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Motor neuron disease is a condition that selectively damages the nerves controlling the muscles of the body and sparing the nerves that are responsible for sensations like touch, pain, temperature and movement. It is a progressive disease; sometimes its rate of deterioration may be slow but it may also progress very rapidly with the life expectancy of a mere 3 to 5 years since its symptoms start showing. It usually begins with a single extremity or one aspect of motor function, however, it eventually takes a more generalised turn and rapidly weakens every muscle in the body leaving a conscious mind trapped in a crippling body.
The term motor neuron disease encompasses different disorders. These disorders are classified based on the kind of neurons that are damaged i.e upper motor neurons or lower motor neurons and the progression of the disease. The diseases that come under the group of motor neuron disease are:
Amyotrophic lateral sclerosis (ALS) - One of faster progressing disorders
Primary Lateral Sclerosis (PLS) - Upper motor neuron affection
Progressive bulbar palsy (PBP) - Affects both, upper and lower motor neurons and starts with speech and swallowing affections.
Progressive muscular atrophy (PMA) - Lower motor neurons are affected and has a comparatively slower rate of deterioration.
Kennedy disease - Presents as an MND, however, is a hereditary condition which affects adult males causing slowly progressive weakness and wasting of muscles with only lower motor neuron involvement and other features.
There are no known causes of motor neuron disease. So far there have been some studies implying genetic etiology and a few genes have been identified, however, the exact cause remains unknown. Some risk factors have been identified, such as higher chances in males above 50 years, with an existing family history of the disease. Some pathophysiological mechanisms like glutamate toxicity, oxidative stress and chronic inflammation have also been postulated in MND.
While the core affection of the disease is increasing weakness of the muscles, these symptoms can begin either in upper limbs, lower limbs, trunk and respiratory muscles or bulbar region (Speech and swallowing). Depending upon the type of the disease progression of symptoms may vary. The symptoms start in one region and progress to other regions as the disease progresses.
Lower motor neuron involvement commonly exhibits fasciculations in the muscles, including tongue muscles, that progress from one region to another, and flail muscles with progressive weakness.
Upper motor neuron involvement usually presents with severe muscles cramps, tightness in the muscles that restrict movements causing slow movements, and progressive increase from one region to another.
Apart from these, the following symptoms are generally noticed -
Foot drop due muscle weakness feet become flail and floppy and drop down while walking making it difficult to walk.
Wasting of muscles Thinning of muscles, which gives a hollow appearance to the body contours, like flattening of shoulders, hollowness below clavicles and flattening of hand prominences.
Fine motor impairment loss of ability to use fingers to perform tasks of precision like writing, buttoning etc.
Emotional disturbances Uncontrolled emotions like laughing fits, crying spells, temper tantrums are also one of the symptoms of the disease.
Speech disturbances As the disease progresses to the neck and bulbar region, speech difficulties begin, which may feel as an additional effort being taken while talking, to slurring of speech and eventually lead to complete loss of useful speech.
Neck drop Neck drop occurs due to weakness of the neck extensors, thus, making it difficult for them to hold their neck up even for a few seconds.
Drooling Due to weakness of oral muscles, there may be drooling of saliva.
Swallowing difficulty Patients may find it difficult to swallow as the bulbar muscle weakness progresses. Initially it starts as coughing while drinking liquids and subsequently progresses with difficulty of swallowing solid as well as liquids and eventually causing inability to swallow.
Inability to perform rapid eye movements In the advanced stage of the disease weakness muscles can cause inability to perform rapid eye movements.
Facial muscle weakness It may begin to appear as though the muscles of the face are drooping.
Orthopnoea Difficulty of breathing while sleeping in supine position.
Dyspnea Difficulty in breathing while performing day to day tasks.
Respiratory weakness Eventually the weakness of respiratory muscles leads to inability to breath and patients are dependent on support of an artificial ventilatory systems.
Motor Neuron Disease can be diagnosed on the basis of clinical symptoms, ruling out other conditions, via MRIs, and Electromyography and Nerve Conduction Studies (EMG/NCS).
Currently, MND is treated with a combination of medical, surgical and rehabilitative treatments. Pharmacological management consists of Riluzole. Riluzole inhibits the release and modulates the post-synaptic activity of Glutamate which is found to cause excitotoxicity in MND. It is the only medicine that has shown effect on the survival duration.
With no pharmacological means of altering the disease process, current management of MND is widely palliative and symptom oriented. Regular moderate intensity physical exercise with various rehabilitative therapies like physiotherapy, occupational therapy, speech therapy and respiratory therapy and in the later stages of the disease artificial ventilatory support, management of swallowing difficulty and percutaneous endoscopic gastrostomy (PEG) are routinely used.
Marked progressive axonal degeneration of motor neurons in the spinal cord and motor cortex is noted in MND. Currently the aim of cell therapy is to protect the existing motor neurons and attempt to bring about regeneration and repair in the damaged motor neurons.
Stem cells have a potential to regenerate nerve cells as well as have a positive effect of preserving the existing nerve cells. Stem cells can effectively find their way to the site of damage and bring about successful repair and prevent further damage.
They further demonstrate immunomodulatory, anti-inflammatory and cytoprotective properties. The growth factors like vascular endothelial growth factor, secreted by these cells bring about angiogenesis. These paracrine effects of stem cell transplantation lead to neuroprotection and subsequent alteration in the disease course and progression.
Cell therapy has been shown to be beneficial in the animal studies showing improved motor function. The safety of autologous stem cells transplantation has been established and allogeneic cells transplantation is being studied.
Cell therapy has been shown to be beneficial in prolonging survival, improving respiratory function, muscle strength and bulbar impairment. It also has been known to slow down the disease progression and rate of decline of the respiratory function. Cell therapy has been tested widely and has been repeatedly found to be safe and beneficial in MND.
Motor neuron disease, unlike other disorders, is a rapidly progressive disease and therefore the aim of cell therapy is to halt or slow down the progression of the disease. We conducted a study in Neurogen Brain and Spine Institute where in the survival and rate of disease progression of patients with MND that underwent cell therapy was compared with the patients that did not take cell therapy. We found that there was a significant benefit in survival, which means that the life span was prolonged in patients that underwent cell therapy and the disease progressed slowly.
The patients that were treated with cell therapy also found some symptomatic benefits like clearer and relatively louder speech, improved tongue movements, reduced speech fatigability, reduced choking, improved swallowing, reduced saliva drooling, increased respiratory capacity, better neck control, better limb function, better ambulation, fine motor activities, static and dynamic standing and sitting balance.
A 38 year old female was admitted at out center with a diagnosis of definite MND according to El-escorial criteria. When she visited our center, she had hypertonicity in all 4 limbs. Right lower extremity had severe spasticity with modified Ashworth grading of 3 while all other limbs it was 1. Voluntary control was also affected. Reflexes were exaggerated. Speech was unclear, with intelligibility score of 3. She was independent in her activities of daily living with some modifications and moderate support. Functional independence measure score was 98/126.
She underwent Autologous bone marrow mononuclear cells intrathecal and intramuscular transplantation 3 years after the onset of the disease. She was advised to take rilutor and a short course of Lithium for 6 weeks. She demonstrated significantly positive changes suggestive of slowing of disease progression.
At 6 months due to the beneficial effects noted she underwent repeat stem cell transplantation. Frequency of falls while walking reduced from 15 - 18 times in three months to 2-3 times in three months. The voluntary control improved from fair to good. Strength of distal wrist muscles improved from grade 2++ to a functional grade of 3++ and distal hand muscles from 0 to 1. Speech was clearer and louder. Inspiratory capacity improved from 450 ml to 500 ml.
It is interesting to note that the muscle strength in her distal hand muscles improved. De Carvalho et al 2005 reports a 17% decline of ALS-FRS scores every 6 months. The rate of drop of ALS-FRS score in this case was much slower suggesting slowing of disease progression. She had not deteriorated in the span of 9 months which was an improvement in itself as MND is a progressive condition and there is timely deterioration of function.