Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is one of motor neuron diseases

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1. Amyotrophic Lateral Sclerosis By Dr Mohammud Ibraheem

2. OUR POINTS The motor neuron system Discovery of ALS Definition of ALS Epidemiology Etiology Pathophysiology DIAGNOSTIC EVALUATION

3. THE MOTOR NEURON SYSTEM The motor neuron system is composed of: Upper motor neurons reside in the primary motor cortex of the brain, and their axons comprise the corticobulbar tract and the corticospinal tract (connecting to the spinal cord). Lower motor neurons (alpha motor neurons or anterior horn cells), are located in motor nuclei in the brainstem or the anterior gray matter of the spinal cord. Their axons connect to muscles of the bulbar region or limbs.

4. DISCOVERY The first detailed description was by Jean Martin Charcot in 1869, in which he discussed the clinical and pathological characteristics of “Amyotrophic Lateral Sclerosis ,” a disorder of muscle wasting ( amyotrophy ) and gliotic hardening (sclerosis) of the anterior and lateral corticospinal tracts

5. DEFINATION ALS is a neurodegenerative disorder of undetermined etiology that primarily affects the motor neuron cell populations in the motor cortex, brainstem, and spinal cord. It is progressive, and most patients eventually succumb to respiratory failure.

6. EPIDEMIOLOGY 90-95 % of cases are sporadic ALS . 5%-10% of cases are familial ALS . For sporadic ALS, male-to-female ratio is 1 to 2 . Within the US, the prevalence is 5.2/100,000. Worldwide prevalence is between 4.1 and 8.4 per 100  000 . The incidence is between 0.6 and 3.8 per 100 000 person-years

7. EPIDEMIOLOGY The incidence increase with increases in age, particularly after 40 years of age. Risk of ALS increases with age until the eighth decade. The average age of onset is between 51 and 66 years. Patients with fALS tend to have an earlier age of onset compared with patients with sALS

8. EPIDEMIOLOGY The risk factors for ALS are High levels of physical fitness/athleticism and slimness Age Family history Ethnicity; a higher incidence is associated with White ethnicity. Cigarette smoking, exposure to certain organic solvents and pesticides US military persons; other occupations with risks associated with ALS include veterinarian, hairdresser, and power-production plant operator.

9. ETIOLOGY A precise , single etiology of sALS is yet unproven. Studies suggest that sALS may likely involve complex interactions between a combination of multiple genetic environmental factors . In sporadic cases, the disease risk attributable to genetics approaches 60% and 40% related to environmental factors

10. Common causes of adult-onset AD ALS C9ORF72:: Hexanucleotide repeat as an intronic expansion in chromosome 9 open reading frame 72 9p SOD1::Missense mutations in Cu/Zn superoxide dismutase 1 21q TDP43::Missense mutations in TAR DNA binding protein-43 1p FUS::Missense mutations in fused in sarcoma 16q

11. ETIOLOGY Superoxide dismutase type 1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others. C9ORF72 gene is a hexanucleotide repeat expansion (GGGGCC ). Typically, 5–10 copies of this hexanucleotide repeat expansion are present in the gene, but ALS patients with the expansion may have hundreds to thousands of repeats. This hexanucleotide repeat expansion occurs in approximately 34% of fALS and 5% of sALS

12. ETIOLOGY TDP-43 is a DNA/RNA binding protein composed of 414 AAs, encoded by the TARDBP gene; TDP-43 homeostasis is critical for normal cellular function. Excess TDP-43 in the cytoplasm may result in the formation of inclusion bodies leading to cellular dysfunction whilst nuclear depletion may induce widespread FUS encodes a ubiquitously expressed 526 AA protein belonging to the FET family of RNA binding proteins

13. PATHOPHYSIOLOGY The pathology of ALS is characterized by the degeneration and gliosis of axons within the anterior and lateral columns of the spinal cord. Motor neurons within the spinal cord anterior horns and Betz cells within the motor cortex are also lost . Bunina bodies Intracellular TDP-43 inclusions

14. Bunina bodies Classic pathologic features of ALS include Bunina bodies, small eosinophilic cytoplasmic inclusions found in the cytoplasm of surviving motor neurons in nearly all types of ALS; however, their significance has not yet been explained.

15. TDP-43 intracytoplasmic inclusions Ubiquitinated cytoplasmic inclusions that contain transactive response DNA-binding protein 43 ( TDP-43) are present in nearly all patients with ALS. TDP-43 intracytoplasmic inclusions represent the pathologic link between the phenotypes of ALS and FTD.

16. DIAGNOSTIC EVALUATION CLINICAL PRESENTATION PHENOTYPES OF ALS INVESTIGATIONS DIFFERENTIAL DIAGNOSIS DIAGNOSTIC CRITERIA

17. Clinical features Motor features Pseudobulber features Cognitive features

18. Motor Features 70 % of patients with ALS present with weakness of the limbs, which is typically asymmetric and distal at onset. 25%of patients present with bulbar symptoms, which manifest as difficulty speaking , chewing, or swallowing. A small minority of patients have respiratory onset, and less than 1% present with diffuse fasciculations and a wasting syndrome. Extraocular movements are spared until late-stage disease .

19. Motor Features The progressive nature of symptoms is a critical component to diagnosis. Symptoms begin insidiously in an affected region and progress in that region as spread to other regions also occurs. Some patients with ALS will describe “ sudden” onset or stepwise symptoms, but careful review of their history will typically reveal progressive symptoms before the loss of a particular functional ability

20. Motor Features UMN weakness is caused by loss of downgoing inhibition in the corticobulbar and corticospinal tracts and leads to increased tone spasticity , slowness of movement, increased tendon reflexes , presence of pathologic reflexes.

21. Motor Features LMN weakness is caused by damage to the anterior horn cell or its axon and results in: pure motor weakness, reduced reflexes, muscle atrophy, fasciculations , cramps .

22. Motor Features In the bulbar segment, these symptoms and signs can manifest as dysarthria and dysphagia, along with facial weakness. UMN, spastic dysarthria is characterized by slow and strained speech, often with spastic dysphonia. LMN, flaccid dysarthria is characterized by weakness of lingual , facial, and palatal muscles causing imprecise, breathy, and hypernasal speech .

23. Motor Features Laryngospasm and involuntary cheek or tongue biting. Facial weakness and dysphagia often lead to sialorrhea. Brisk and pathologic reflexes include the jaw jerk, palmomental signs, and facial reflexes

24. Motor Features Cramps may frequently occur in the limbs, thoracic region, neck Cramps are often brought about by activity that causes contraction and shortening of the involved muscle.

25. Motor Features Respiratory insufficiency is typically thought to be caused preferentially by LMN dysfunction of the diaphragm and accessory muscles of respiration resulting in: shortness of breath, orthopnea , sleep-disordered breathing, paradoxical breathing.

26. Pseudobulbar Affect Pseudobulbar affect is a disorder of emotional expression that is caused by disruption of corticopontocerebellar pathways. Patients describe laughing or crying that is not under voluntary control and is out of proportion to their internal emotional state . excessive yawning in some cases.

27. Cognitive Features Up to 50% of patients with ALS have neuropsychological abnormalities, most commonly manifesting as Executive dysfunction. A smaller population of patients with ALS (5% to 15%) have frank frontotemporal dementia (ALS-FTD ).

28. Cognitive Features Most patients with ALS-FTD present with the behavioral variant of FTD, demonstrating :: Disinhibition , Lack of empathy, Poor initiation, Impaired executive functioning Disorders of language production manifesting as the nonfluent / agrammatic variant of primary progressive aphasia

29. Cognitive Features Common tools for evaluation of cognitive functions include: the Edinburgh Cognitive and Behavioral ALS Screen ( ECAS) the ALS Cognitive Behavioral Screen (ALS-CBS)

30. Phenotypes of als Limb onset Bulbar onset Progressive muscular atrophy Primary lateral sclerosis ALS- plus syndrome

31. Limb onset ALS (LO) LO present in 70% of patients . LO ALS is classified as flail arm syndrome or brachial amyotrophic diplegia , which is characterized by LMN weakness and wasting. It usually starts proximally and often symmetrically, then progresses distally to a point where upper extremity function is severely impaired. flail leg syndrome or pseudopolyneuritic variant, which is characterized by LMN weakness and wasting, but of the lower extremities and with distal onset. Patients have a slower rate of progression to the involvement of other body segments and respiratory muscle weakness

32. Bulbar onset ALS Bulbar onset ALS accounts for 25% of patients and is characterized by UMN and LMN involvement of the cranial nerves, usually manifesting as speech difficulties dysphagia This is followed by limb involvement in later stages

33. lower motor neuron-onset ALS The disease is initially exclusively involving the LMN. Most Patients go on to develop clinical signs and symptoms of UMN disease. Those patients who never show clinical evidence of UMN involvement, corticospinal tract involvement is detected at autopsy in up to 50% to 66% of patients with an antemortem diagnosis of PMA

34. U pper motor neuron-dominant ALS These patients have slower progression, lacking weight loss, and LMN symptoms/signs in the first 4 years of the disease. Most of them will develop LMN manifestations, however, and at this point is known as upper motor neuron-dominant ALS. These patients have a better prognosis than typical ALS but worse than patients with PLS

35. ALS-plus syndrome There are any additional symptoms/signs besides LMN and UMN disease, such as dementia (mostly frontotemporal ), extrapyramidal , autonomic dysfunction, ocular motility disturbance, sensory loss,

36. ALS-plus syndrome 15% of patients with ALS demonstrating criteria for FTD. 30 % to 50% diagnosed with ALS will develop varying degrees of cognitive impairment. While not overt dementia, patients can experience changes related to executive function and fluency, as well as behavioral changes as apathy and disinhibition .

37. investigations Electrophysiologic tests Imaging Markers

38. ELECTROPHYSIOLOGY NCS demonstrate preservation of sensory responses with normal or reduced motor amplitudes. As comorbid sensory polyneuropathy may occur. Sensory involvement that maps to the regions of weakness should suggest an acquired or inherited polyneuropathy distal latencies >30% prolonged, conduction velocity <70% normal, or conduction block, which, if present, suggest demyelinating neuropathy as CIDP

39. ELECTROPHYSIOLOGY Motor responses are often preserved in early or slowly progressive ALS because of collateral sprouting of the remaining motor neurons. Needle EMG should demonstrate signs of active denervation (fibrillation potentials and positive sharp waves) along with chronic denervation in multiple myotomes .

40. IMAGAING The role of radiology is the exclusion of other possible etiologies, a few subtle imaging findings have been associated with the upper motor disease found in ALS. Studies have shown patients with ALS to demonstrate iron accumulation within the precentral gyrus , which is known as the “motor band sign.”

41. MRI GRE sequence demonstrating iron deposition in the precentral gyrus (motor band sign)

42. IMAGAING Advanced MRI methods detect an early degeneration of upper motor neurons as well as other systems involvement such as the sensory system or basal ganglia, demonstrating that ALS is a multisystem disorder

43. MARKERS OF ALS Specific biomarkers have been developed for certain forms of familial ALS, including CSF superoxide dismutase 1 (SOD1) neurofilaments (NF ), TDP-43 the tau protein

44. DIFFERENTIAL DIAGNOSIS In patients with isolated findings of diffuse weakness, a broad differential should be considered, including Myopathy, A defect in neuromuscular junction transmission, Polyradiculopathy , Motor predominant polyneuropathy.

45. DIFFERENTIAL DIAGNOSIS A myopathy is typically excluded by the presence of fasciculations , the pattern of weakness (distal and asymmetric), the degree of creatine kinase elevation (typically <1000 U/L in ALS), the lack of myopathic findings on needle EMG.

46. DIFFERENTIAL DIAGNOSIS Myopathic processes as fascioscapulohumeral muscular dystrophy and inclusion body myositis, may be asymmetric , but in these instances the overall pattern of weakness typically suggests the underlying diagnosis. Some myopathies have modest creatine kinase elevations or have a “neurogenic appearance” on needle EMG (both are common with inclusion body myositis). Rarely, it may be necessary to resort to muscle biopsy to confirm a neurogenic process.

47. Diagnostic criteria

48. diagnostic criteria The revised El Escorial and Awaji criteria are common diagnostic criteria used for the clinical diagnosis of ALS. It is important to note that these are classification criteria and not a measure of disease severity.

49. Revised El Escorial and Awaji diagnostic criteria

50. Staging of ALS Staging systems that aim to inform disease progression and prognosis have also been proposed and are starting to gain ground and acceptance. The King’s staging system classifies ALS into stage 1, symptom onset (involvement of first region); stage 2A, diagnosis; stage 2B,involvement of second region; stage 3, involvement of third region; stage 4A, need for gastrostomy; stage 4B, need for noninvasive ventilation.

51. Thank you