Motor Neuron Disease | Prof. S R Chandra | The White Army

Yes. Shall I start?

So today we will have an awareness session on motor neuron disease, as uh June 21st is declared as Motor Neuron Disease Awareness Day. So I thought it is appropriate to uh have this week's session on M&D.

So, what is awareness? Awareness is self-realization and the path to performing one's duty with no attachment to the results. Surrendering to the highest power and cultivating love and compassion for all beings. That is the common meaning of awareness. Uh, so what is awareness with reference to motor neuron disease?

So, the what is uh the purpose of this awareness day is to bring together the affected persons, sorting out whatever is possible, and guide the caregivers. So that is the purpose uh for this title, Motor Neuron Disease Awareness Day.

So, this disease is uh coming under ICD 10 CM code for motor neuron disease. Uh, and we shall approach this topic as etiology, clinical presentation, classification, differential diagnosis, some of our own observations. Each one of us, as we travel through life, we make some some observations which will add to the literature on a particular disease. Uh, it may be very small compared to all the research available in the world, but still, it is worth it. So that I will mention, then treatment and take-home message.

So, what is the motor system? So, the motor system consists of the corticospinal tract of the upper motor neuron. So, so upper motor neuron um, then the brain motor nuclei, and anterior horn cells of the spinal cord. So that is the motor system. And this particular disease affects all the three parts of this motor system, that is supranuclear, nuclear in the brainstem, and the spinal cord.

So, what is a motor neuron? A motor neuron is part of the central nervous system, and it connects the motor pathways to various glands, muscles, and organs throughout the body. So that is a motor neuron. So, and these are cells which allow us to move, speak, swallow, breathe, and do all motor activities. So, a motor neuron is a nerve cell that functions to transmit signals from the central area of the nervous system to the effector site, like muscles and glands. So, a motor neuron can be broadly seen as consisting of a cell body, axon, and dendrites. And we have different types of motor neurons: the unipolar neurons, which has got the body and the axon; the bipolar, which has got a body and a dendrite and an axon; and pseudounipolar, which is a cell body which divides like a T; and a multipolar neuron. So, this is the motor neuron. You are having the cell body, the dendrites, the body, the axon, and which connects with the end organ. So, this is a sensory neuron which is having the cell body in the middle. It is a bipolar neuron, and it is having dendrites and axons which connect, which is carrying information.

So, what is a motor unit? This is the multipolar motor neuron. So, motor neuron disease is a disease of the multipolar motor neuron, and this forms what is called a functional motor unit, which we call it as the motor unit. So, a motor unit is the number of muscle fibers supplied by a single motor neuron. So, when the motor neuron comes and its axon is coming, it supplies a number of muscle fibers. So, a motor neuron with its axon ending on a number of muscle fibers. This unit together is called as the motor unit.

So, for this disease, there are several hypotheses, several uh genes, and all those things. But the early theory is a McCombs proposed sick motor neuron theory. So, he suggested that a sick motor neuron, irrespective of what cause, and all was not postulated. So, he said that the disease is due to a sick motor neuron, that we call it as a McCombs theory, that abnormalities in the motor neurons is the pathology, not just the muscle cells. So, he said that the disease is due to disease of the motor neuron and not the muscle. So, that is the first uh search in response uh in uh with reference to the cause.

And so, how do we classify these disorders? We have chronic conditions where the upper motor neuron and lower motor neuron is involved together. The classical amyotrophic lateral sclerosis. Second is the purely upper motor neuron, which we call as the primary lateral sclerosis. The purely lower motor neuron, which is multifocal motor neuropathies, motor neuropathy with paraproteinemia, and motor predominant neuropathies, motor neuronopathies. Then sensory causes of secondary causes of motor neuron disease. Then you have got acute anterior horn cell disease like poliomyelitis, herpes, coxsackie virus infections. So, these are the common conditions which affect the motor system, both acute and the non-acute ones.

And the classification of the genetic causes of the motor system diseases and element, that is a familial ALS and the sporadic ALS. The familial ALS has autosomal dominant, autosomal recessive, and sporadic types. And the lower motor neuron, pure lower motor neuron, is spinal muscular atrophy, under which we have got the X-linked spinobulbar muscular atrophy, otherwise called as Kennedy's disease. Then GM2 gangliosidosis, the Tay-Sachs and the Sandhoff, which in which which also produce muscle symptoms. And you got the upper motor neuron type, which is familial paraparesis, adrenomyeloneuropathy, ALS plus syndromes, that is ALS plus parkinsonism, ALS plus frontal dementia, they are all called ALS plus syndrome. So, the genetic conditions are classified as MN plus LM, that is the well-known ALS. Ply LM, under which you got the SMS, Kennedy's disease, and gangliosidosis. Ply, you have got the primary lateral sclerosis, adrenomyeloneuropathies, ALS plus syndromes, so-called bulbar palsy, and the and the so-called bulbar palsy. So, these are the diseases which affect the motor system due to various reasons.

So, the clinical features, when do you suspect? When there is a pure motor syndrome. So, when the patient presents with a disease which is not affecting any other system, but only the motor system, and there can be both upper motor neuron and lower motor neuron features, and it can have a unique pattern of motor unit. That is, McCombs sick motor neuron theory, what is that? I will tell. And presence of fasciculations. What is this motor unit pattern? We have got a root pattern, we have got a track pattern, we have got a nerve pattern. Supposing the ulnar nerve is involved, the muscle supplied by the ulnar nerve will be weak. If you have C1 root, the muscle supplied by the C1 root, which goes beyond the ulnar, ulnar nerve is one of the beneficiaries of the C1 root, but C1 root is much more than that. So, C1 root indicates all the small muscles, not just the hypothenar muscles and the adductor pollicis, and all, and the intrinsic muscles, which is ulnar. Whereas C1 root, all the small muscles and the medial forearm muscles, as well as the uh wrist flexors. So, this is root pattern. So, root pattern will be the muscles involved, supplied by that root, which is more than a nerve. And if you have plexus pattern, that will be multiple nerves. So, multiple nerves coming from the plexus are involved. It is called plexus pattern.

What is this unique motor neuron unit pattern? We saw what is a motor unit. A cell body with a number of muscles that it innervates is the motor unit. As we know, each muscle has got several motor units. So, selection within a radicular pattern. So, when a patient comes with a small muscle wasting, we may think, is it an ulnar nerve? Is it C1 root? Or is it an early anterior horn cell disease? So, if you find that the muscles involved are not respecting the nerve, not respecting the C1 root, but they select some of the muscles within the radicular zone or within the nerve zone, that is, yes, finger might drop. A finger drop. That finger alone does not respect D1. D1 is much smaller than that. That is called a motor unit pattern. That is selection within a radicular zone or a nerve zone. Within a nerve zone or a radicular zone, all the muscle fibers will not be affected. Only a small portion will be affected, that is supplied by the motor unit, and you have got presence of fasciculations.

Then, if there is a pseudobulbar variety, when the upper motor neuron is affected, patients will have emotional lability with the tendency to laugh or cry, because we have got a cortical bulbar inhibition on expression of emotions. Cortex, frontal cortex, frontal cortex will tell us, if you cry with a person who loves you, they will try to sort out your issue. If you laugh with a person who loves you, they will try to share it. But if you cry or laugh to a stranger, they are not going to help you or share your emotions. So, we have got a frontal control on emotional expression. This frontal control mechanism will fail when there is a frontal cortex to bulbar invasion is getting disconnected due to the suprabulbar involvement of the motor pathways. In those situations, patients will laugh or cry in social situations where the patient is not going to get any sympathy or benefit. And they will have release reflexes, frontal release reflexes, all the pouting, snout, facial reflexes, and frontal lobe and basal ganglia features can occur, depending if it is an ALS plus syndrome. M&D plus syndromes, you have frontal lobe and basal ganglia obvious features can be there. And they can have tongue with dysarthria, swallowing defects, limbs, exaggerated reflexes, Hoffman reflex, finger flexion reflexes, crossed adductor reflex, with or without involvement of the abdominal and plantar reflexes. So, uh, and console disease is one condition where you have all the features of motor system involvement, but abdominal reflex can be retained, and plantar responses need not be extensor. So, pure motor syndrome with upper motor alone, lower motor alone, combined involvement without sensory features. So, that is, in short, uh, from the cortex, we saw what is the motor system, from the motor area in the cortex to the brainstem motor nuclei, to the spinal motor nuclei, anywhere, in varying combinations, uh, involvement is a a feature of motor neuron disease.

So, fasciculations, what are fasciculations? Fasciculations are spontaneous contractions of a motor unit of a muscle supplied by the motor unit, due to ectopic conduction in the terminal axon. I showed what is a motor system, that is a cell body with a number of muscles that it supplies. That's a motor system. There is axoplasmic flow, which is anterograde and retrograde. Anterograde is from the cell body to the muscles that it innervates. Retrograde is from the muscles to the cell body. So, when there is activity like this, the anterograde axoplasmic flow stops short at the terminal axon because there is buyback. This is called dying back. When the cell body is sick, the distalmost part will not get nutrition because the axoplasmic flow has a pressure dynamics, and the pressure is best towards the cell body, and as you move away from the cell body, the pressure uh uh falls down. Just like you are living near a water tank, when the water level is very less, also we will get water. But if you live far away from the water tank, when the water level comes down, we will not get the uh water supply. It is like that. So, the terminal axons do not carry the axoplasm. So, there is a dying back. The terminal axon becomes starved and it becomes damaged and thus disconnected functioning from the cell body. So, when there is an afferent or retrograde transmission from the motor unit to the cell body, when it tries to go back, suddenly it finds that it cannot reach the cell body. So, it is stopped there because of the dying back that has happened. So, the cell body will not be able to connect with the uh retrograde information coming from the motor unit. So, that will come back through the same pathway through which it traveled, that results in unwanted excitation of the motor unit, that is fasciculation. So, fasciculation is spontaneous contraction of a group of muscle fibers which are supplied by the motor neuron, due to ectopic conduction in the terminal axon, because of the uh dying back that is happening.

So, subjective involvement of some muscles severely and sparing of others within the territory of a root or nerve, apart from being purely motor, is the point in favor of anterior horn cell disease, that is the motor unit pattern, which I just now told. So, it may be, you think that a small muscle is wasted, is it ulnar nerve? It will not respect nerve. One muscle may be worst affected, another may be spared. So, that is selection within a nerve or a root is the typical pattern. And extraocular muscles and lower cervical segments do not generally get involved in this disease. The postulate is that they are having maximum mitochondria. So, when the energy failure takes place, they still survive for a very long time. That is the hypothesis. No. So, so that is why fasciculation is happening.

Now, we will see the genetic motor syndromes: upper motor and lower motor, as we saw. Familial ALS, autosomal dominant, autosomal recessive, and mixed autosomal dominant and recessive. You have got uh, low, purely lower motor neuron, that is spinal muscular atrophy. Then you have got X-linked spinobulbar muscular atrophy, that is Kennedy syndrome. And you got GM2 gangliosidosis, under which you got Tay-Sachs disease, Sandhoff disease, under the group of GM2 gangliosidosis, due to deficiency of hexosaminidase A and B respectively. Type A presents with pure neurological features, and type B with neurological with systemic features. Both of them involve the anterior horns. And you got EM, familial paraplegia, and adrenomyeloneuropathies. And and you got adrenal neuropathy is a form of X-linked adrenal leukodystrophy due to abnormality in the very long chain fatty acids. A paroxysmal storage disorder. Then you got adrenomyeloneuropathy, generally affects the spinal cord with with element features. When it is an adrenomyeloneuropathy, there can be Addison's disease additionally, and white matter involvement, resulting in spasticity.

So, we have got now, we are coming to the uh types proper. We have got five classical types. One is the amyotrophic lateral sclerosis, which all of us are aware. The patient will have spasticity, they will have small muscle wasting, and they can or may not have um so-called bulbar features and respiratory involvement. And primary lateral sclerosis, which affects only the upper motor neurons. Patient and progressive bulbar palsy. Patient will present with severe dysarthria and swallowing defect, and because of the bulbar muscle involvement. This is the worst type and shortest survival. And progressive muscular atrophy is a rare type that affects the lower motor neurons of the spinal cord. And FALS arm and FALS leg variants, a type of M&D that can affect the lower motor neurons, leading to progressive weakness of arms or legs. So, that is, these are the five classical conditions: ALS, primary lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, FALS arm and FALS leg variants.

So, now we will see what is ALS. It's a progressive degeneration of the motor neurons of the primary motor cortex, brainstem, and spinal cord. The incidence varies from 1 to 3 per lakh persons, with a point prevalence of 4 to 6 per lakh, and it increases after the age of 75. Males are more affected than females. And we have got the bulbar. Several types are there. The bulbar onset type is more common with the older women. Pseudobulbar is more common with men, and 5% of ALS is limb onset. It starts in the limbs. The mean age of onset is 60 to 65 years, and average survival from onset of symptoms is about 2 to 4 years. And the site of onset and age of onset are important prognostic factors. Bulbar onset has got a median survival of 2.5 years, and 3.5 years to 13 years for limb onset type. And younger patients have longer survival.

So, classical ALS starts with small muscle wasting, the deltoid muscles, the brachial muscles, and progresses to involve the other muscles of the limb. And in majority of the cases, it is asymmetrical. One limb starts earlier than the other limb. And rarely, it can remain confined to one limb, even very late into the course of onset of the disease. And they can have fasciculations, mostly unlike sort of fasciculations due to stress. The patient will be not aware until it is pointed out to the patient. And bulbar muscles are affected later in some of these groups, which are not bulbar bar onset. And bulbar onset is more common in older women. And finally, all muscles of the body will be involved at the end. And kyphoscoliosis, that is kyphotic uh defect, is common. The patients become kyphotic, and diaphragmatic weakness and girdle type weakness may develop in some of these patients. The wasted muscles show fasciculations, whereas they are less prominent in unaffected muscles. Then the initially they may have episodes of tripping and falling over trivial foreign bodies on the floor. They don't know why they tripped. When you examine the signs, maybe very little. And they can have fine movement in the upper limbs, in the form of handling buttons. They might complain of stiffness and cramps, and fasciculations are usually pointed out by the doctor. Uh, and muscle strength and bulk decreases over a period of time. Reflexes remain well elicited, and gross asymmetry in involvement and a patchy pattern is very common. And diaphragmatic weakness is usually seen in uh, so superoxide dismutase mutation cases. They are young people. They present with orthopnea, nocturnal dyspnea, because when they lie down, the diaphragm goes up. And mostly they are investigated by cardiologists and pulmonologists, and later only the disease comes to the neurologist. And the hemiplegic type is otherwise called Mills variant. And types are the other variant forms of uh, Yamanic ALS. And fasciculations can be brought out when you strongly suspect uh uh this, and you are not finding the uh fasciculations, you can put the muscle into action. You can tap the muscle, or expose to the cold, or subcutaneous injection of neostigmine in a small dose will bring out the fasciculations which are not visible at one time. And atrophy of small muscles of the hand gives rise to claw hand, and with there is extension of the metacarpal joint and flexion of the interphalangeal joint. And in the feet, the intrinsic muscles atrophy, and they put an exaggerated arch, which resembles a pes cavus. And uh, the course is continuously progressive. And uh, non-prognostic factors include younger age is better, older age is bad, bulbar onset is bad, limb onset is better, and respiratory onset is bad, non-respiratory is better. And so, survival is very less in the bulbar type. And younger and younger people have a better survival, non-bulbar onset.

The pathogenesis is really not known. Multiple factors are considered. And genetic factors are postulated in about 20% of patients. And 2% with sporadic ALS have superoxide dismutase gene mutation. Other genes which are postulated are alsin, senataxin, TDP43, through toxic gain of functions, and glutamate-induced excitotoxicity. Based on this, uh, only treatments of plant, antiglutamate, inhibi, and glutamate inhibitors, things like that. And then this excitotoxicity leads to calcium influx and neuronal cell death. And then next is oxidative stress, mitochondrial dysfunction, embedded axonal transport, slowing of the anterograde and retrograde transport from the motor neuron, and abnormal assembly with accumulation of neurofilaments and or intracytoplasmic inclusions. Bunina bodies are seen in sporadic and familial. And embedded axonal transport slowing of anterograde and retrograde axoplasmic flow is seen in mouse models. And neurofilament aggregation, abnormal assembly with accumulation of neurofilaments, protein aggregation, that is intracytoplasmic inclusions, are hallmark of both sporadic and familial ALS. Then you have got microglial and dendritic axonal activation produced by inflammatory cytokines like tumor necrosis factor. And there is deficiency of neurotrophic beneficial neurotrophic factors, leading to apoptosis. Some slow virus is also postulated due to coexistence of polio in many patients. Patients who have polio in childhood, uh, later they develop antidons disease involving the previously unaffected body parts, that is called progressive post-polio syndrome. Therefore, the possibility of a slow virus etiology is postulated. And the role of trauma is postulated in the literature, with the past history of brachial plexus injury or nerve injuries, later developing more incidence of M&D in such patients.

So, there is degeneration and loss of motor neurons with astrocytic and intraneuronal inclusions called Bunina bodies. They are eosinophilic hyaline intracytoplasmic inclusions that stain positively with the cytokeratin, and they are present in a good number of patients. And rabiculated inclusions are seen, which are called skin-like inclusions. And you got spherical bodies. And TAR DNA binding protein 43, that is TDP43, that is why we have got an extension of these patients to FTD. So, TDP43 is seen with frontotemporal dementia, ALS, and some overlap with Parkinson's disease. Then hyaline conglomerates or neurofilament inclusions with familial ALS, and these are eosinophilic inclusions in the spinal cord and stain with the phosphotungstic acid and monophosphorylated stain for phosphotungstic acid monophosphorylated neurofilaments.

So, the criteria. So, these are the etiology and pathological changes, genetic changes, storage materials, other path mechanisms, we have briefly gone through. And what are the criteria for diagnosis? That is revised El Escorial criteria. Revised El Escorial criteria to make a diagnosis of ALS. There should be a clinical or electrophysiological evidence of progression within the region or other regions, as well as exclusion of ALS mimics. ALS mimics: myeloradiculopathies, and then spinal tumors, demyelination. So, exclusion of ALS mimics and demonstration of involvement of the motor system clinically and laboratory-wise. And definite ALS is element signs in three regions. So, presence of upper motor and lower motor in three regions. Probable ALS is upper motor and lower motor in two regions. And probable laboratory-supported ALS is human and element signs or only human signs in one region and evidence of denervation by electrophysiology. And probable ALS is human and element signs in one region or human signs in at least two regions. So, that is the uh, based on this, we call them definite, probable, probable with laboratory support, and possible.

So, this is um, summary, what I just mentioned, only is written with a little more elaboration. Evidence of element degeneration by clinical, electrophysiological, or neuropathological neuropathology. In clinical practice, we rarely do, except in the research setting. And evidence of human degeneration by examination, like exaggerated reflexes, finger flexion reflex, um, spasticity, and progressive spread of symptoms and signs within in a region or other region are determined by history or examination, together with the absence of electrophysiological or pathological evidence of other diseases. And neuroimaging evidence of other diseases should not be there. The like junction anomaly, myeloradiculopathy, those syndromes should not be there. So, definite ALS, we have seen the criteria. Three regions, two regions is probable, and possible is probable with lab supported is one site with EMG showing denervation in two regions, and possibly element and signs in one region, or signs in two or more regions. And human and element signs in two regions and no signs. These are all varying grades of diagnostic certainty.

So, this picture uh shows, you can see the wasting of the first dorsal interossei, increased in the interosseous groove, small muscle wasting, and the patient's fingers going in for uh claw. So, this is a tongue which is atrophic with multiple grooves. The bulbar type of ALS disease shows the atrophic tongue with fibrillations. So, this is the atrophic tongue. This is what I said, the finger drop. So, you are having a person who is having a finger which is supplied by the ulnar. It is supplied by the C1 and root, but other areas supplied by the ulnar nerve or other muscles supplied by the ulnar nerve are not affected. So, that is finger drop. So, finger drop is selection within an or root. So, it is in that distribution, but neither the ulnar distribution is completely covered, nor the C1 root is completely covered. So, that is the typical dropped finger. This is the dropped head. So, neck muscles get involved. So, the patient is unable to lift the head. And this is the dropped head syndrome.

Then there is a pseudoneuritic variety where patients present with foot drop. Some of these patients in the early stage are diagnosed as intravertebral disc prolapse. They may have back pain. They may have radiological evidence of uh uh disc. But it, you have to carefully look for the angle jerk will be normal. Sensations will not be affected. But if the person presents with element signs and somebody does not carefully suspect and disease, they will operate an incidental disc. So, later it will continue to progress, and then you wake up. That is a pseudoneuritic form of amyotrophic lateral sclerosis, which will present with asymmetrical foot drop, and incidental imaging findings will give the patient the wrong treatment.

Then familial um ALS, clinical phenotype indistinguishable from the sporadic ALS. So, familial ALS and the sporadic ALS clinically resemble each other. Symptoms include progressive muscle weakness, stiffness, sparing of eye muscles and sphincters, and sensory symptoms occurring without physical signs. They can have aches, pains, paresthesias, but you may not be able to demonstrate any sensory signs. We have got several types. Type one is ALS1. It is due to specific superoxide dismutase gene mutation and associated with the predominantly element pattern. And all these ALS have all the genetic varieties of J ALS have a poor prognosis. And they can have paresthesia, shooting pain points, but they will not have any sensory signs. Type two is a juvenile onset, and it is seen in Tinian families, and it is to 2q33 locus, and gives rise to no, this was the one which is associated with alsin. These patients are predominantly upper motor. Type one is lower motor. Type two is upper motor. Type three is resembling the classical ALS without any atypical features, and around late middle age, and mean survival is poor, and it is linked to chromosome 18. Type four is linked to chromosome 3q34, and the protein is senataxin. Type three, we, type two, we saw it is alsin. Type four is senataxin gene mutation, dominant variety, and juvenile onset around 25 years of age, and distal uh, and bulbar muscles are generally spared. And type five is again autosomal recessive, and it is linked to chromosome, and it is manifesting between the age of 8 to 18 years, and significant atrophy occurs with exaggerated reflexes, and they will be having lot of element features, and survival is good in this case. And type six and seven are linked to 16q12, and the phenotype resembles the limb onset ALS. And because the limb onset variety has long survival. And type eight is 20q13 chromosome, and age of onset is middle age, and element features dominate. So, these are the eight types of familial ALS due to different types of gene association.

Next is the progressive muscular atrophy, purely element type. Males are more affected. Uh, survival is 5 years in 72%, and they run in families. Mutation in superoxide dismutase gene is commonly associated, and lesions may or may not be symmetrical. Initial disease starts in the proximal arms with twitching and cramp-like pain, and then on selective element degeneration leading to weakness and wasting. So, starts proximally and then travels distally, that is in the, and starts in the upper limbs, and then comes the lower limb, that is the progressive muscular atrophy type. You have got the progressive bulbar palsy, that is very serious, and the shortest survival, and it is a element condition. They will have, because of the tongue, the lips, and the facial and pharyngeal muscles get involved. Uh, they present with appropriate features of the tongue and the palate, and they will have involvement of the muscles of mastication and phonation, uh, later. And lower facial muscles can be involved, and there can be emotional lability and emaciation because swallowing is difficult. Jaw jerk remains normal. And eventually respiratory muscles become affected. A purely herpetic form with trinucleotide expanded repeat expansion is called Kennedy syndrome, that is also upper liet.

So, this is one of our patients with the bulbar palsy, which we said is um, more common with elderly females. She is anarthric. She cannot do anything, but she can comprehend. She can read, she can write, but she cannot speak anything. It's a very unfortunate condition, very painful to see these patients. So, this is another patient, because it is more common with the females. The voice is somehow not playing. Okay. Uh, this is then primary lateral sclerosis. This is an uncommon type, only human signs, usually starts in the sixth decade in the lower limb. So, progressive muscular atrophy, proximal upper limb, and progressive primary lateral sclerosis, lower limbs, and they have upper motor neuron signs, and very, very late, they can have some element signs, and variable progression. And it has to be differentiated from treatable conditions like progressive multiple sclerosis, tropical paraplegia, HIV-associated myopathy, and vitamin B12 deficiency. So, symptoms and signs are the typical feature of primary lateral sclerosis. Stiffness, spasticity, then atrophy, and they have usually an ascending pattern. And bulbar onset occurs in a very small percentage of patients. Early dysarthria is seen, but without involvement of swallowing. So, they can have dysarthria, but swallowing may be normal. And many patients tend to gain weight due to lack of exercise. And virtually all patients develop emotional lability, loss of facial expressions, restricted to the lower face, and urinary urgency is seen due to detrusor hyperreflexia.

So, this is the biracial variant or the amyotrophic brachial diplegia, that is otherwise called Walpian-Burnheart syndrome. Walpian-Burnheart syndrome is an upper limb variety, brachial, with the wasting of the muscles involving the whole of the uh, both upper limbs. Lower limbs are normal. Then we have got brachial diplegia. You know, this involves, this males are more affected again, localized wasting and weakness of one or more of the limbs. Uh, starts with upper limbs, and human signs develop in the legs. So, they get with the element signs in the upper limbs and women signs in the lower limb, and male dominant disease. Then we have got FALS arm and FALS leg syndrome. The FALS arm is a element disorder characterized by progressive predominantly proximal weakness and wasting, and also included in this category where patients have typical patterns of wasting for FALS arm, but also had pathological deep tendon and other pathological reflexes in the form of upper limbs at some point during the disease, without hypertonia or clonus. So, they have exaggerated flex, but you don't have any hypertonia or clonus. And functionally, they are very disabled with the weakness. And there can be bulbar involvement during the course of the disease. And distal upper limb weakness or wasting without proximal involvement is the uh, typical feature of the FALS arm. FALS leg is an element disorder of the lower limb, and it starts with distal onset weakness and wasting, and it is um, slowly progressing. Sometimes here also you get increased reflexes and wasting, and later they can involve the bulbar muscles, and hypertonia in the lower limbs, and wasting and weakness beginning usually proximally in the legs, without distal involvement at presentation. So, FALS limb, FALS arm starts distally. Biracial starts proximally. FALS leg starts proximally. We got the Mills variant. Mills variant is a rare form of this one, hemiplegic variant. So, it's one upper limb and one lower limb becomes affected by the pure motor involvement, that's Mills variant. You got the Madras motor neuron disease. This was first recognized in South India in 1970 by Professor Jaganathan and Arjunas of Government General Hospital, Madras, presently called Chennai. And they presented with bulbar and limb involvement, brisk jerks, extensor response, sensory features like deafness, and some of them had cardiac involvement and optic atrophy. Are more affected in the second decade, very early disease, and it may be unilateral or bilateral cells, and bulbar muscles become involved in 60% of patients. So, it is um, younger age onset, unlike ALS, which is late onset. Motor is younger age onset. Uh, so, there is Indian workers have incriminated defect of glucose utilization in the spinal motor neuron to have a causal role, which was, so, glucose utilization defect, glucose transport defect was postulated by some experiments by late Professor Walmeidan, who was the professor of neurochemistry at Madras Medical College. And although this condition was initially described in patients from Madras in South India, similar cases are now encountered in many parts of India and many parts of the world. Then you have got the monomelic atrophy. It tends to remain confined to one limb. Males more affected, distal muscles more affected, and non-familial, and usually affects adolescence and adults. That is monomelic atrophy, and characterized by weakness, wasting, fasciculations, and in some cases, the involvement may be only focal or segmental, one extremity or one part of one extremity, and human signs are usually absent. The course is benign because generally it does not involve the respiratory muscles or bulbar muscles. So, the course is benign. And Indian studies, a large series of 1,153 patients was studied by Professor Nalini Atal from National Institute of Mental Health and Neurosciences, and she found that it is male dominant, and distribution pattern, survival, all those were studied and published by Professor Nalini. Then some other Indian others, who apart from the Madras motor disease and Professor Nalini's elaborate case series, we have got Chopra's wasted leg syndrome, described by Professor Chopra from PGI Chandigarh, and Gowri Devi syndrome is one upper limb is a former director of National Institute of Mental Health and Neurosciences, Bangalore. Here I am, that's a Japanese, both upper limbs, distal both upper limbs. Then you have got another condition called Brown-Vialetto-Van Laere syndrome. Brown-Vialetto-Van Laere syndrome, variable onset and course, bulbar and pseudobulbar features, young onset, rapid. So, that is young onset, and facial land is early onset with rapid progression, bulbar involvement, and respiratory involvement predominates. That's a facial variety. You got the spinobulbar atrophy of Kennedy, that's an X-linked disorder, affects only males, and onset is 3rd to 5th decade. Much younger can also have, can have, and the males are affected, and females are carriers. The genetics is, it is in the, it's a CAG expansion disorder, and in the Xq11-12 locus, and it's a normal increased repeat size of this anomaly, and there is also genetic anticipation in the family members of these patients. Then you have got positive correlation exists between the size of the repeat expansions and the rapidity of progression and degree of uh, wasting. And there is androgen insensitivity, because of that they develop gynecomastia and testicular atrophy. And usually adulthood, first sign is a form of muscle cramp, proximal weakness and wasting, and then bulbar symptoms and signs, and fasciculations.

Then what are these overlap syndromes? So, classical ALS with the frontal lobe syndrome, that is FTD-ALS, or ALS with Parkinsonism-Dementia Complex of Guam. So, these are overlap syndromes where, in addition to the motor neuron involvement, hemispheres and subcortical gray matter get involved. Several genes, chromosomes, which code progranulin, have been linked to the frontotemporal with ALS. The ubiquitinated inclusions, which are mitochondrial inclusions, then TDP, that is TDP43, which are all more global. So, they are coming under the overlap group of motor neuron disease. So, ALS-FTD complex, overlap between dementia and ALS is demonstrated by the presence of cognitive and behavioral dysfunction, and incidence is variable. And patients with FTD-ALS histology is FTD-U type in 50%. And Parkinson-dementia. So, when they have an additional features of Parkinson and dementia, uh, that comes under that. And and this is the NIMHANS data, which is published, and I think you can search that data. And you should remember one group of disorders called riboflavinopathy, which is coming under the Brown-Vialetto syndrome. The patient, but it is treatable with high-dose riboflavin, specifically riboflavin transporter deficiency. It's a rare genetic disorder characterized by deafness, muscle weakness, early onset, wasting of upper limb more than lower limb, second, eighth, ninth, 10th, and 12th cranial nerves get involved. Lower limb and trunk and diaphragm also gets involved, and rarely some sensory features may be there. Then, this is caused by variation in SLC52A2 or SLC52A3 mutation. Classical phenotype is what is the Brown-Vialetto-Van Laere syndrome and the facial syndrome. They are otherwise having a very short lifespan because of the uh, bulbar muscle involvement, but now it is treatable. The acyl carnitine in the blood shows accumulation of short and long chain fatty acids, and riboflavin 10 to 50 mg per kg per day. So, high dose riboflavin is available. It is called Riboam 300 mg tablets. So, that can be used.

Next is the purely element varieties, that is spinal muscular atrophy. They are motor neuronopathies. They have a definite pattern of inheritance. Pure anterior horn degeneration, areflexic, and they are divided into several types based on the age of onset and genetics. The SMA0 is autosomal recessive, onset in utero, needs respiratory support at birth, and it is mostly fatal. And SMA1 is autosomal recessive. Other is called Werdnig-Hoffmann, onset within the first 6 months, and death by 2 years. And SMA2 is autosomal recessive again, and you have got intermediate onset, that is 6 to 18 months, and um, they survive into adulthood. Some of them stop progressing. They are called arrested Werdnig-Hoffmann syndromes. Then you got SMA3, again autosomal recessive, which is otherwise called Wiler-Kugelberg, onset is after 18 months, and survive to adulthood. And SMA4 can be both autosomal recessive and dominant, adult onset type, mostly after 30 years, and the progression is slow. So, this is the way classification of SMA. And they are mainly, so this is briefly the clinical and genetic pattern of the uh, various kinds of motor neuron motor system disorders.

And how are you going to evaluate them? These are mainly aimed at excluding treatable causes. I, I spoke about the riboflavinopathy. So, gangliosidosis disorders. So, we should always look for the treatable conditions. Nerve conduction studies and electromyography. There is motor neuropathy with multifocal conduction block, which is purely motor, and it will look like M&D. So, electrophysiology will help us to differentiate. Then role of infections, toxins, paraproteinemias, paraneoplastic conditions, endocrine causes, nutritional causes, inherited metabolic, vascular, compressive problems will have to be excluded before we put the patient into the diagnosis of M&D. Draw a pedigree chart always whenever possible.

And this is a fasciculation motor. This is a normal motor action potential. And uh, this is, if normally a resting muscle does not produce any discharge. If this normal motor action potential is seen in a resting muscle, that is fasciculation. So, evaluation, one is clinical. Then you go to electrophysiology, where resting muscle shows motor action potential, which resemble normal motor action potentials, that is fasciculation. And you can have fibrillations. You can have positive sharp waves. Fibrillations are shorter duration and of low amplitude. Fasciculations exactly resemble a motor unit, but they are normally not seen in a resting muscle. So, normal motor action potential seen in a resting muscle is fasciculations. Much shorter duration, much lower amplitude is fibrillation. And you have got these are fibrillations, and these are fasciculations. And you have got positive sharp waves, that is a downgoing deflection, that is called positive sharp waves. So, these patterns with normal nerve conduction in a resting muscle is one of the classical clues of ALS diseases, of positive sharp waves. Then, uh, there is, so, clinical with the EMG evidence of denervation with normal nerve conduction, and there is all these genetic tests and role. It is done only for research purpose, because it is not seen in all the patients, less than only 20%. So, that is not diagnostic. So, no specific diagnostic test. So, nerve conduction and EMG is essential. Mild elevation of CK can happen. And CSF is done in atypical cases. If you are thinking of a HIV myopathy or vitamin B12 related myopathies, then you do the uh, other investigations. And neuroimaging to exclude other diagnoses. So, some infections which can produce uh, similar uh, pattern of motor system involvement, until we carefully examined, have to be looked for. Infections, toxins, drugs, and immunological disorders associated with antibodies, paraneoplastic syndromes, all these should be excluded. And that is the purpose of investigation. So, it's an exclusion diagnosis.

Then secondary M&D, we have got basedow paraplegia, that is hyperthyroidism, where the patient is having increased tone, exaggerated reflexes, wasted muscles, and jerk may not be there. So, always remember there is called basedow paraplegia. Then hyperparathyroidism, then vitamin deficiencies, folate and vitamin E deficiency, mitochondrial disorders, and gangliosidosis, all these will resemble M&D. So, they should be excluded.

Then MRA features, um, muscle MRI will show the pattern of muscle atrophy. And MRI of the, this is one typical feature we call because of the corticospinal tract undergoing degeneration. It produces hyperintensity, that is called cobra head sign. So, cobra head sign due to selective hyperintensities in the corticospinal tract. So, this is another, again, the same motor pathways showing hyperintensities. And this is otherwise hyperintensities of the pyramidal tract. It is otherwise called as a flower vase, so it's like a wine glass sign. So, there is, so, cobra head, wine glass tracing, the motor neuropathies. So, this, you see the muscle biopsy will show group atrophy. So, one group of muscles will have the same number of size. So, one group, one motor unit will be small, another motor unit will be uh, large. So, that is the pathological features. Muscle biopsy is generally not done.

Then, uh, you have got, so, this is another condition where you can see the clawing, which is not involving typically the ulnar nerve. So, this will resemble, but this is a nerve disease. This mononeuritis. The mononeuritis, we can classically see that the unlike the dropped finger, where we saw it is respecting a nerve pattern. Then you, so, those are mimics which we should remember. The purpose of investigations is to rule out the mimics. So, the, because M&D is an exclusion diagnosis.

Then, if you are in a research institute and you want to investigate for the genes, we can do all these superoxide dismutase, TDP43 first, and C9orf72, that is seen in overlap syndromes, and TBK1. So, all these genes are associated. It can be done for research purpose. And your therapeutic options, and tofersen is an antisense oligonucleotide that is a gene known as superoxide dismutase one. So, these are the various genes which have been described. And you can see this is a spinal glioma. So, patient will present like a syringomyelia, that is wasting and weakness. But there can be, they will have dissociated suspended anesthesia, depressed reflexes. So, that will help us to differentiate. So, it's an important imitator, spinal gliomas.

So, this is one of our patients who was referred to us as bulbar onset. You can see her atrophic tongue. Tongue. She was drooling continuously. She could not swallow. But only one feature was very atypical. She did not have any sensory features. Only one. She said the disease was very short duration. It was less than 1 month. So, we did the MRI and we found a lesion like this. And, this lesion we saw, and we can see that it is uh, in the brainstem, displacing the brainstem, and mass effect. Because this area is a very sensitive area where you cannot take a biopsy or you cannot radiate. We told about the problems. It did not look like demyelination. The shape, mass effect, everything looked like a mass only. But keeping a remote possibility of a demyelination, we gave her a course of steroids, with which clinically she showed remarkable improvement, but imaging remained the same only. So, this is um, another person. He's a doctor who presented with difficulty in walking, fibrillation, and fasciculations. He also did not have any sensory signs, but he had a girdle sensation. Symptom-wise, he had girdle sensation. Signs were not there. And he was investigated uh, in premier centers and diagnosed as motor neuron disease. But he also, then finally, this person also, like the previous lady, the unique feature was very fast and very rapidly progressive. And he lived in another country. And when he got this condition, he came here. This is during the COVID season. And because of the rapid progression, is there any alternate possibility that was considered? And he had girdle sensation, which is generally not seen in M&D. Even though he was given the label of M&D from a prestigious center, with these odd features, rapid progression, girdle sensation, he gave history of taking Sputnik vaccine. So, actually, I wanted to write this group of disorders. He completely reversed, but left with a mild atrophic tongue. There is no progression. Now it is about 3 years. Patient is doing very well, but mild tongue atrophy, which happened at that time, is persisting. He completely reversed with the steroids. So, this is following Sputnik vaccine. So, we have described a new phenotype of superoxide dismutase, and we published that case. That is a family who had a psoriasis as well as autonomic dysfunction. So, they had a typical motor system disease with additional autonomic features, lack of hair, decreased sweating, and psoriasis from skin changes. And we did the genetics, and we identified the SOD mutation. And this is what we added to the literature. So, these few patients which mimicked M&D, we have not published. So, that's, uh, that we are gathering. And this is another, this case we already published before. I retained, so we could do the complete workup, and the we identified a new phenotype and genotype. So, new phenotype because autonomic involvement and psoriasis skin lesions, and new mutation of the SOD. So, this we added to the literature. So, these are the dry skin because of the trophic changes and loss of uh, sweating, dry skin, and the person who has psoriasis from skin lesions. And these are the muscle biopsy, and this is the DNA showing the new mutation. And this is what we did, the sweat quantitative sweat test, which showed absence of sweating. And this is the result of the sweat test. So, this also. Then we had another group of mimics. These persons were also reported as spinal muscular atrophy because the group atrophy was seen. So, what is the importance is pathology should be always correlated with the clinical features. So.

A patient, young female, presented with progressive muscle weakness and other features. She actually had retained reflexes, but the previously investigated persons suspected that to be SMA, even though she had retained reflexes. So they did the muscle biopsy, sent the specimen, and told, "We are suspecting SMA, and when you have disused type one atrophy happen." So the patient was bedbound, not working for nearly, uh, several months, nearly one year. So, uh, type one atrophy happened due to disuse. So, histopathology showed group atrophy. Clinician suspected SMA. So, pathologist said, "It is consistent with the SMA group atrophy." So she was banned like that.

And, uh, later, when I came to that medical college, this person was brought to me again. And because it was a very brisk jerk, I immediately palpated her thyroid, and she had a parathyroid adenoma. So this is the patient with a drooped shoulder and all those things, and this was her, and muscle wasting and deformed elbow, and this is the parathyroid adenoma which was operated because the duration of her bedbound stage was more than one year. I was not sure whether she had the typical peppers or scale and calcification in the kidney. Everything was there. This is published in the Japi. Every picture is there in that.

And, uh, about an year after surgery, she became like this. She got married, and unfortunately, she has no children. And recently, I happened to see her. She is 51 years now. Uh, her husband died due to MI, and her whole story is sad. The initial part, she was diagnosed SM and she was bed for nearly two years, and after that, when we identified the parathyroid adenoma and operated her, she became normal like this. But, uh, even the return to the normal life did not last long. She lost her husband, no children, and she had recently come to see me, and it was a very sad thing.

This patient I saw so many years back before I went to Nim, when I was in tran medical college. No. Then we have, uh, described patients who presented with myasthenia, M and D overlap. That is also published, but I could not trace my old picture of this patient. It is in the publication, the picture is there, Journal of General Practice. So I have published this, and that can be searched in this. And person had myasthenia, later he developed angatrophy and M and D. So that is one reason where an autoimmune process still holds good for patients with M and D. Many hospitals have a habit of giving IVIG as a trial to patients with M and D. So this is another mimic, HMSM. Are you can see the pattern which is not at all like the motor unit pattern. So always remember differentials.

So that is the, um, important thing. Once you confirm your patient is having classical degenerative variety of motor disease, there is hardly anything we can do for the patients. Always remember the differentials for prognostic and therapeutic importance. So all these things we have gone through. My radical of the infos, progressive policy, multi-systemic, all these can have resemblance to M and D. So look for all these in every case. And management of this is emphasized by a care team, community-based therapist, palliative specialist, and psychology, psychiatric, social work people, and family therapy, all that is very important to go through the phase of a, uh, disease like this.

They can have excessive salivation because of the bulbar involvement, for which we can give symptomatic management that will reduce the embarrassment with use of anticholinergic medication, toxin to the salivary glands, or you can even give radiation to the parotid gland. So this refractory sialorrhea is reduced. And pseudobulbar effect can be reduced by drugs which reduce that, uh, social uninhibited laughter and crying, and fatigue. You have to, uh, treat with the Rel. Relucol is useful in reducing fatigue, and cramps are treated with gabapentin, vitamin A, reliants are all tried in difficult cramps, and spasticity can be treated with muscle relaxants, and depression is treated with mood stabilizers. Anxiety should be addressed, and your insomnia should be treated. And you have, uh, then you are coming to the disease-specific therapy, that is religma. So that can be, if you give a prescription, they give it, but we have not found wonderful results. But when nothing is there, you can give this, and it is supposed to slow down the respiratory muscle involvement. And to person is a new year drug which is now in the market for in patients in whom you have demonstrated the superoxide dismutase mutation.

Then you have got a SMART trial, M and D SMART trial, that is to promote protection, repair, and neuroplasticity, where various drugs are tried. Tacrolimus, which is an immunosuppressant used in patients who have organ transplant, that is tried, and non-004 is tried, and oraxin, amro. These are various drugs which are coming under the M and D SMART trial. And other drugs is edavarone. We give intravenous infusion. We have given it to a fairly good number of patients. Uh, we cannot say that it produces wonders, but, uh, something, uh, some brief period of well-being is expressed by the patients. Then respiratory management, non-invasive home ventilation is the advisable one.

So you apply all the criteria, assess the symptoms, monitor every 3 months, and, um, end stage, how you manage with the PEG and other things for, uh, symptomatic management. This is a flowchart for diagnosis and management of ALS and SMA. We have got these two, uh, medicines. One is Solen, for Solenma, that is a single dose medication. And, uh, you have got another multi-dose medication that is Spinda. This has to be given as several doses. So these are the therapeutic options. All these medications I have not tried many of them. I don't know. Some of them are new drugs.

So when you see this kind of disease, we become very desperate and dejected. So, uh, so we have to understand that whatever we have studied as MBBS, MD, or DM is very little, and what remains to be learned is as vast as the universe. And understand, the patient is your master. You, as a scholar, have to be a saint, a gentle scientist, wise, knowledgeable, sensitive, humbled, and good beyond imagination. Because our job is not a profession. It is practice of a dharma. So you should be owner of unselfish love for the skill of sharing suffering is a divine, divine gift. You can share money, you can share a house, you can share clothing, but sharing, uh, suffering is what we are supposed to do, and we are, our profession is to share suffering. It's a divine gift that you are given the opportunity to shoulders. So we should feel very proud of our doctor-patient relationship and respect and never try to contaminate that noble relationship by any selfish, uh, requirements.

So this is a thank you slide. So any doubts is there? Because I thought I will go through this. Main purpose is to, uh, differentiate treatable conditions. I have seen vertebral artery aneurysm, cranial junction anomalies being labeled as M and D. They are treatable conditions. So all these should be evaluated and looked for. So any questions are there? I can answer. Any questions are there? Otherwise, shall I stop? No questions. So, shall we stop the class? Leave the meeting. Stop sharing. Thank you.