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.