lymphotrophic virus type I), human immunodeficiency virus (HIV) infection
• Primary progressive multiple sclerosis (PPMS). Of note is that the most common presentation of PPMS (80% of patients) is progressive spastic paraparesis, mainly in the legs.^[63]

Hereditary spastic paraparesis

The main differential diagnosis for HSP is PLS, and this distinction is important for genetic counseling of family members and for the patient's prognosis, because HSP generally carries a more favorable prognosis.^[2] Other conditions in the differential diagnosis of HSP are very similar to those of PLS listed earlier. One study showed that in most patients with a sporadic adult-onset UMN syndrome, differentiation between HSP (with sporadic presentation) and PLS based on clinical characteristics is unreliable, and therefore genetic testing is required.^[2]

In addition, the differential diagnosis includes dopa-responsive dystonia and arginase deficiency. Given that both of these disorders are treatable, dopa-responsive dystonia should be excluded in a child with progressive gait disturbance and lower extremity spasticity of unknown etiology, whereas arginase deficiency should be considered in a young child with progressive loss of developmental milestones and spasticity.

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease are closely related conditions, with the only distinguishing feature being the presence or absence of deafness, respectively.

The differential diagnosis of Brown-Vialetto-Van Laere syndrome includes Fazio-Londe disease, Madras motor neuron disease (MMND), and Boltshauser syndrome (sensorineural hearing loss, distal muscular atrophy, and vocal cord paralysis, which is the only lower cranial nerve sign).

MMND has a unique geographic distribution (predominantly reported from Southern India) and clinically resembles Brown-Vialetto-Van Laere syndrome, with the exception of the presence of UMN signs in addition to LMN signs in the majority of patients, a male predominance, and an uncommon familial inheritance (ie, mostly sporadic).^[64]

In the differential diagnosis of Fazio-Londe disease, Roeleveld-Versteegh et al reported 2 pediatric cases of mitochondrial respiratory chain defects presenting as progressive bulbar paralysis.^[65]

Spinal muscular atrophy

The differential diagnosis of SMA includes congenital muscular dystrophy, congenital myopathy, congenital neuropathy (eg, congenital hypomyelination neuropathy), disorders of carbohydrate metabolism, myasthenia gravis, and ALS (especially juvenile forms). For SMA types III and IV, a limb-girdle muscular dystrophy is the main differential diagnosis.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The main differential diagnosis for SBMA is ALS. This diagnosis can usually be made based on history and physical examination.

Postpolio syndrome

PPS is a diagnosis of exclusion. Thus, a careful medical history and clinical examination are necessary to exclude all other conditions that may cause similar symptoms, which include ALS, multiple sclerosis, collagen vascular diseases, depression, hypothyroidism, myasthenia gravis, inclusion body myopathy, and infectious myopathy.