Motor neuron disease
William Huynh, Thanuja Dharmadasa, Smriti Agarwal, Jashelle Сада and Matthew C. Kiernan
Motor neuron disease (MND) or amyotrophic lateral sclerosis (ALS) is a rapidly progressive and universally fatal neurodegenerative disorder of the human motor system that was first described in 1869 by Jean-Martin Charcot (Cleveland & Rothstein, 2001; Simon, Huynh, Vucic, Talbot & Kiernan, 2015). The condition is commonly referred to as Lou Gehrig’s disease, in honour of the great New York Yankees baseball player who developed the disease in the 1930s (Kiernan & Turner, 2015) (Figure 9.1). MND is characterised by degeneration of motor neurons in the brain and spinal cord that usually begins insidiously with focal weakness and subsequent relentless progression to involve most muscles, including the diaphragm ultimately resulting in death due to respiratory paralysis (Al-Chalabi et ah, 2016). The average overall survival is approximately 3-5 years but varies immensely depending on clinical phenotype and genetic factors, with approximately 10% of patients surviving more than 8 years (Brown & Al-Chalabi, 2017; Simon, Huynh, Vucic, Talbot & Kiernan, 2015). Although previously considered as a pure motor disorder, cumulative evidence from imaging, neuropathological and clinical studies now suggest that MND affects extra-motor systems, representative of a multisystems disease that extends beyond upper and lower motor neurons. In particular, a significant proportion (up to 50%) of patients with MND develop cognitive impairment and behavioural changes (van Es et al., 2017).
AC is a 64-year-old man who presented with progressive weakness in his limbs over the past 18 months. He first noticed wasting and weakness that started in his right hand which then over the pursuing 3 months spread to affect the left hand.
FIGURE 9.1 Lou Gehrig (1903—1941), the New York Yankees baseball player
nicknamed ‘the Iron Horse’, began a streak of 2,130 consecutive games in June 1925 that ended when he developed left leg weakness 14 years later. (A) The ALS split-hand refers to preferential wasting of abductor pollicis brevis and first dorsal interosseous muscles, with relative preservation of the lateral abductor digit minimi. (B) A photograph of Gehrig (right) with teammate ‘Babe’ Ruth (left), on display at Yankee Stadium, confirms wasting of his left first dorsal interosseous (close-up shown in panel C). It developed after initial ipsilateral leg weakness, and this pattern of spread of symptoms to contiguous body regions is typical in MND.
Source: Kieman & Turner (2015); reproduced with permission (copyright licence 4340721264708)
About 2 months later bulbar symptoms became apparent with dysphonia and dysarthria followed by mild dysphagia mainly for liquids. Respiratory symptoms have also become an issue in more recent times with dyspnoea upon minimal physical activity. There is no significant personal or family medical history and he does not drink alcohol nor smoke cigarettes.
On examination he was cachectic and there was prominent wasting with severe weakness of the intrinsic muscles bilaterally and a split-hand appearance (preferential thenar over hypothenar muscle wasting). There were frequent upper limb fasciculations. Tongue appeared mildly wasted and weak and jaw jerk was brisk. Facial muscle and neck strength were otherwise preserved. He had moderate dysphonia and mild flaccid dysarthria. Reflexes were globally brisk with spreading and there was unsustained ankle clonus bilaterally. He had moderate wrist weakness but preserved more proximally. In the lower limbs there was mild right ankle dorsiflexion weakness.
Brain and spinal cord MRI was normal. Nerve conduction studies (NCS) demonstrated normal sensory responses in the upper and lower limbs, but markedly reduced or absent distal motor responses in the upper and lower limbs associated with an abnormal split-hand index. Needle electromyography (EMG) showed widespread neurogenic changes with active denervation in all four limb muscles as well as denervation observed in the trapezius muscle.
Transcranial magnetic stimulation (TMS) studies to assess for cortical excitability demonstrated a reduction in short-interval cortical inhibition (SICI) in both motor cortices indicative of cortical hyperexcitability. He also underwent a cognitive assessment and he scored 86/100 on the Addenbrooke’s Clinical Examination (normal range being >88), with his worst performance in measures of executive functioning.
The clinical presentation of AC together with the electrophysiological features was consistent with an upper limb onset MND with features to suggest early cognitive impairment with executive dysfunction. A positron emission tomography (PET) scan was arranged to exclude an underlying malignancy given his significant weight loss but did not reveal evidence of a neoplastic process. The brain images, however, did show reduction in glucose metabolism in the frontal and parietal lobes bilaterally as well as temporal regions.
The incidence of MND is approximately 1-2.6 per 100,000 persons annually, while the worldwide prevalence is estimated to be 4—6 per 100,000 (Huynh & Kiernan, 2015; Talbott, Malek & Lacomis, 2016). The average age of onset of MND is currently 58-60 years but may vary depending on demographic factors such as geography with much younger age of onset observed in the Chinese population (Chen et al., 2015; Sabatelli, Conte & Zollino, 2013; Talbott, Malek & Lacomis, 2016). Sporadic MND (90-95%) constitutes the majority of cases, while the remaining 5-10% are hereditary, termed familial MND, although sporadic MND is postulated to involve genetic susceptibility to environmental risk factors (Huynh & Kiernan, 2015; Talbott, Malek & Lacomis, 2016). Age of onset appears to be slightly younger at 57-52 in familial cases (Kiernan et al., 2011), but clinical features are indistinguishable between sporadic and familial cases. Lifetime risk is higher in men (1 in 350) than for women (1 in 400), although the incidence between men and women is about the same in familial disease (Kiernan et al., 2011; van Es et al., 2017). There is evidence to suggest that the incidence and prevalence of MND is lower in populations of mixed ancestral origin than in European populations, with ditferences in age of onset in genetically heterogeneous populations (generally about 10 years earlier) (van Es et al., 2017). An onset in the late teenage or early adult years is suggestive of familial disease (Brown & Al-Chalabi, 2017).
MND is characterised by progressive motor deficits involving any voluntary' muscle usually resulting in heterogeneous presentations that range from hand weakness to dysarthria to a foot drop depending on the initially involved region (Figure 9.2; see also Plate 2 in the colour section). Motor neurons in the oculomotor nuclei and in Onuf s nucleus however, appear to be resistant therefore sparing of eye movement and sphincter control is often observed (van Es et al., 2017). The classical
FIGURE 9.2 Pattern of motor involvement in different ALS phenotypes. A colour version of this image is shown as Plate 3 in the colour section, where red indicates LMN involvement and blue indicates UMN involvement. Darker shading indicates more severe involvement, (a) In spinal-onset ALS, patchy UMN and LMN involvement is observed in all limbs.
(b) In bulbar-onset ALS, UMN and LMN involvement is observed in the bulbar muscles, (c) In progressive muscular atrophy, LMNs in arms and legs are involved, often proximally. (d) In primary lateral sclerosis, UMNs of arms and legs are primarily involved, but later in the disease, discrete LMN involvement can be detected, (e) In pseudopolyneuritic ALS, only LMNs restricted to the distal limbs are involved, (f) In hemiplegic ALS, unilateral UMN involvement with sparing of the face, and sometimes discrete LMN involvement, can be observed, (g) In flail arm syndrome, LMN involvement is restricted to the upper limbs, but mild UMN signs can be detected in the legs, (h) In flail leg syndrome, LMN involvement is restricted to the lower limbs, and is often asymmetric. ALS, amyotrophic lateral sclerosis; LMN, lower motor neuron; UMN, upper motor neuron.
Source: Swinnen & Robberecht (2014); reproduced with permission (copyright licence 4342890349018) hallmark of MND is the presence of both upper and lower motor neuron signs involving brainstem and multiple spinal cord regions of innervation on neurological examination (Kiernan et al., 2011) with the onset of disease often being focal but with the eventual spread to other body regions. The progression and spread of the disease appears to be both local (within the same region for example distal to proximal in the one limb) and between neuroanatomically linked regions (contralateral or rostrocaudal) (van Es et al., 2017).
Upper motor neuron (UMN) disturbances involving the limbs result clinically in spasticity, weakness, and brisk deep tendon reflexes, while lower motor neuron (LMN) limb features include muscle wasting and weakness with fasciculations. Bulbar UMN dysfunction is evident by the presence of spastic dysarthria characterised by slow, laboured, and distorted speech with a nasal quality and associated with a brisk gag and jaw jerk. Bulbar LMN dysfunction is identified by tongue wasting, weakness, and fasciculations that is accompanied by flaccid dysarthria and dysphagia. Flaccid dysarthria results in nasal speech caused by palatal weakness, hoarseness, and a weak cough (Duffy, Peach & Strand, 2007; Kiernan et al., 2011).
The initial clinical presentations constituting 95% of all ALS, may be classified according to region: (1) limb-onset MND (70%); (2) bulbar onset MND (25%). Alternatively it may be sub-divided into much rarer extremes of LMN or UMN involvement: (1) progressive muscular atrophy (PMA), with pure LMN involvement, and typically limb-onset; or (2) primary lateral sclerosis (PLS), characterised by predominant UMN involvement, typically lower limb or bulbar in site of onset, both of which are rare (Huynh et al., 2016; Kiernan et al., 2011). Pathological and novel neuroimaging and electrophysiological studies, however, often disclose evidence of involvement in either UMN or LMNs that appear to be clinically unaffected in these variants and hence considered part of different ends of the MND clinical spectrum. Initial trunk or respirator)' involvement is very rare (5%) and is associated with a very poor survival (Kiernan et al., 2011; Swinnen & Robberecht, 2014).
Early hand dysfunction in MND preferentially affects the ‘thenar hand’, which includes the abductor pollicis brevis and first dorsal interosseous muscles (Figures 9.1 A and 9.3C). In contrast, there is relative sparing of the hypothenar muscles (abductor digiti minimi). This dissociated atrophy of the intrinsic hand muscles is virtually unique to MND and is explained by the marked vulnerability of the hand-corticomotoneuronal system. The muscles involved underlie pincer and precision grips (prehensility), which are dependent on the corticomotoneu- ronal system, a prime pathological target of the disease (Eisen et al., 2017).
Disease progression in MND is characterised by an organised process of non- random spread of symptoms from site of onset to subsequent body regions, with preferred and most rapid symptom development to the contralateral limb. The organised development of symptoms to contiguous anatomical regions appears to be consistent throughout the spectrum of MND (Simon, Huynh, Vucic, Talbot & Kiernan, 2015; Walhout, Verstraete, van den Heuvel, Veldink & van den Berg, 2018) (Figure 9.4; see also Plate 4 in the colour section).
FIGURE 9.3 Clinical features of muscles wasting in a patient with MND. (A) Proximal and symmetrical upper limb wasting resulting in an inability to lift arms against gravity (‘man-in-the-barrel’ or flail arm variant MND). (B) Significant wasting of supraspinatus and infraspinatus muscles, as well as substantial loss of deltoid muscle. (C) Preferential wasting of the thenar muscles combined with the first dorsal interossei, the so-called ‘split- hand’, is a typical feature in MND.
PLS is characterised by slower progression and deterioration of function with sparing of respirator)' function and less-severe weight loss than seen in classical MND. The diagnosis of PLS includes the presence of upper motor neuron dysfunction, in the absence of other neurological findings, or alternative explanations on diagnostic testing including familial causes such as hereditary spastic paraparesis (HSP), structural, metabolic, infectious and inflammatory aetiologies. Ultimately PLS is a diagnosis of exclusion (Statland, Barohn, Dimachkie, Floeter & Mitsumoto, 2015). Some patients may present with UMN-predominant MND at onset but may develop evidence of LMN involvement. For this reason, sufficient time is usually required to lapse before a definitive diagnosis of PLS is made - usually 3-5 years, depending on the criteria used (ibid.).
Upper motor neuron involvement can be asymmetrical with an extreme form being the hemiplegic variant called Mills syndrome or progressive hemiplegia. In this phenotype, unilateral upper motor neuron involvement usually starts in the lower limb, followed by slow progression to the ipsilateral upper limb and relative sparing of the face. After a variable time however, the disease spreads to the initially unaffected contralateral side (Swinnen & Robberecht, 2014). Patients may have lower motor neuron onset that remains limited to the upper limbs for at least 12 months, while the lower limbs are unaffected by weakness, although
FIGURE 9.4 Patterns of disease and the pathogenesis of motor neuron disease.
(a) Representation of the hypothesis of contiguous cortical and spinal spread as an explanation of clinical patterns of disease, with the focus of disease onset in the motor cortex representing the right upper limb, (b) Pathology may then spread within the ipsilateral motor cortex and involve the spinal cord through the corticospinal tract, (c) Independently, pathology may spread within the spinal cord both through contiguous anatomic spread from the initial focus in the right cervical spinal cord, (d) Pathology may continue to spread within the motor cortex involving the contralateral hemisphere by spreading across the corpus callosum, and (e,f) through ongoing descending transmission through the corticospinal tract. This mechanism of spread may help explain the complex patterns of clinical involvement and spread seen in amyotrophic lateral sclerosis patients.
Source: Simon, Huynh, Vucic, Talbot & Kiernan (2015); reproduced with permission (copyright licence 4340750880994) some UMN features may be observed. This phenotype called flail arm syndrome (synonyms include scapulohumeral form of MNI), man-in-a-barrel syndrome or brachial amyotrophic diplegia) has a male predominance (male-to-female ratio 4:1) (Figures 9.ЗА and 9.3B). Most patients with this syndrome however develop more widespread disease after a period of about 20 months. Other rarer variants include the flail leg and dropped head syndrome.