The features of ALS were first clearly described as a clinico-pathological entity by Jean Martin Charcot in 1869 and in subsequent articles in 1874 [43
]. However, before that Bell (1824), Aran (1850), Duchenne (1851), and Cruveilher (1853) made important observations that contributed to the understanding of the clinical and pathological syndrome [45
Approximately two thirds of patients with typical ALS have a spinal form of the disease (classical 'Charcot ALS'). They present with symptoms related to focal muscle weakness where the symptoms may start either distally or proximally in the upper limbs and lower limbs. Rarely, patients may notice focal muscle wasting before onset of weakness, and some patients may present with a spastic paraparesis. Patients may have noticed fasciculations (noticed as involuntary muscle twitching) or cramps preceding the onset of weakness or wasting for some months (or years), but rarely are these the presenting symptoms. The weakness is usually of insidious onset, and patients may notice that symptoms are exacerbated by cold weather. Although it is usually asymmetrical at onset, the other limbs develop weakness and wasting sooner or later, and most patients go on to develop bulbar symptoms and eventually respiratory symptoms (although not necessarily in that sequence). Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. During late stages of the disease patients may develop 'flexor spasms', which are involuntary spasms occurring due to excess activation of the flexor arc in a spastic limb. Occasionally encountered symptoms include new bladder dysfunction (such as urgency of micturition), sensory symptoms, cognitive symptoms and multi-system involvement (e.g. dementia, parkinsonism).
Patients with bulbar onset ALS usually present with dysarthria of speech, which may initially only be apparent after ingestion of small amount of alcohol. Rarely, patients may present with dysphagia for solid or liquids before noticing speech disturbances. Limbs symptoms can develop almost simultaneously with bulbar symptoms and in the vast majority of cases will occur within 1–2 years. Almost all patients with bulbar symptoms develop sialorrhoea (excessive drooling) due to difficulty swallowing saliva and mild UMN type bilateral facial weakness which affects the lower part of the face. 'Pseudobulbar' symptoms such as emotional lability and excessive yawning are seen in a significant number of cases.
About 5% of cases with ALS present with respiratory weakness without significant limb or bulbar symptoms [51
]. These patients present with symptoms of type 2 respiratory failure or nocturnal hypoventilation such as dyspnoea, orthopnoea, disturbed sleep, morning headaches, excessive day time somnolence, anorexia, decreased concentration and irritability or mood changes [53
The examination early in the course of limb onset disease usually reveals focal muscle atrophy especially involving the muscles of the hands, forearms or shoulders in the upper limbs, and proximal thigh or distal foot muscle in the lower limbs. Fasciculations are usually visible in more than one muscle group. Spasticity is evident in the upper limbs by increased tone and a supinator 'catch', and in the lower limbs with a patellar 'catch' and clonus together with hypertonia. Tendon reflexes are pathologically brisk in a symmetrical manner, including the finger jerks in the upper limbs and positive crossed adductor reflex in the lower limbs. Abnormal spread of tendon reflexes beyond the stimulated muscle group may be evident. The Hoffmann's sign may be positive in the upper limbs and plantar response is often extensor. In patients with bulbar dysfunction, dysarthria may arise from either LMN pathology or pseudobulbar palsy from UMN disorder, leading to slow slurred speech or a nasal quality. On examining the cranial nerves, the jaw jerk may be brisk, especially in bulbar-onset disease. An upper motor neurone type facial weakness affects the lower half of the face causing difficulty with lip seal and blowing cheeks, but often varying degrees of UMN and LMN facial weakness coexist. The gag reflex is preserved and is often brisk while the soft palate may be weak. Patients develop fasciculations and wasting of the tongue, and tongue movements are slowed due to spasticity. The rest of the cranial nerves remain intact, although in late stages of the disease patients may very rarely develop a supranuclear gaze palsy [54
]. Sensory examination is almost always unremarkable. As disease progresses, patients develop the characteristic picture of the combination of upper motor neurone and lower motor neurone signs coexisting within the same central nervous system region, affecting the bulbar, cervical, thoracic and lumbar territories. Respiratory failure and other pulmonary complications are the usual cause of death in ALS. However, patients who are kept alive by tracheostomy assisted ventilation are found to eventually develop a profound state motor paralysis termed the 'totally locked-in state' (TLS), were there is paralysis of all voluntary muscles and varying degrees of oculomotor impairment [56