Movement disorders: Focused ultrasound thalamotomy shows early promise for treatment of essential tremor

Neurologists in the 19th century recognized that muscle weakness could be due to primary disorders of muscle or secondary to loss of neuromuscular integrity, as happens when peripheral nerves are cut or when motor neurons degenerate. Furthermore, it was observed that there are forms of motor neuron degeneration which selectively affect upper motor neurons or lower motor neurons. A combination of upper and lower motor neuron dysfunction was named amyotrophic lateral sclerosis (ALS) by Charcot and Joffroy (Ringel, et al 1993). Jean-Martin Charcot first characterized the disease in 1874, naming the illness Amyotrophic lateral sclerosis (ALS) (Swash, 2001). In USA, ALS or Lou Gehrig's disease are terms used to describe all forms of the disease, whatever the combination of upper and lower motor neuron involvement (Ringel, et al 1993). ALS is now a term which classifies the most common form of the illness and is often used synonymously with MND (Swash, 2001). In the UK the umbrella term motor neuron disease (MND) is more common. MND is a disease of middle to late life with a mean age of onset of 58 years, (Ringel, et al 1993).


Introduction
Neurologists in the 19 th century recognized that muscle weakness could be due to primary disorders of muscle or secondary to loss of neuromuscular integrity, as happens when peripheral nerves are cut or when motor neurons degenerate. Furthermore, it was observed that there are forms of motor neuron degeneration which selectively affect upper motor neurons or lower motor neurons. A combination of upper and lower motor neuron dysfunction was named amyotrophic lateral sclerosis (ALS) by Charcot and Joffroy (Ringel, et al 1993). Jean-Martin Charcot first characterized the disease in 1874, naming the illness Amyotrophic lateral sclerosis (ALS) (Swash, 2001). In USA, ALS or Lou Gehrig's disease are terms used to describe all forms of the disease, whatever the combination of upper and lower motor neuron involvement (Ringel, et al 1993). ALS is now a term which classifies the most common form of the illness and is often used synonymously with MND (Swash, 2001). In the UK the umbrella term motor neuron disease (MND) is more common. MND is a disease of middle to late life with a mean age of onset of 58 years, (Ringel, et al 1993).
Actually, motor neuron diseases (MND) are a group of degenerative disorders that selectively affect motor neurons in the brain and spinal cord. Two groups of motor neurons are involved, lower motor neurons located in ventral horns of the spinal cord and brainstem motor nuclei, and upper motor neurons located in the cerebral cortex together with pyramidal tracts in spinal cord. The term MND is a broad spectrum term including amyotrophic lateral sclerosis.

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 ALS 2 (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.

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).

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).

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).

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)

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)

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)

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)

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)

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).

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)

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).

Clinical presentation of motor neurone disease
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, brainstem lesions (syrinx, stroke,………. etc) 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 diagnosis of MND and differentiation from MND mimics.  (Swash et al. 1986)  corticospinal pathways in the cord are similarly, asymmetrically affected (Ingram and 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)  weakness of one leg followed by other leg and patient will require a wheelchair to assist him  Swallowing 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 andTakeda, et al, 1994), sensory abnormalities (Takeda et al, 1994) (Pugdahl et al, 2007) and ophthalmoplegia (Takeda, et al, 1994) in MND. On the other hand, there are good pathological accounts of the involvement of sympathetic and parasympathetic neurons, (Takeda, et al, 1994), Onuf's nucleus (which innervates the pelvic floor sphincteric muscles), (Takeda, et al, 1994) peripheral sensory nerves, (Isaacs, et al. 2007) and oculomotor nuclei. (Takeda, et al, 1994). However, in practical terms, the presence of prominent ophthalmoplegia, sensory signs or sphincter dysfunction should raise doubts regarding the diagnosis of MND, unless there are a clear alternative explanation. Death usually results from ventilatory muscle weakness causing respiratory failure.

Cognitive function impairment in motor neuron disease
Cognitive impairment is increasingly being recognized in MND. Subtle subclinical cognitive defects and frontal lobe dysfunction may be demonstrated in up to half of MND patients with detailed neuropsychological testing (Ringholz, et al. 2005). Several genetic mutations of MND have been identified in association with frontotemporal dementia and/or parkinsonism (Valdmanis and Rouleau. 2008). It is well recognized that MND is a multisystem disorder (Geser, et al, 2008) with compromise of regions beyond the motor system, including cortical areas which are consistently involved in FTD. It comes as no surprise, therefore, that a proportion of patients presenting with MND manifest cognitive and/or behavioural changes which may be severe enough in some instances to reach criteria for frank FTD. (Irwin, et al, 2007).

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)
There is icreasing clinical, imaging and neurophysiological evidence that ALS represents a multisystem neurodegerative disease. Neurodegeneration is not restricted to motor neurons, but also includes parts of the brain other than the motor cortex, especially the preforntal and/or anterior temporal lobe, that contribute to the clinical syndrome. In some cases an evident dementia that resembles frontotemporal degeneration (FTD) was observed. It is now suggested that ALS and FTD are closely related conditions with overlapping clinical, pathological, radiological, and genetic characteristics. The presence of a frontal dementia in ALS has also crucial practical consequences for management of the patients, whose disorder requires critical life decisions for enteral nutrition and respiratory complications. (Zago, et al. 2010).

The new classification of cognitive and behavioral disorder in ALS
In 2009, Strong and colleagues articulated new guidelines to direct ongoing investigations of cognitive and behavioral syndromes in ALS (Strong et al., 2009 neuropsychological status of ALS patients a framework was based on four different axes. Axis I is based on the EL Escorial criteria proposed in 1998, that includes possible, probable, and definite ALS clinical subtypes. This multidimensional approach incorporates several criteria (Brooks et al, 2000). The novelty of the classification lies primarily in Axis II with the proposal of five categories which classify ALS patients along a continuum: (1) ALS patients cognitively and behaviorally intact: (2) ALS patients with mild cognitive impairments; (3) ALS patients with mild behavioral impairment; (4) ALS with a full-fledged fronto-temporal dementia; (5) ALS with other non FTD-forms of dementia.
Axis III indicates the presence, in addition to frontotemporal impairments, of additional non-motoneuronal disease manifestations such as extrapyramidal signs, cerebellar degenerations, autonomic dysfunctions, sensory impairments, and ocular motility abnormalities. The absence of the above indicates a "pure form," while their presence defines "complicated forms" with additional pathological motor aspects. Axis IV, instead, provides the search for factors which could modify the course of the disease. Several disease modifiers have been reported in literature associated with longer survival, age at symptom onset (< 45 years), gender (male/sex), and site of the disease onset (bulbar or limb).

Language
Language deficits are occasionally found in the early stages of the disease. (Abrahams, et al. 2004).
The spectrum of language impairment in MND is wider than simply a problem in speech production due to dysarthria, but it is yet to be fully characterized. Reduced verbal output (adynamism) evolving into mutism has been reported, as well as echolalia. Perseverations, stereotypical expressions, (Bak and Hodges. 2004), true non-fluent aphasia with phonological and/or syntactic deficits and comprehension impairment have been reported in isolated cases. (Tsuchiya, et al. 2000) MND has also been associated with apraxia of speech, in which there is breakdown in articulatroy planning, producing slowed, effortful and dysprosodic speech with problems repeating multisyllabic words. Apraxia of speech is often accompanied by orobuccal apraxia but not necessarily with aphasia. (Duffy, et al ,2007).

Memory
It has been difficult to categorize the pattern of memory impairment, but current evidence suggests that memory problems are related to abnormalities in retrieval of the information secondary to frontal dysfunction. (Neary, et al. 2000). Memory problems involve primarily immediate recall, (Phukan. et al. 2007) but impairment of visual memory also has been implicated, (Kew, et al.1993) Frontal, temporal and thalamic hypoperfusion on SPECT has been shown to correlate with the severity of memory impairment. (Montovan, et al. 2003).
Most strikingly, learning and memory were found to be significantly improved in patients in the later stages of the disease, (Lakerveld et al, 2008).
Definite ALS Upper and lower motor neuron signs in at least three body regions (upper limb, lower limb, bulbar, thoracic).

Clinically probable ALS
Upper and lower motor neuron signs in at least two regions, with some upper motor neuron signs necessarily rostoral to the lower motor neuron signs

Clinically probable ALS: Laboratory-supported ALS
Clinical signs of upper and lower motor neuron dysfunction in only one region, or when upper motor neuron signs alone are present in one region and lower motor neuron signs defined by electromyographic criteria are present in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.

Clinically possible ALS
Clinical signs of upper and lower motor neuron dysfunction are together in only one region, or upper motor neuron signs are found alone in two or more regions, or lower motor neuron signs are found rostral to upper motor neuron signs and the diagnosis of clinically probable: laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiological, neuroimaging or clinical laboratory studies. Other diagnoses must have been excluded * (Brooks, 1994 andBrooks, et al. 2000) ** Als: amyotrophic lateral sclerosis Table 4. Revised El Escorial criteria for the diagnosis of ALS.*

Diagnostic criteria for motor neuron disease (amyotrophic lateral sclerosis, ALS) by** Leigh and Ray -Chaudhuri 1994
The diagnosis of ALS requires the presence of:

Investigations
There are no specific investigations for MND. Till now there are no specific biochemical or pathological markers of MND. The aim of Elctrophysiological, Imaging and laboratory investigations is to exclude MND mimics and/ or to support clinical signs presented by the patients. Allum and Shaw (2010) clarified that investigations are important adjuncts to the clinical diagnosis of MND. Properly used they can provide supportive evidence of the clinical findings and help delineate the extent of disease. Investigations are also important to identify benign or treatable MND mimics.

Treatment plan of motor neuron disease
Although MND is still incurable disease up till now, in the last two decades MND management has evolved rapidly. Symptomatic treatment of MND still had the upper hand of management plan, especially for respiratory and bulbar complications. A team of work including neurologist, highly qualified nurses, ICU specialist in respiratory complications, psychologist, dietition, physiotherapy and speech therapist must be involved for management plan and follow up of MND patients, table (5).
Thus treatment strategy of MND was aimed towards; 1. Delay Progression of the disease and prevent further loss of motor neurons especially in the early stage of the disease 2. Symptomatomatic treatment to alleviate symptoms of the disease aiming to maintain quality of life

Pharmacological treatment
Riluzole (2-amino-6-(trifluoromethoxy) benzothiazole, RP 54274) is the only drug licensed to treat ALS. Although the drug reduces glutamate-induced excitotoxicity, its précis mechanism in ALS is unknown. A Cochrane Library meta-analysis (including three doubleblind randomized placebo controlled trials by (Miller, 2002) suggests that riluzole provides a 9% gain in the probability of surviving one year and adds approximately 2 months to patient survival.

Riluzole, exerts the following pharmacologic effects:
 An inhibitory effect on glutamate release.  Inactivation of Voltage -dependent sodium channels.  Ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptor (Riluzole monograph 2011).
 Dosage 50mg twice daily  Side Effects Nausea and vomiting, Asthenia, somnolence Headache, dizziness, and vertigo  Serious Adverse Effects  Elevation in liver transaminases. Regular monitoring of liver function is advised (every month for 3 months, every 3 months for a further nine months then annually thereafter).  Rare cases of neutropenia have been reported. White cell count must be checked in the case of febrile illness Contraindications-Renal and hepatic impairment Pregnancy and breast-feeding (Brockington and Shaw, 2003)

a. Respiratory complications
Respiratory impairment is common in MND and may develop because of respiratory muscle weakness, impaired bulbar function causing aspiration or obstructive sleep apnea, or defects in central control. Dyspnea may be due to infection, pulmonary embolus, or airway obstruction from mucous plug or inhaled pharyngeal contents. (Howard and Wiles,1989).
Symptoms of respiratory insufficiency may be subtle and develop insidiously. Patients may report dyspnea, orthopnea, sleep fragmentation due to hypoventilation, morning headaches, daytime somnolence and fatigue, poor concentration/memory and nocturia. Others may be asymptomatic. Respiratory muscle weakness is an in dependent predictor of quality of life. (Bourke, et al, 2001) and respiratory failure is the most common cause of death in ALS patients. Assessment of respiratory insufficiency includes history, physical examination, rarly morning arterial blood gas, and overnight pulse oximetry.
Nocturnal hypoventilation may present as daytime hypersomnolence, lethargy, morning headaches, poor concentration, depression, anxiety, and irritability, while obstructive sleep apnea is characterized by snoring and restless sleep with abnormal movements. (Howard and orrell 2002).

Types of mechanical ventilation
There are several types of ventilatory aids. These are broadly classified in terms of invasive versus noninvasive.
As its name suggests, invasive techniques require an endotracheal tube or more commonly a tracheostomy. For patients in advanced respiratory failure (ie, no respiratory muscle function), invasive ventilators can assume complete control of ventilation. (Simonds. 2003).
Non-invasive ventilatory aids can be divided into two groups, negative or positive pressure ventilators. Negative pressure is exerted to the chest or abdominal wall mechanically to assist inspiration. Positive pressure devices can be set to deliver variable inspiratory and expiratory pressures, triggered by spontaneous effort (Simonds. 2003).

b. Management of Dysphagia
Management of Dysphagia includes modification of food and fluid consistency, postural advice (e.g. chin tuck: flexing the neck forward on swallowing to protect the airway), and parenteral feeding.
A percutaneous endoscopic gastrostomy (PEG) placement is indicated for those who have symptomatic dysphagia or significant weight loss. (Miller, et al. 2002). Patients and their families should be suitably counseled regarding the benefits and risks of the procedure.

Conclusion
Motor neuron disease is of the most common neurodegenerative disorders of unknown etiology, and had no specific treatment. ALS is the commonest type, and in most literatures is used as a synonym for motor neuron disease. Diagnosis is still clinical, mainly, and the investigatory tools have a definite role for diagnosis of other motor neuron mimics. Once motor neuron disease is diagnosed, the prognosis is usually bad, especially when bulbar, and respiratory complications are evident.