**2.1 Clinical features**

The diagnosis of ALS is based on a catalogue of criteria specified by the World Federation of Neurology (www.wfneurology.org). These criteria are known as the "El Escorial" criteria, named after the Spanish historic site El Escorial. The original criteria of 1994 (Brooks, 1994; Mitsumoto, 1997) have been revised in 1998 (Brooks et al., 2000; Ross et al., 1998), which are known as the "Airlie House" criteria, named after the conference site at Warrenton, VA, U.S.A. In 2006, a consensus conference at Awaji-shima defined criteria of electromyographic and nerve conduction measurements for the diagnosis of ALS (de Carvalho et al., 2008).

The clinical features comprehend the presence of (i) lower motorneuron (LMN) signs such as the loss of muscle strength, muscular atrophy, fasciculations, hyporeflexia, hypotonicity or flaccidity, or muscle cramps, in at least two limbs; (ii) upper motorneuron (UMN) signs such as extensor plantar responses, spasticity, or pathologic hyperreflexia, in at least one region (bulbar, cervical, or lumbosacral), and (iii) the progression of the disease defined as increasing symptomatic impairment by history in the same region or new regions (Ferguson & Elman, 2007).

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials 5

With regard to the diagnoses and prevalence of these in ALS patients, there are only few

Psychiatric Diagnosis Prevalence (percentages, rounded) and

Dementia 10 (Lillo et al., 2011)

Apathy 40 (Lillo et al., 2011) Cognitive impairment 50 (Woolley & Jonathan, 2008) Sleep disturbances Unknown (Hetta & Jansson, 1997)

Fatigue Unknown Psychosis Unknown

In the following paragraphs, I will shortly describe the major psychiatric abnormalities in

In the concept of a "continuum" of TDP-43 proteinopathies (Geser et al., 2009), ALS is classified together with fronto-temporal dementia (Giordana et al., 2011; Lillo & Hodges, 2009; Nakano, 2000; Woolley & Jonathan, 2008; Yoshida, 2004; Zago et al., 2011). This has

Another pathophysiological pathway discussed in the pathogenesis of FTD is the

Cognitive impairment and frontal lobe dysfunction is seen in about 40-60% of ALS patients

In the current understanding, it is difficult to distinguish whether psychiatric abnormalities in ALS patients are integral part of the CNS disease, or if they are a secondary phenomenon. For example, sleep disturbances are a common problem in ALS patients, but besides anxiety, they may also result from reduced mobility, muscle cramps, or swallowing

Fatigue is also a common problem in ALS patients, which does not describe physical

exhaustion, but a pathological state of mind (Jackson & Bryan, 1998; Lou, 2008).

Table 1. Common psychiatric symptoms and diagnoses reported in ALS patients.

also been shown on the morphological level (Tsujimoto et al., 2011).

(Abrahams et al., 1996; Evdokimidis et al., 2002; Witgert et al., 2009).

Stereotypical behavior 20 (Lillo et al., 2011) Reduction in motivation 80 (Lillo et al., 2011)

reference

30(Atassi et al., 2011; Lillo et al., 2011); 15 (Ferentinos et al., 2011); 10 (Kurt et al., 2007)

data available, which are summarized in **Table 1**.

Depression

ALS patients and current findings.

progranulin pathway (Sleegers et al., 2010).

problems (Hetta & Jansson, 1997).

**2.2.1 Dementia** 

**2.2.2 Sleep** 

**2.2.3 Fatigue** 

Fig. 1. Spectrum of motor neuron disease (MND). Currently, the understanding of MND comprehends a variety of neurodegenerative syndromes with progressive degeneration of motor neurons.

Neuropathological findings defining the MND spectrum are, on the cellular level, the progressive degeneration of upper and/or lower motor neurons, respectively, and on the molecular level, the presence of intraneuronal inclusion bodies which are immunopositive for ubiquitin-(Ub) and the 43 kB TAR DNA-binding protein (TDP-43) (reviewed in Colombrita et al., 2011; Geser et al., 2010), named Bunina, or Hirano, inclusion bodies (Rowland, 2009).

Moreover, sensory signs (except those attributable to aging), neurogenic sphincter abnormalities, other progredient diseases of the central nervous system (CNS) or peripheral nervous system (PNS) must be absent. Additionally, ALS-like syndromes must be ruled out. These include myelopathy, structural lesions of the spinal cord, multifocal motor neuropathy, hyperthyroidism, hyperparathyroidism, hematologic malignancy associated with monoclonal gammopathy, lead poisoning, a history of radiation to the CNS, and hexosaminidase A deficiency in patients younger than 30 years of age.

The revised criteria defined a certain probability level for the diagnostic criteria (Brooks et al., 2000), which have been questioned by the later electrophysiological consensus (de Carvalho et al., 2008; Sathasivam, 2010).

At present, a consensus conference has defined morphological markers by MRI, which may lead to a biomarker for ALS diagnosis (Kiernan et al., 2011; Turner et al.).

### **2.2 Neuropsychiatry of ALS**

Only in recent years, psychiatric and behavioural symptoms of ALS patients came into the focus of interest. It has become clear that psychiatric symptoms are not only secondary phenomena of a disabilitating disease, but are also inherent and specific in ALS. On the other hand, the etiopathological connections remain unknown.

With regard to the diagnoses and prevalence of these in ALS patients, there are only few data available, which are summarized in **Table 1**.


Table 1. Common psychiatric symptoms and diagnoses reported in ALS patients.

In the following paragraphs, I will shortly describe the major psychiatric abnormalities in ALS patients and current findings.

### **2.2.1 Dementia**

4 Amyotrophic Lateral Sclerosis

Fig. 1. Spectrum of motor neuron disease (MND). Currently, the understanding of MND comprehends a variety of neurodegenerative syndromes with progressive degeneration of

Neuropathological findings defining the MND spectrum are, on the cellular level, the progressive degeneration of upper and/or lower motor neurons, respectively, and on the molecular level, the presence of intraneuronal inclusion bodies which are immunopositive for ubiquitin-(Ub) and the 43 kB TAR DNA-binding protein (TDP-43) (reviewed in Colombrita et al., 2011; Geser et al., 2010), named Bunina, or Hirano, inclusion bodies

Moreover, sensory signs (except those attributable to aging), neurogenic sphincter abnormalities, other progredient diseases of the central nervous system (CNS) or peripheral nervous system (PNS) must be absent. Additionally, ALS-like syndromes must be ruled out. These include myelopathy, structural lesions of the spinal cord, multifocal motor neuropathy, hyperthyroidism, hyperparathyroidism, hematologic malignancy associated with monoclonal gammopathy, lead poisoning, a history of radiation to the CNS, and

The revised criteria defined a certain probability level for the diagnostic criteria (Brooks et al., 2000), which have been questioned by the later electrophysiological consensus (de

At present, a consensus conference has defined morphological markers by MRI, which may

Only in recent years, psychiatric and behavioural symptoms of ALS patients came into the focus of interest. It has become clear that psychiatric symptoms are not only secondary phenomena of a disabilitating disease, but are also inherent and specific in ALS. On the

hexosaminidase A deficiency in patients younger than 30 years of age.

lead to a biomarker for ALS diagnosis (Kiernan et al., 2011; Turner et al.).

other hand, the etiopathological connections remain unknown.

Carvalho et al., 2008; Sathasivam, 2010).

**2.2 Neuropsychiatry of ALS** 

motor neurons.

(Rowland, 2009).

In the concept of a "continuum" of TDP-43 proteinopathies (Geser et al., 2009), ALS is classified together with fronto-temporal dementia (Giordana et al., 2011; Lillo & Hodges, 2009; Nakano, 2000; Woolley & Jonathan, 2008; Yoshida, 2004; Zago et al., 2011). This has also been shown on the morphological level (Tsujimoto et al., 2011).

Another pathophysiological pathway discussed in the pathogenesis of FTD is the progranulin pathway (Sleegers et al., 2010).

Cognitive impairment and frontal lobe dysfunction is seen in about 40-60% of ALS patients (Abrahams et al., 1996; Evdokimidis et al., 2002; Witgert et al., 2009).

### **2.2.2 Sleep**

In the current understanding, it is difficult to distinguish whether psychiatric abnormalities in ALS patients are integral part of the CNS disease, or if they are a secondary phenomenon. For example, sleep disturbances are a common problem in ALS patients, but besides anxiety, they may also result from reduced mobility, muscle cramps, or swallowing problems (Hetta & Jansson, 1997).

### **2.2.3 Fatigue**

Fatigue is also a common problem in ALS patients, which does not describe physical exhaustion, but a pathological state of mind (Jackson & Bryan, 1998; Lou, 2008).

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials 7

A consensus conference has defined electrophysiological criteria for the diagnosis of ALS

The quality of life is assessed by questionnaires such as the Short form – 36 (SF-36), Short form – 12 (SF-12), ALSQ-40, or the Sickness Impact Profile (reviewed in Epton et al., 2009;

Pathophysiological mechanisms involved in ALS include (reviewed in Mitsumoto et al.,

genetic factors (reviewed in Pasinelli & Brown, 2006; Robberecht, 2002; Ticozzi et al.,

mitochondrial and SOD1 dysfunction (reviewed in Benatar, 2007; Shi et al., 2010;

neurofilament and protein aggregation such as TDP-43 proteinopathies (reviewed in

neuro-inflammation (reviewed in Graber & Dhib-Jalbut, 2009; Holmoy, 2008; Lipton et

the lack or dysfunction of neurotrophic factors (reviewed in Maurer et al., 2008;

These pathophysiological mechanisms all end in motor neuron degeneration as the final pathway in disease progression (reviewed in Bruijn et al., 2004; Carlesi et al., 2011; Thatte &

To address the genetic influence in ALS, two databases have been established. The ALSoD database (alsod.iop.kcl.ac.uk) contains detailed information about genes involved in ALS pathophysiology, and the ALSGene database lists genetic association studies

**4.2 Pathophysiological considerations in the planning of ALS treatment strategies**  Most pre-clinical trials in ALS research started with the pathophysiological model of the disease. In counteracting the pathophysiology of the disease, motor neuron survival and stabilization of motor neuron function is increased (reviewed in Bedlack et al., 2007; Carlesi et al., 2011; Fornai et al., 2011; Ilieva et al., 2009; Pradat et al., 2010; Silani et al.,

Current strategies for treatment concepts reach for counteracting the individual

 Anti-excitotoxicitory drugs. Excitotoxicity is mainly modulated by the release of glutamate and contributes to an acute toxicity. Typical molecules involved are the NMDA and AMPA receptors and the glial glutamate transporter Excitatory amino-acid

pathophysiological actors. They including the following groups of agents:

**4. The pathophysiological rationale for therapeutic interventions** 

 excitotoxicity (reviewed in Bogaert et al., 2011; Foran & Trotti, 2009), oxidative stress (reviewed in Kaur & Ling, 2008; Orrell et al., 2008),

**4.1 Pathophysiology of motor neuron degeneration in ALS** 

 impaired axonal transport (reviewed in Costa et al., 2010), apoptosis and cell death (reviewed in Sathasivam et al., 2001),

Geser et al., 2010; Worrall et al., 2000),

al., 2007; Weydt & Moller, 2005), and

(www.alsgene.org) (Lill et al., 2011).

Siciliano et al., 2010; Traynor et al., 2006).

(de Carvalho et al., 2008).

**3.4 Assessment of the quality of life** 

2006; Wijesekera & Leigh, 2009):

Valentine et al., 2005),

2011),

Dahanukar, 1997).

2011).

McGuire et al., 1997; Williams et al., 2008).

### **2.2.4 Depression and anxiety**

The patients know about the devastating nature of ALS with only a short survival time remaining at the point of time at diagnosis, with a deteriorating quality of life, and without a pharmacological treatment option towards "healing". Therefore, a high prevalence of depression and anxiety in ALS patients would be expected. On the other hand, prevalence rates for depression in ALS patients range from 0-44% in the literature, whereas structured interviewing according to DSM-IV criteria reveals rates of 9-11% (Averill et al., 2007; Ferentinos et al., 2011; Kurt et al., 2007). Prevalence rates for anxiety in ALS have been reported with 0-30% (Kurt et al., 2007). Interestingly, the rate of depression and anxiety is not as high as expected (Huey et al., 2010; McLeod & Clarke, 2007; Norris et al., 2010), which means that the quality of life addressed by an individual is not dependent on the remaining lifetime.
