**4. Aetiology, pathology and pathogenesis of motor neuron disease**

MND is one of the complex and misunderstood diseases that health care professionals may encounter for various different reasons: (1) there are multiple different forms of the disease (Strong and Rosenfeld.2003), (2) the pathogenesis is not fully delineated (Wijesekera and Leigh.2009), (3) diagnosis can occur only by exclusion, (4) there exists only FDA approved medication, riluzole, for the treatment of ALS2 (Washington.2007), and despite this, (5) there is no cure for this disease.

Environmental exposures during the Gulf war have been proposed as the explanation for an increased incidence of ALS among Gulf War veterans (Haley 2003, Horner et al, 2003)**.** 

#### **4.1 Neuropathological findings in MND**

Gross changes were frontotemporal atrophy, which was usually mild to moderate, neither circumscribed nor of a 'Knife-blade' type, and atrophy of the anterior roots in the cervicothoracic spinal cord, which was seen in cases with definite lower motor neuron involvement. Cortical atrophy was marked in the limbic system including the temporal pole, parahippocampus and amygdala but usually spared the hippocampus in typical ALS – Dementia (ALS-D) cases. (Yoshida 2004).

Histological changes included neuronal loss and gliosis with sponginess in layers II and III of frontotemporal cortices with predominant involvement of the limbic system including the anterior cingulated gyrus, anterior temporal and insular lobes, parahippocampus, subiculum and amygdale in typical cases. (Yoshida 2004).

The full pathogenesis of ALS is not well understood as it has not been fully elucidated by medical research. However, several key factors can be noted including: (1) Genetics, (2)

males are more commonly affected than females (1.4:1). The incidence increases with age with a mean age of onset of 63 years, (Ringel, et al 1993). It ranks as the third most common neurological degenerative disorder after Alzheimer's and Parkinson's disease (Talbot 2002). In Guam, the incidence of MND has fallen from 87/100,000 in 1962 to 5/100,000 in 1985,

Within the Caucasian population of Europe and North America, where most of the studies have been conducted, the lowest reported incidence of MND was 0.6 per 100.000 person – years in Italy,(De Domenice, et al. 1988) and the highest reported was 2.4 per 100.000 personyears in Finland(Murros and Fogelholm.1983). However, a lower incidence rate of 0.3/100,000

In the only well-conducted study of MND incidence among black African population, the incidence of MND was noted to be 0.9 per 100,000 person-years in Libya, (Radhakrishnan, et

The incidence of MND is said to be increasing, but this is probably the result of improved diagnosis, better awareness of the disease and an aging population, (Leigh and Ray-Chaudhuri.1994). The incidence increases after the age of 40 years, peaks in the late 60s and

MND is one of the complex and misunderstood diseases that health care professionals may encounter for various different reasons: (1) there are multiple different forms of the disease (Strong and Rosenfeld.2003), (2) the pathogenesis is not fully delineated (Wijesekera and Leigh.2009), (3) diagnosis can occur only by exclusion, (4) there exists only FDA approved medication, riluzole, for the treatment of ALS2 (Washington.2007), and despite this, (5) there

Environmental exposures during the Gulf war have been proposed as the explanation for an increased incidence of ALS among Gulf War veterans (Haley 2003, Horner et al, 2003)**.** 

Gross changes were frontotemporal atrophy, which was usually mild to moderate, neither circumscribed nor of a 'Knife-blade' type, and atrophy of the anterior roots in the cervicothoracic spinal cord, which was seen in cases with definite lower motor neuron involvement. Cortical atrophy was marked in the limbic system including the temporal pole, parahippocampus and amygdala but usually spared the hippocampus in typical ALS –

Histological changes included neuronal loss and gliosis with sponginess in layers II and III of frontotemporal cortices with predominant involvement of the limbic system including the anterior cingulated gyrus, anterior temporal and insular lobes, parahippocampus,

The full pathogenesis of ALS is not well understood as it has not been fully elucidated by medical research. However, several key factors can be noted including: (1) Genetics, (2)

person-years was reported among Asian population, in China, (Fong, et al. 1996).

**4. Aetiology, pathology and pathogenesis of motor neuron disease** 

early 70s, and declines rapidly after that, (Logroscino, et al. 2008).

(Rodgers-Johanson, et al. 1986).

al. 1986).

is no cure for this disease.

**4.1 Neuropathological findings in MND** 

Dementia (ALS-D) cases. (Yoshida 2004).

subiculum and amygdale in typical cases. (Yoshida 2004).

Excitotoxicity, (3) Oxidative stress, (4) Mitochondrial dysfunction, (5) Impaired axonal transport, (6) Neurofilament aggregation, (7) Protein aggregation, (8) Inflammatory dysfunction and contribution of non-neuronal cells, (9) Deficits of neurotrophic factors and dysfunction of signaling pathways, and (10) Apoptosis, (Wijesekera and Leigh.2009 and Shaw. 2005).

#### **4.2 Genetics**

Up to 90% of all ALS cases, occurs without family history, (sporadic ALS) and about 10% of cases are familial ALS (FALS). SALS is clinically indistinguishable from FALS, but the average age of onset in FALS is somewhat earlier, (Celveland and Rothstein (2001). Enteroviral infections and mutations of superoxide dismutase 1gene (SOD1) have been implicated in the pathogenesis of MND (oluwale et al 2001). About 25% of ALS cases, (Celveland and Rothstein (2001)**,** and 2% of the sporadic cases, are linked to mutations in the gene encoding copper/zinc superoxide dismutase (SOD1). It is Known that there may be as many as six gene loci that code for the ALS phenotype, but only three have been identified. Several other mutations have also been documented to possibly take part in the pathogenesis of ALS, (Wijesekera and Leigh, 2009)**.** Since the link between SOD1 and FALS was first established, >90 FALS-linked SOD1 mutations have been discovered, (Celveland and Rothstein (2001). Most of these mutations are point missense mutations, (Anderson, et al. 2003). Most of the genetics are transmitted via the autosomal dominant route, though some are autosomal recessive and others may be sex-linked, (Wijesekera and Leigh.2009).

#### **4.3 Excitotoxicity**

Excitotoxicity is a term used to signify the damage that occurs to neuronal cells that are characterized by overstimulated glutamate receptors, as glutamate is the major excitatory neurotransmitter in the human central nervous system (Riluzol monograph. 2011). As SOD1 codes for the major reuptake protein of glutamate, a mutation limits the concentration levels of that reuptake protein, allowing an excessive amount of glutamate to be present in the neuronal synapse. It is also postulated that glutamatergic toxicity plays a direct role in the destruction of neuronal cells in patients with ALS.( Shaw. 2005).

#### **4.4 Oxidative stress**

Oxidative stress is of particular interest to researchers due to the fact that the SOD1 gene mutation that is known to cause ALS, normally codes for an anti-oxidant protein. (Riluzol momgraph. 2011)

#### **4.5 Mitochondrial dysfunction**

There are many new data which supports the theory that mitochondrial dysfunction plays an important role in the pathogenesis of ALS. Multiple cases of dysfunctional mitochondria have been noted in post-mortem analyses of ALS patients. (Wijesekera and Leigh.2009) Dysfunctional mitochondria have also been linked to the SOD1 gene mutation in mice models. (Shaw. 2005)

Motor Neuron Disease 205

Dilemmas of symptoms and signs are described for diagnosis of MND and its subtypes. Motor symptoms of both upper and lower motor neuron dysfunction can occur in any muscle group, including limbs, and, or bulbar regions. Combinations of the previous motor symptoms is not characteristic for MND and can be observed in many diseases, known as "MND Mimic Disorders" such as, Kennedy's diseases, multifocal motor neuropathy,

Meticulous evaluation by thorough history and examination by two or more specialists of neurology are required for diagnosis of MND. Special investigations are required for

**Preclinical stage Diagnosis stage Progression stage Terminal stage** 

 weakness of one leg followed by other leg and patient will require a wheelchair to assist him Swallowing Problems Respiratory

 Respiratory insufficiency symptoms

> and signs of tachypnea,

2007.)

24 hours Medication, Diet, Hygiene and special

> attention for respiration.

orthopnea, excessive daytime sleepiness, poor concentration, memory and appetite

tachycardia, syncope and confusion, (Radunovic et al

Nursed and care for

muscle weakness and dyspnea All these

> symptoms are observed in different combinations according to different subtypes

of MND

The classical concept that MND only affects the motor system is obsolete. MND is considered to be a multisystem neurodegenerative disease. There is increasing clinical evidence for autonomic dysfunction (Baltadzhieva, et al 2006 and Takeda, et al, 1994), sensory abnormalities (Takeda et al, 1994) (Pugdahl et al, 2007) and ophthalmoplegia

**5. Clinical presentation of motor neurone disease** 

diagnosis of MND and differentiation from MND mimics.

Swash 1987) Onuf''s sacral nucleus (innervate anal and urinary sphincter muscles) are always spared (Schroder, and Reske Nelson 1984) Ocular motor nuclei are also relatively resistant (Mulder 1982)

Table 1. Stages of Motor Neuron Disease (MND)

2. Severe and early presentations of bulbar symptoms.

**6. Bad prognostic factors for MND** 

1. Late age of onset.

3. Respiratory complications.

 Selective involvement of motor neurons in the anterior horns of the spinal cord early and late in the disease (Swash et al. 1986) corticospinal pathways in the cord are similarly, asymmetrically affected (Ingram and

brainstem lesions (syrinx, stroke,………. etc)

 Long duration (months or even

years Disease spread through motor

system Usually

Asymptomatic

#### **4.6 Impaired axonal transport**

The theory that axonal transport is a key to ALS pathogenesis stems from SOD1 transgenic mice models. Mice from these models often show slowed anterograde and retrograde axonal transport. Although no human ALS patient has presented with this problem, yet it is known to occur in several other neuromuscular disorders of the human body. (Wijesekera and Leigh.2009)

#### **4.7 Neurofilament aggregation**

Abnormal neuronal assembly, including accumulation of neurofilaments, are often seen in ALS patients. Neurofilaments can combine with a toxic form of peripherin, an intermediate filament protein, and become toxic to neurons even at modest concentration levels. This combination has been found in the spinal cord of ALS patients and not in controls. This evidence points to neurofilament aggregation as being a part of ALS pathogenesis. (Wijesekera and Leigh.2009)

### **4.8 Protein aggregation**

Long debates as to whether protein aggregation take a part in disease pathogenesis have been occurred. It is possible that these inclusions may simply be innocent bystanders, or even beneficial to the cells. (Wijesekera and Leigh.2009)

### **4.9 Inflammatory dysfunction and contribution of non-neuronal cells**

It has been recently discovered that SOD1 mutations alone are insufficient to cause ALS in transgenic mice, making the case that non-neuronal cells, as microglial and dendritic cells, may play a part in ALS pathogenesis (Shaw, 2005). ALS patients commonly experience activation of the non-neuronal microglial and dendritic cells. This activation has been shown to produce inflammatory cytokines such as interleukins and tumor necrosis factor (TNF). However, recent trials have yet to see success in utilizing immunomodulatory drug therapies to curve the progression of ALS. (Wijesekera and Leigh.2009).

#### **4.10 Deficits of neurotrophic factors and dysfunction of signaling pathways**

Lowered levels of neurotrophic factors have been noticed in post-mortem analysis of several ALS patients. In addition, three mutations in the Vascular Endothelial Growth Factors (VEGF) gene were thought to be associated with an increased risk for developing ALS. However, recently these finding have come under scrutiny due to an inability to replicate research results. (Wijesekera and Leigh.2009)

#### **4.11 Apoptosis**

Current research also skews towards examining if ALS motor neuron destruction occurs via a programmed cell death, or apoptosis. Several studies have shown that cell death due to ALS often occurs because of this programmed apoptosis, yet these findings are still being reviewed and discussed heavily. ( Shaw. 2005)**.**

The theory that axonal transport is a key to ALS pathogenesis stems from SOD1 transgenic mice models. Mice from these models often show slowed anterograde and retrograde axonal transport. Although no human ALS patient has presented with this problem, yet it is known to occur in several other neuromuscular disorders of the human body. (Wijesekera and

Abnormal neuronal assembly, including accumulation of neurofilaments, are often seen in ALS patients. Neurofilaments can combine with a toxic form of peripherin, an intermediate filament protein, and become toxic to neurons even at modest concentration levels. This combination has been found in the spinal cord of ALS patients and not in controls. This evidence points to neurofilament aggregation as being a part of ALS pathogenesis.

Long debates as to whether protein aggregation take a part in disease pathogenesis have been occurred. It is possible that these inclusions may simply be innocent bystanders, or

It has been recently discovered that SOD1 mutations alone are insufficient to cause ALS in transgenic mice, making the case that non-neuronal cells, as microglial and dendritic cells, may play a part in ALS pathogenesis (Shaw, 2005). ALS patients commonly experience activation of the non-neuronal microglial and dendritic cells. This activation has been shown to produce inflammatory cytokines such as interleukins and tumor necrosis factor (TNF). However, recent trials have yet to see success in utilizing immunomodulatory drug

Lowered levels of neurotrophic factors have been noticed in post-mortem analysis of several ALS patients. In addition, three mutations in the Vascular Endothelial Growth Factors (VEGF) gene were thought to be associated with an increased risk for developing ALS. However, recently these finding have come under scrutiny due to an inability to replicate

Current research also skews towards examining if ALS motor neuron destruction occurs via a programmed cell death, or apoptosis. Several studies have shown that cell death due to ALS often occurs because of this programmed apoptosis, yet these findings are still being

**4.6 Impaired axonal transport** 

**4.7 Neurofilament aggregation** 

(Wijesekera and Leigh.2009)

**4.8 Protein aggregation** 

even beneficial to the cells. (Wijesekera and Leigh.2009)

research results. (Wijesekera and Leigh.2009)

reviewed and discussed heavily. ( Shaw. 2005)**.**

**4.11 Apoptosis** 

**4.9 Inflammatory dysfunction and contribution of non-neuronal cells** 

therapies to curve the progression of ALS. (Wijesekera and Leigh.2009).

**4.10 Deficits of neurotrophic factors and dysfunction of signaling pathways** 

Leigh.2009)
