Motor neuron disorders

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Motor neuron disorders

CLASSIFICATION

Diseases that affect motor neurons can be classified as either primary, secondary, or multisystem (Table 27.1). The terms ‘motor neuron diseases’ and ‘motor neuron disorders’ are used to refer to any disease affecting motor neurons. The specific term ‘motor neuron disease’ is used in Europe as a synonym for amyotrophic lateral sclerosis (ALS) and related disorders.

Table 27.1

Classification of disorders affecting motor neurons

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

NOMENCLATURE

ALS, progressive bulbar palsy (PBP), and progressive muscular atrophy (PMA) are generally considered to be variants of a single clinicopathologic syndrome. Primary lateral sclerosis (PLS) is regarded by many workers as a distinct entity because there is no involvement of lower motor neurons. These conditions (Table 27.2) are characterized as follows:

Table 27.2

Nomenclature of motor neuron disease

ALS, amyotrophic lateral sclerosis; PBP, progressive bulbar paresis; PMA, progressive muscular atrophy; PLS, primary lateral sclerosis.

ALS is a neurodegenerative disorder affecting upper and lower motor neurons, and can be associated with variable pathology of non-motor systems.

PBP is a syndrome of progressive dysarthria and dysphagia. Approximately 25% of patients who later develop other features of ALS initially present with PBP.

PLS is a condition in which upper motor neuron signs occur in the absence of lower motor neuron signs, and pathologic changes are restricted to the motor cortex and corticospinal tracts.

PMA is a condition in which lower motor neuron signs correlating with a loss of anterior horn cells occur in the absence of upper motor neuron signs, and in which the upper motor neurons are preserved.

Clinical criteria for diagnosis divide cases into definite and probable ALS (Table 27.3). Since several diseases can be associated with motor neuron loss, secondary causes of motor neuron disease must be excluded.

Table 27.3

Revised World Federation of Neurology criteria for diagnosis of ALS

The diagnosis of ALS requires:

1. The presence of:

a. Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination;

b. Evidence of UMN degeneration by clinical examination;

c. Progression of the motor syndrome within a region or to other regions, as determined by history or examination; and

2. The absence of:

a. electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN or UMN degeneration; and

b. neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs

Four diagnostic categories are recognized:

1. Clinically definite ALS: on clinical grounds alone, evidence of UMN plus LMN signs in the bulbar region and in at least two spinal regions, or the presence of UMN signs in two spinal regions and LMN signs in three spinal regions

2. Clinically probable ALS: on clinical grounds alone, UMN plus LMN signs in at least 2 regions with some UMN signs rostral to LMN signs

3. Probable, laboratory supported ALS: this is defined, after proper application of neuroimaging and clinical laboratory protocols has excluded other causes, as:

a. clinical evidence of UMN and LMN signs in only one region; or

b. UMN signs alone in one region and LMN signs defined by EMG criteria in at least two limbs

4. Possible ALS is defined, once other diagnoses have been excluded, as:

UMN plus LMN signs in only one region;

UMN signs alone in 2 or more regions;

LMN signs found rostral to UMN signs

The category of suspected ALS, previously included in the El Escorial criteria has been discarded

UMN, upper motor neuron; LMN, lower motor neuron; ALS, amyotrophic lateral sclerosis.

EPIDEMIOLOGY OF ALS

Incidence is ~2/100 000.

Prevalence is ~5/100 000.

Mean age of onset of sporadic ALS is ~60 years.

Male:female ratio is 1.5:1.

Typically, ALS progresses to death from respiratory failure or aspiration bronchopneumonia within 5 years of onset. Approximately 10–20% of patients develop disturbed frontal lobe cognition.

MACROSCOPIC APPEARANCES

The anterior nerve roots may appear shrunken and gray when compared with the posterior sensory roots (Fig. 27.1). The spinal cord may be atrophic. In most instances, the brain is macroscopically normal, but in a small proportion of cases, the precentral gyrus appears atrophic (Fig. 27.2). In patients with dementia, the frontal and temporal lobes may be atrophied.

27.1 Spinal cord from patients with ALS.
(a) Cervical spinal cord. The upper motor (anterior) roots appear normal while the lower cervical anterior roots are severely atrophic. (b) Thoracolumbar spinal cord showing extensive atrophy of the anterior nerve roots.

27.2 Shrinkage of part of the precentral gyrus in severe amyotrophic lateral sclerosis.
The leptomeninges have been stripped.

MICROSCOPIC APPEARANCES

The most characteristic finding is loss of motor neurons and astrocytosis in the spinal cord, brain stem, and motor cortex (Fig. 27.3). The remaining motor neurons in the spinal cord and brain stem may show cytoskeletal abnormalities.

27.3 Loss of neurons in ALS.
(a) Marked depletion of neurons from the anterior horn of the spinal cord. (b) Loss of neurons and gliosis of the hypoglossal nucleus.

ETIOLOGY OF ALS

The cause of sporadic ALS is unknown, but recent research has provided insights into the role of genetic factors, proteins involved in RNA processing and excitotoxic damage.

The protein TDP-43 is central to pathogenesis

The pathological aggregation of TDP-43, an RNA/DNA-binding protein, is central to the development of neurodegeneration. Inclusion bodies in MND are immunoreactive for TDP-43 (see Fig. 27.8).

Some patients have a mutation in the TDP-43 gene, TARDBP, causing ALS.

Several other proteins probably interact along a pathway leading to TDP-43-linked neurodegeneration. Mutations in genes coding for these proteins may also lead to MND characterized by pathological TDP-43 accumulation.

TDP-43 is also important in FTLD, where an important group of familial cases is caused by mutation in the granulin gene (Chapter 31).

The protein FUS is involved in some cases

Pathological aggregation of FUS, a protein involved in RNA processing, is seen in a proportion of cases linked to mutation in the gene. FUS inclusions correspond to basophilic inclusions (see Fig. 27.14).

Excitotoxic damage

The excitotoxic neurotransmitter glutamate has been implicated in ALS, and riluzole, a glutamate release inhibitor and sodium channel blocker, has been shown to prolong patient survival.

Immune mechanisms

Autoantibodies to L-type calcium channels have been described in ALS.

Genetic factors

5–10% of patients with ALS have an autosomal dominant inherited form of disease, and familial ALS typically starts 10 years earlier than sporadic disease.

The average age of onset of familial ALS is about 10 years earlier than the sporadic disease with a median survival time of about 24 months.

Some gene abnormalities act as risk factors for ALS, as follows:

• Deletions within the C-terminal domain of the NEFH gene coding for the neurofilament heavy subunit, have been found in several sporadic ALS patients and it is believed that this may be a susceptibility factor.

• Short expansions of glutamine forming a polyglutamine tract in the ataxin-2 protein are associated with increased risk of ALS.

GENETIC FORMS OF MOTOR NEURON DISEASE

A summary of the main genetic forms of MND is presented below.

Type of MND	Linkage	Gene
ALS1 AD adult	21q22	Cu/Zn SOD1 10–120% AD cases
ALS2 AR Juvenile	2q33	Alsin
ALS3 AD adult	18q21	Unknown – possibly commonest form of AD ALS
ALS4 AD Juvenile	9q34	SETX Senataxin
ALS5 AR Juvenile	15q15	SPG11 Spatacsin
ALS6 AD Adult	16p11.2	FUS Fused in sarcoma
ALS7 AD Adult	20p13	Unknown
ALS8 AD Adult	20q13.33	APB VAMP-associated protein B
ALS9 AD Adult	14q11	ANG Angiogenin
ALS10 AD Adult	1q36	TARDBP TAR DNA-binding protein
ALS11 AD Adult	6q21	FIG4 PI(3,5)P(2)5-phosphatase
ALS12 AR/AD Adult	10p15-p14	OPTN Optineurin
ALS 15	p11.23-p11.1	UBQLN2 gene
FTDALS	9p21	C9orf72 (GGGGCC)n expansion

AD, autosomal dominant; AR, autosomal recessive.

Inclusion bodies (Figs 27.4–27.8) may be seen in sections stained with hematoxylin and eosin (H&E) (Fig. 27.4), but the distinctive inclusions are more readily visualized by immunostaining for ubiquitin or P62 (Fig. 27.5). Inclusions are seen in both sporadic and familial ALS. In many patients with motor neuron disease there is aggregation and mislocation of the protein TDP-43. Normally located in the nucleus (Fig. 27.7) the protein accumulates in the cytoplasm and forms inclusions in disease (Fig. 27.8). More rarely, ALS of juvenile onset is associated with the formation of cytoplasmic aggregates of FUS (fused-in-sarcoma) protein, another protein normally located in the nucleus.

27.4 Neuronal inclusion bodies in ALS.
(a) Bunina bodies (arrow) are small eosinophilic inclusions, 2–5 μm in diameter. They are often arranged in small beaded chains and are sparse in most ALS cases. (b) Motor neuron containing a small hyaline inclusion. (c) This motor neuron contains a small spherical hyaline inclusion. (d) Many hyaline inclusions appear as large homogeneous bodies that displace the Nissl substance. (e) Uncommon inclusions superficially resemble the Lewy bodies seen in Parkinson‘s disease but do not contain alpha synuclein.

27.5 Neuronal inclusions in ALS can be detected by anti-P62 or anti-ubiquitin antibodies.
These images are all anti-P62. (a) Inclusions may appear as compact, dense structures. (b) Skein inclusions may wrap around the nucleus (c) inclusions may extend into the nerve cell process. (d) Anti-P62 staining may show granular cytoplasmic material as well as filamentous skeins.

27.6 Ultrastructure of ALS inclusions.
Ultrastructural examination of ALS inclusions shows that they consist of haphazard arrays of 10–15 nm filaments associated with granules. (a) Low magnification. (b) Higher magnification. (c) The filaments may form parallel bundles with intervening granular material. The core protein is now known to be TDP-43.

27.7 TDP-43 immunostaining.
TDP-43 stains all nuclei, both in motor neurons and glial cells. In ALS, TDP-43 staining moves from the nucleus to the cytoplasm. In the pathological images below, note that nuclei are blue, reflecting relocation of nuclear TDP-43.

27.8 TDP-43 pathology in ALS.
(a) The majority of motor neurons in this spinal cord show inclusions immunoreactive for TDP-43, with loss of normal nuclear staining. (b) Some neurons show absent nuclear staining with granular cytoplasmic TDP-43 staining. (c) Skein-like inclusions as seen on P62 or ubiquitin immunostaining are also revealed by anti-TDP-43. (d,e) These two neurons show dense TDP-positive inclusions with threads extending into the nerve cell processes.

NECROPSY IN CASES OF MOTOR NEURON DISEASE

The brain and spinal cord should be fixed intact for subsequent histopathological examination.

Skeletal muscles and peripheral nerves should be sampled for histology, and, if possible, enzyme histochemistry and electron microscopy as occasionally peripheral neuropathy or primary muscle disease is clinically mistaken for ALS.

Postmortem blood samples should be taken for autoantibodies in appropriate cases.

Material may be archived for DNA analysis, especially in familial cases.

DIFFERENTIAL DIAGNOSIS OF ALS (SEE ALSO TABLE 27.1)

It may be difficult clinically to distinguish the progressive lower motor neuron degeneration syndromes of late onset spinal muscular atrophy (SMA type III), X-linked bulbospinal neuronopathy (spinobulbar muscular atrophy; Kennedy’s disease), and motor neuropathies associated with high titers of anti-ganglioside antibodies from variants of ALS.

Guam-type motor neuron disease is associated with neurofibrillary tangles in the cerebral cortex and spinal cord.

Motor neurons in the pons and medulla are often involved in the disease process and show histologic changes identical to those in the spinal anterior horn cells. The number of neurons in nuclei of the third, fourth, and sixth cranial nerves and Onufrowicz’s nuclei in the sacral cord is usually normal, but the cells may contain TDP-43-positive inclusions.

Loss of Betz cells may be evident in the motor cortex and be associated with astrocytic gliosis and microvacuolation (Fig. 27.9). Inclusions are not commonly found.

27.9 Histology in ALS motor cortex showing microvacuolation and neuronal loss, mainly in the outer layers.

Degeneration of myelinated fibers in the corticospinal tracts (Figs 27.10, 27.11) is usually more marked distally in the spinal cord than proximally in the internal capsule and cerebral peduncles. There may also be a loss of myelinated fibers from the spinocerebellar tracts and posterior columns and some workers suggest that this is characteristic of familial cases. The degeneration of anterior horn cells results in a loss of nerve fibers from the anterior roots with associated endoneurial fibrosis (Fig. 27.12).

27.10 Loss of corticospinal fibers in ALS.
(a) The internal capsule (arrow) and cerebral peduncle. (b) Pyramids (arrows) in the medulla. (c) The crossed ‘c’ and uncrossed ‘u’ corticospinal tracts in the cervical spinal cord.

27.11 Fiber degeneration in ALS.
(a) Sections through the cervical cord showing predominantly lateral (crossed) corticospinal tract and anterior spinal nerve root degeneration. (b) Marchi preparation demonstrating the products of fiber degeneration in the lateral and anterior corticospinal tracts. (c) Infiltration of the degenerating lateral corticospinal tract by CD68-immunoreactive macrophages.

27.12 Axon loss from nerve roots in ALS.
The nerve fascicle on the right contains many myelinated axons and is part of a sensory nerve root. The nerve fascicle on the left is part of a motor root and shows severe loss of myelinated axons (PTAH).

EXTRA-MOTOR INVOLVEMENT IN ALS

It is becoming increasingly apparent that ALS can be a multisystem disease with extra-motor involvement (Fig. 27.13). Affected regions may show variable neuronal loss and gliosis, and contain neurons with TDP-43 inclusions.

27.13 Extra-motor inclusions in ALS.
Inclusions are seen with anti-p62 immunochemistry. (a) Dot-like inclusions in granule cells of the hippocampal dentate fascia. (b) Small inclusions in neurons of layer II in the frontal cortex.

Frontotemporal dementia with TDP-43 pathology in the non-motor cortex is now recognized as a common form of non-Alzheimer primary degenerative dementia (see Chapter 32).

JUVENILE ALS WITH BASOPHILIC INCLUSIONS

An uncommon form of neurodegeneration, juvenile ALS with basophilic inclusion typically affects younger patients and leads to motor weakness. Inclusion bodies can be seen in motor neurons in H&E sections as well-defined basophilic structures (Fig. 27.14). It is recognized that these inclusions can be immunostained using antibodies to FUS (fused in sarcoma). Mutations in the gene coding for FUS have been found as a cause of this form of disease in some patients. This condition, presenting as juvenile ALS, is related to forms of frontotemporal lobar degeneration which are also characterized by FUS pathology in the group of FTLD-FUS discussed in Chapter 31. While mutations in the FUS gene have been found in ALS cases they are absent in FTLD-FUS.

27.14 Basophilic inclusions disease.
(a) Faintly basophilic inclusions are seen in motor neurons. (b) These are immunoreactive with anti-FUS antibodies.

X-LINKED BULBOSPINAL NEURONOPATHY (SPINOBULBAR MUSCULAR ATROPHY, KENNEDY’S DISEASE)

The disease is due to expansion of a tandem CAG repeat region in the first exon of the androgen receptor gene on the proximal part of the long arm of the X chromosome. Variable phenotypic expression between and within families is not clearly related to the size of the expansion.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

There is degeneration of facial, hypoglossal, and spinal cord motor neurons with neurogenic wasting of the corresponding skeletal muscles (particularly in the tongue). The third, fourth, and sixth cranial nerve nuclei are spared. Histologically, nuclear inclusions, detectable by immunostaining for the N-terminus of the AR protein or ubiquitin, can be found in affected spinal and brainstem motor neurons. Nuclear inclusions can also be found in non-neural tissues including skin, dermis, kidney, heart, and testis.

X-LINKED BULBOSPINAL NEURONOPATHY (KENNEDY’S DISEASE)

Is an X-linked recessive disorder affecting males, usually around the third decade (a milder form of disease is reported in elderly males).

Causes slowly progressive lower motor neuron weakness of facial, bulbar, and proximal limb muscles, associated with gynecomastia

Commonly associated with infertility and primary sensory neuronopathy.

SPINAL MUSCULAR ATROPHY (SMA)

SMA is a disorder characterized by progressive lower motor neuron degeneration and four main features are used to subdivide SMA into different groups (Tables 27.4, 27.5).

Table 27.4

Features used to classify SMAs

Age of onset

Infantile

Juvenile

Adult

Distribution of weakness

Scapuloperoneal (proximal)

Distal

Complex

Severity and clinical progression

Acute (rapidly progressive to death)

Chronic (slowly progressive)

Pattern of inheritance

Autosomal recessive

Autosomal dominant

X-linked recessive

Table 27.5

Classification of SMA

AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive.

SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS

Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct. In contrast to SMA1 where respiratory impairment is a late event, in SMARD this develops as an early part of the disease. SMARD is related to mutation in the immunoglobulin μ-binding protein-2 gene on chromosome 11.

BULBOSPINAL MUSCULAR ATROPHY

Loss of neurons from the lower cranial nerve nuclei leading to progressive bulbar paresis occurs in two very uncommon inherited disorders that occur in childhood: Fazio–Londe disease and Brown–Vialetto–van Laere syndrome. An abnormality of the C20orf54 gene, which encodes the human homolog of a rat riboflavin transporter, has been implicated in both conditions.

FAZIO–LONDE DISEASE

This condition is characterized by the onset of bulbar palsy at 2–5 years of age, and there are three subtypes (see also p. 146):

autosomal recessive with early respiratory symptoms and rapid progression

autosomal recessive with an onset in mid-childhood and a long clinical course

autosomal dominant.

Neuropathologic examination shows a loss of cochlear nerve fibers and dense astrocytosis in the ventral cochlear nuclei. There is also neuronal loss from the motor nuclei of the lower cranial nerves and variable degeneration of the spinocerebellar tracts, Purkinje cells, posterior columns, Clarke’s column, and anterior horn cells.

HEREDITARY SPASTIC PARAPARESIS

Hereditary spastic paraparesis is a heterogeneous condition characterized by slowly progressive spastic paraparesis with autosomal dominant, autosomal recessive, and X-linked recessive types.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Neuropathologic examination shows predominantly distal degeneration of corticospinal and posterior column tracts (see Chapter 25 for the differential diagnosis of distal degeneration of long axons in the CNS). In some cases this is associated with a loss of Purkinje cells and degeneration of cerebellar dentate nuclei.