The motor neuron diseases (MNDs) are categorized by their pathological affinity for the voluntary motor system including anterior horn cells, certain motor cranial nerve nuclei, and corticospinal/bulbar tracts. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is the most notorious of these disorders. The boundaries of what is and what is not ALS, particularly in the context of early diagnosis of individual patients, remain imprecise. In this Chapter, in an attempt to distinguish ALS from other MNDs, we consider ALS to be a disorder that has the following characteristics: (1) the clinical manifestations are dominated by signs attributable to voluntary motor system dysfunction, (2) the disease progresses rapidly both within and between different body regions, (3) that life expectancy is <5 years from clinical onset in the vast majority of cases, (4) and that no other etiology can be identified.

Despite its characterization as a motor system degeneration, ALS is best conceptualized as a multisystem disorder.¹ This perspective is reinforced by both a clinical and pathological overlap between ALS and frontotemporal lobar degeneration (FTLD) (pathological) and frontotemporal dementia (clinical).² Consequently, ALS is more correctly considered as a disorder in which dysfunction of the voluntary motor system involvement is the dominant source of morbidity (in the majority of cases) but in which involvement of other neurological systems at times clinically, and more commonly pathologically, develops.

The uncertain etiology of sporadic ALS (sALS) and the increasingly complex biology of ALS contribute to a lack of coherence in ALS nosology. This confusion applies to both historical and contemporary perspectives. In 1849 and 1850, respectively, Duchenne and Aran described progressive muscular atrophy (PMA), a disorder they believed to be of muscular origin. PMA has been long recognized however, to result from anterior horn cell degeneration.³ In 1860, Duchenne first described a syndrome of progressive dysphagia and dysarthria and coined the term progressive bulbar palsy (PBP).³ In 1874, Charcot and Cruveilhier recognized that corticospinal tracts and anterior horn cells were often affected concomitantly. Their description serves as the basis for our current construct of ALS.³ In the next year, Erb described primary lateral sclerosis (PLS), a progressive disorder of corticospinal tracts, without (at least initially) evidence of muscle atrophy, fasciculation, or weakness.³ ALS, PMA, PBP, and PLS are accepted by most, but not all neurologists as interrelated entities. PMA and PLS are clinically defined by the type of motor neuron affected. PBP on the other hand, is defined by site of disease onset, regardless of the type of motor neuron involved. Although survival in PMA and particularly PLS will on average exceed that of ALS, there is considerable overlap.^4–10 Survival in ALS does not differ significantly between different disease categories as described by the El Escorial criteria (EEC) (see below) including the original EEC-suspected category that is synonymous with PMA, that is an exclusively lower motor neuron (LMN) presentation.⁹ Many patients with these initially limited MND (PBP, PMA, and PLS) phenotypes evolve into ALS. Unfortunately, phenotypic classification does not provide a mechanism by which to predict the natural history of disease in an individual patient. Patients with prolonged (>5 years) survival have a similar distribution of phenotypes as do patients with typical natural histories.¹¹ Individual patients fulfilling ALS criteria may have indolent courses whereas patients with PMA may progress rapidly with approximately a third of PMA patients dying within 3 years of symptom onset.^8,12

Recognizing the pragmatic limitations imposed by the imprecise MND boundaries, Lord Brain, in his text of 1962, proposed the “lumped” concept of MND, presumably to acknowledge and circumvent uncertainties of the split classification. To this day, MND serves as a synonym for ALS and other forms of MND within the United Kingdom.³ Arguably, it represents the most intellectually honest means to classify these disorders until a biological basis to justify lumping or splitting becomes available.

There have been three international consensus conferences that have attempted to provide an ALS classification scheme that is both accurate and clinically pragmatic. The first of these met in El Escorial, Spain in 1990. As there were no recognized effective treatments at that time, the primary goal was to define ALS with a high degree of sensitivity and specificity for research purposes. The proceedings of this meeting led to the subsequent publication of the EEC (Table 6-1).¹³ Shortly thereafter, Riluzole was reported to alter the natural history of the disease, the first (and to this date only) drug treatment shown to do so.¹⁴ In response to this, with promise of other effective treatments, and in recognition that the stringency of the EEC would hamper enrollment into clinical trials, a subsequent meeting was held in Airlie House, Virginia in 1998.¹⁵ The purpose of this convocation was to modify the EEC in order to allow earlier diagnosis without reducing diagnostic specificity thus facilitating for earlier and expedited clinical trial enrollment.

Unfortunately, the Airlie House revision of the EEC may not have resulted in earlier participation in clinical trials.⁹ Despite the virtual universal acceptance of EEC and its Airlie House modifications as the “gold standard” for ALS diagnosis, they may continue to sacrifice sensitivity for specificity.¹⁶ Patients with early MNDs are frequently restricted from participation in clinical trials at a time in their disease when they are presumably most likely to be treatment responsive. Studies suggest that only 56% of patients clinically thought to have ALS will fulfill definite or probable Airlie House diagnostic criteria at the time of diagnosis.⁹ In addition, it has been recognized that the EEC classification at diagnosis, for example, definite, probable, possible, or suspected, does not correlate with clinical course and survival.⁹ Furthermore, up to 10% of a clinically defined ALS population will die without achieving either of these levels of diagnostic certainty.⁹ In support of this, postmortem examination of patients who would not fulfill definite or probable ALS diagnostic criteria because of phenotypes restricted to upper motor neuron (UMN) or LMN findings will have pathological confirmation of ALS.^17,18 The diagnosis of probable or definite ALS via EEC is dependent upon either clinical or lab demonstration of both UMN and LMN findings in two or three body regions (cranial, cervical, thoracic, lumbosacral) respectively. The reliable demonstration of UMN findings can be difficult and subjective, particularly in the thoracic and cranial regions. In addition, there is no reliable surrogate marker for UMN involvement as there is for lower motor disease (EMG). For these reasons, the early diagnosis of ALS via EEC/Airlie House criteria remains problematic.

In an attempt to improve sensitivity without sacrificing specificity in ALS diagnosis, a third consensus conference of experts convened in Awaji Island, Japan in 2006.^19,20 The premise of conference participants was that fasciculation potentials, particularly when “complex or unstable,” represented an adequate surrogate for fibrillation potentials and positive waves as a marker of ongoing denervation. In an attempt to maintain adequate disease specificity, the authors dictated that these unstable and complex fasciculation potentials had to occur in the context of two additional features: (1) the patient had clinical features suggesting ALS, and (2) fasciculation potentials had to occur in muscles concomitantly with chronic motor unit action potential (MUAP) changes. Subsequent studies supported the Awaji hypothesis by suggesting that diagnostic sensitivity increased from 28% to 60% in comparison to EEC while maintaining the same specificity of 96%.^21,22

Although marketed as an evidence-based document, none of the citations supporting the widespread application of the Awaji criteria have offered convincing evidence that patients achieving an early diagnosis of ALS utilizing these criteria evolve into definite ALS as determined by existing gold standards of either a typical clinical course or postmortem confirmation. In addition, the proponents imply that the demonstration of “unstable” fasciculation potentials provides a reliable means to distinguish ALS from less malignant causes of fasciculation potentials.^19,20 In a separate manuscript however, one of the authors of the Awaji manuscript refute the contention that “benign” and “malignant” fasciculation potentials can be reliably distinguished from one another.²³ We are in agreement with all three sets of criteria that consider both a clinically weak muscle and a strong muscle that electrodiagnostically displays both ongoing and chronic changes of denervation to be equivalent in defining the anatomical extent of the disease. We, like others, remain unconvinced that fasciculation potentials, unstable or otherwise, should be accepted as a surrogate marker of ongoing denervation in the absence of other EDX abnormalities.²⁴

Aran first reported the occurrence of ALS in multiple family members in 1848. Nonetheless, the concept of familial ALS (fALS) was dismissed by Charcot and largely ignored until the discovery of the first ALS gene mutation in the early 1990s (Table 6-2). At least 5–10% of ALS cases associated with 13 currently recognized gene mutations occur as a result of a single gene (Mendelian) mutation.²⁵ In addition, it seems likely that genetic influence confers disease susceptibility in some portion of sporadic cases. It has been reported that there is an approximate eightfold increased lifetime risk of developing ALS in siblings or progeny of apparent sALS patients.²⁶

fALS, like sALS displays phenotypic heterogeneity. Other than for an earlier average age of onset, there are no distinguishing features that allow clinical distinction between inherited and sporadic cases. The full spectrum of phenotypic heterogeneity of ALS is evident even within different point mutations of the same fALS (SOD1) gene (Table 6-3). fALS may occur with juvenile or adult onset, slow or fast progression, limb or bulbar onset, UMN or LMN predominance, and in the presence or absence of frontotemporal dysfunction.^27–30 Not only do all of these different phenotypic variations occur in both fALS and sALS, they seem to occur with similar prevalence rates. As in sALS, fALS patients may never fulfill the clinical EEC requirements for probable or definite ALS during the patient’s lifetime.

As alluded to previously, the historical conceptualization of ALS, either inherited or sporadic, is that of a degenerative disorder of anterior horn cells and pyramidal tracts. This construct is confounded by the recognition that both the clinical manifestations and pathology of ALS may affect extrapyramidal, cerebellar, and particularly, cognitive systems.^1,2 It has been estimated that anywhere from 10% to 75% of ALS patients will have subtle or overt abnormalities in executive function, behavior, and/or language if carefully sought for, implicating frontotemporal lobar dysfunction (FTD).^2,27,31,32 Estimates of overt dementia range from 15% to 40%.² Conversely, if patients with FTD are carefully examined, it has been suggested that 14% will have signs of definite ALS and additional 36% signs of possible disease.³³ MND may precede, occur concurrently, or follow the onset of FTD.³⁴ In this chapter, we will use the acronym FTD to represent frontotemporal dysfunction without necessarily implicating overt blown dementia. The intent of this departure from consensus criteria nomenclature is that it allows us to consider the full spectrum of frontotemporal deficits, not only those fulfilling the Neary diagnostic criteria for dementia.^2,35,36

Estimates of FTD prevalence however, originate in large part from Western cultures where prolonged survival and the use of tracheostomy-assisted mechanical ventilation (TAMV) occur infrequently. Experiences in cultures where long-term ALS survivors are more prevalent, related to increased utilization of TAMV, suggest that the occurrence of dementia increases over time in ALS patients. This further supports the concept of ALS as a multisystem disorder.^37,38 ALS with dementia or involvement of other neurological systems is designated as ALS plus by the EEC.^13,39 Frontotemporal dysfunction in fALS is increasingly recognized but has not been as well described as in sALS. This may reflect ascertainment bias as FTD has been estimated to occur less in those with SOD1 mutations, the most historically prevalent genotype of fALS prior to the recognition of the C9ORF72 mutation.^2,40

Although the focus of this chapter is ALS, the strong association with FTD and FTLD justifies a few comments relevant to the epidemiology of the latter disorder. In addition to ALS, FTLD may occur in association with cortical basal ganglionic degeneration, progressive supranuclear palsy, or other neurodegenerative conditions. In approximately 10% of cases, it is associated with an apparent autosomal dominant mode of transmission.⁴¹ The genes most commonly related to heritable FTD that have been identified to date include microtubule-associated protein tau (MAPT) and progranulin (PGRN). MND occurs uncommonly with these mutations. Like fALS however, the locus for many fFTD cases remains unidentified.⁴¹

FTD co-associates with a number of fALS genotypes. Recently, hexanucleotide repeat mutations of the C9ORF72 gene have been identified as the most common cause of fALS and/or frontotemporal dementia, representing 12% of fFTD, 3% of apparent sFTD, 24% of fALS, and 4% of apparent sALS in North America.⁴² In Finland, the impact of this mutation is even greater with 46% of fALS and 21% of apparent sALS cases resulting from chromosome 9 open reading frame 72 (C9ORF72) gene expansion.⁴³ Other mutations that are less frequent causes of FTD, but more common causes of ALS with or without FTD occur in the chromatin-modifying protein 2B (CHMP2B), fused in sarcoma (FUS), TAR DNA-binding protein (TARDBP), polyphosphoinositide phosphatase (FIG4), ubiquilin 2, and valosin-containing protein (VCP) genes.^25,44 As mentioned, FTD is recognized infrequently with SOD1.⁴⁰

Within the general population, MNDs are uncommon. The incidence of ALS averages 1.8/100,000 across all studies. This incidence appears to be increasing both within and outside the boundaries of an aging population.¹ The average age of onset is 56 years for sporadic disease and 46 years for most dominantly inherited forms of the disease.^25,27 Teenagers and the elderly may be afflicted. Although it is widely believed that environmental factors must play at least some role in ALS pathogenesis, epidemiologic studies have failed to identify any reproducible risks other than age, gender, increased body mass index, and potentially cigarette smoking.^45–49 The historical inability to identify environmental risks may be related in part to methodology.^48–51 Although ALS has been reproducibly shown to occur 1.5 times more frequently in men, this ratio diminishes with advancing age and may not be true for bulbar-onset disease which seems particularly prevalent in older women.^49–52 There have been nests of apparent increased incidence. The ALS–Parkinsons–Dementia complex formerly endemic in Guam and other Western Pacific regions is the most notable example.⁵³ The neuronal inclusions in this disorder contain tau however, not the ubiquitin characteristic of typical (non-SOD1) ALS, suggesting that Guamanian ALS may be a different disorder. Otherwise, neither ethnicity, geography, nor occupation has been reproducibly demonstrated to alter risk.

The majority of ALS patients succumb within 2 to 5 years from symptom onset without ventilatory and nutritional support.^9,52,54 The range extends however from less than 1 year to more than 10 years without TAMV. It is estimated that a quarter of individuals will survive more than 5 years.^12,52 A vital capacity of less than 50% of predicted is associated with the need for hospice, death, or need for mechanical ventilation within 6 months.⁵⁵ Progression seems to follow a linear course, although the abrupt loss of a critical function may provide the appearance of stepwise deterioration.⁵⁴ Patients with PBP are said to have a shorter average life expectancy, although many lead protracted existences if aspiration risk is minimized and ventilation preserved or supported.⁵⁴ Young males seem to live longer on average.⁵⁴ Rilutek, participation in a multidisciplinary clinic, noninvasive positive pressure breathing, and possibly percutaneous gastrostomy are interventions that have modest benefits in prolonging life expectancy.⁵⁶

ALS is characterized by painless, progressive muscle weakness and atrophy (Fig. 6-1). The site of onset, the relative predominance of UMN or LMN signs, and the rate of progression are variable. Patients typically present when functional difficulties cause them to acknowledge their deficit. These initial deficits are frequently asymmetric and sometimes monomelic depending on patient vigilance. In instances where the patients do not seek early medical attention, or their physicians do not recognize the significance of the problem, the patients may not be diagnosed until their disorder is fairly advanced, months or even a year or more after onset. The initial deficits may be initially limited in distribution but should affect more than one nerve and nerve root distribution in limb-onset cases. Less commonly, the initial symptoms may be cramps, dysarthria, dysphonia or dysphagia, or related to impaired ventilation. Occasionally, the initial clinical manifestations may be head drop or bent spine syndromes related to paraspinal muscle weakness (Fig. 6-2). In this latter circumstance, the patient may actually present with back pain due to the disordered posture caused by inadequate spine support.

Fasciculations are more commonly recognized by the examining physician than by patients. On occasion, they may be the initial manifestation of MND, particularly in those who have a pre-existing awareness of their potential significance. Patients presenting with a chief complaint of fasciculations without weakness, atrophy, or abnormal EMGs rarely have or evolve into ALS.⁵⁷ In our experience, benign fasciculations are described more than seen, tend to occur most frequently in the calf muscles, and when observed are typically repetitive in the same location in any given muscle at any specific point in time. Conversely, fasciculations that are continuous and multifocal both within and between muscles, even in the absence of weakness, are ominous. This uncommon pattern of visible frequent and multifocal fasciculations without weakness is rarely seen in other circumstances other than MND, anticholinesterase overmedication being one notable exception. Lastly, the absence of fasciculations in patients with painless weakness does not preclude the diagnosis of ALS, particularly in those with excessive subcutaneous tissue.⁵⁸ An increased frequency of muscle cramping is also common in MND. In our experience, provocation of cramps in muscles (with the exception of the calves) during manual muscle testing is seen with some frequency in ALS patients is uncommon in other disorders.

As previously alluded to, the definite clinical diagnosis of ALS is dependent on the demonstration of both LMN and UMN signs, which progress both within and between different body regions. Frequently ALS may be dominated by LMN, or less frequently UMN signs. This may occur at onset or in some patients throughout their entire disease course. Signs of LMN involvement include muscle weakness, atrophy out of proportion to disuse, attenuation or loss of deep tendon reflexes, cramps, and fasciculations.⁵⁹ When LMN weakness impairs coordination, it does so to an extent proportionate to the degree of weakness.⁵⁹ LMN features in cranial musculature in ALS are most frequently and convincingly manifest in the tongue. Atrophy is noted by the crenated, as opposed to the normal rounded edges, and fasciculations best noted with the tongue lying quietly on the floor of the mouth (Fig. 6-3). Tongue strength is best tested by pushing against the bulge in the cheek created by the patient “pocketing” their tongue on either side. Weakness of neck flexion and extension are common in ALS. Weakness of facial (e.g., eye closure) and jaw opening and closing muscles occur but are typically less evident. Ptosis and ophthalmoparesis are notable for their absence.

UMN manifestations are more diverse and, at times, more subjective than their LMN counterparts. The elicitation of Babinski signs, sustained clonus, pathologically hyperactive deep tendon reflexes, and spasticity are objective and universally accepted manifestations of UMN pathology. Unfortunately, they are not overt in a significant percentage of ALS cases, thus confounding and delaying the clinical diagnosis. Other presumptive signs of corticospinal tract pathology include reflex spread (e.g., finger flexion with percussion of the brachioradialis tendon, hip flexion with percussion of the Achilles tendon), synkinesis (coactivation of muscles not required to accomplish a requested movement), Hoffman signs, and preservation of reflexes in a wasted and weak extremity. The latter is arguably the most prevalent of the subjective UMN sign demonstrable in ALS patients.⁵² In cranial innervated muscles, unequivocal UMN signs may be difficult to demonstrate. Increased emotional lability (pseudobulbar affect) and spastic dysarthria are perhaps the most frequently occurring UMN signs in this region but are more subjective than objective. Forced yawning is nonspecific. Exaggerated gag or jaw reflexes are more objective but do not occur with particularly great frequency. Arguably, slowness of attempted rapid blinking or tongue movements, in the absence of weakness, implicates central nervous system (CNS) pathology and provides support for UMN involvement in someone whose presentation is otherwise dominated by LMN signs. The same may be said for synkinesis, for example, the concomitant movement of the jaw with requested, rapid side-to-side tongue movements.

Coordination is impaired early with UMN involvement in a manner disproportionate to the degree of weakness.⁵⁹ There is frequently a “UMN stickiness” resulting in delayed activation of requested movements associated with the normal or near-normal strength. Often, muscles not required for an attempted motion are inappropriately (synkinetically) activated. For example, contralateral foot tapping may occur with requested unilateral foot-tapping movements. With UMN disease, foot dorsiflexion strength may be normal but delayed in initiation and preceded by great toe dorsiflexion. UMN signs may be transient in ALS, as they may develop and then disappear as LMN-induced weakness evolves and trumps UMN manifestations. For example, a Babinski sign may be lost as the extensor hallucis muscle weakens.

Recognizing the value of the EEC and the Airlie House revision, we find it helpful to categorize our patients both by onset site and phenotype. Onset sites include bulbar, upper limb, lower limb, or rarely truncal or ventilatory locations. Phenotypic categories include PMA, lower motor neuron dominant (LMN-D) ALS, ALS, upper motor neuron dominant (UMN-D) ALS, and PLS. We define PMA as muscle weakness and atrophy associated with hypo- or areflexia in involved segments. LMN-D is applied to individuals with dominant LMN features associated with suggestive, but not definite UMN signs as listed above. Typically, these are individuals mentioned above whose deep tendon reflexes are either preserved or mildly increased in the involved body regions. UMN-D disease is defined by the absence of LMN signs clinically but with unequivocal signs of denervation on EMG that are not readily explained by an alternative mechanism. PLS is defined as a progressive UMN syndrome occurring without an alternative explanation without either clinical or electrodiagnostic evidence of LMN disease.

In most series, ALS is the most common presentation of MND, although even in these patients, the morbidity appears to stem primarily from LMN disease.^9,59–62 In probability, most classifications consider LMN-D to represent ALS.⁵² In approximately two-thirds of cases, the initial site of involvement is in a limb, typically distally and asymmetrically located in a hand or foot.^8,9,52,58,59 Initial weakness may occur in proximal muscles as well. A definite diagnosis cannot be made until combined UMN and LMN signs spread over a period of months, both within and outside the initially affected body region. A diagnosis of ALS meeting EEC definite or probable criteria, allowing clinical trial eligibility, is obtained in only 31–56% of cases at the time of the initial examination.⁹ Despite diagnostic limitations imposed by EEC, the combination of UMN and LMN findings confined to multiple segments in one limb is sinister when unassociated with pain or sensory symptoms.

It is estimated that PMA phenotype represents anywhere between 2% and 10% of MND patients.^7,8,22,52,61 This variation is undoubtedly based on whether deep tendon reflex preservation in a weak limb is or is not considered to lie within the boundaries of PMA.⁷ A LMN-D presentation is estimated to occur in 7%, 26%, 29%, and 18% respectively in those whose disease begins in the bulbar, cervical, thoracic, and lumbosacral regions.⁹ These statistics may be biased however, by the ease or difficulty in identifying UMN or LMN signs in any given region. For example, UMN findings in the thoracic region may be underrepresented due to the insensitive clinical means of detection. Of those who do not manifest UMN signs at onset, 22% will develop them and 90% will evolve into EEC probable or definite disease.⁹ Even in the patients who fail to develop UMN features during life, the pathological features of ALS will be identified on postmortem examination.^{17,18,63–65}

Other observations, supporting the concept that PMA and ALS exist as a continuum include the documentation that these disorders have overlapping natural histories. Although PMA and LMN-D patients live longer on average than patients classified as having ALS, individual patients in any of these categories may have malignant courses.^7,8,12 On average, symmetric presentations and individuals who continue to have monomelic involvement after prolong periods of observation tend to have the more indolent courses.^7,8 As would be expected, those whose measurements of ventilatory or limb strength decline precipitously have life expectancies that parallel ALS despite an absence or paucity of UMN signs.^7,8 Additional arguments in support of PMA and LMN-D as part of the ALS spectrum include the recognition that PMA phenotypes occur in at least five different SOD1 fALS genotypes. The A4 V SOD1 mutation, a rapidly progressive PMA phenotype, represents the most common SOD mutation in North America and represents the most dramatic example of this phenomenon.^62,66 FTD prevalence is estimated at 17% in PMA patients, providing further support for a common biology in the two syndromes.⁶⁷

At times, slowly progressive forms of LMN-predominant ALS may remain confined to both upper extremities over protracted periods, producing a syndrome that has been described as flail arm, bibrachial amyotrophic diplegia (BAD), or “man-in-the-barrel” syndrome.^68,69 This disorder more commonly affects the shoulder girdles initially in comparison to the more common LMN-D forms of ALS which are more likely to begin distally and progress more rapidly. A similar more indolent syndrome, referred to a lower extremity amyotrophic diplegia (LAD) may affect both lower extremities, rendering the individual paraparetic for protracted periods before spreading to other regions.⁶⁹ In our opinion, both BAD and LAD are best conceptualized as PMA variants.

Between 25% and 40% of individuals present with “bulbar-onset” disease, that is, dysarthria or less commonly dysphagia.^9,70 As in limb-onset ALS, PBP may be dominated by UMN characteristics, LMN characteristics, or both. As with limb-onset cases, unequivocal UMN and LMN signs occurring concomitantly in cranial innervated muscles, even in the absence of limb involvement, are ominous. As in PMA and PLS, fALS may have a PBP presentation. This PBP presentation more commonly occurs in women than in men. Life expectancy in PBP has been repeatedly demonstrated to be on average less than in limb-onset disease particularly if there is an associated language-dominant FTD.⁷¹ This prognosis does not necessarily apply to individual patients as mortality may be related more to the importance of the functions jeopardized early in the course (breathing and swallowing) than a reflection of the biology of the disease.⁷² In some individuals with sporadic PBP, signs and symptoms may remain confined to the “bulbar” musculature for considerable time, affecting the physicians’ confidence in the accuracy of their diagnosis, particularly with a UMN-D presentation. Some reports suggest both the prevalence and severity of FTD are increased in bulbar as opposed to limbonset cases whereas others do not. FTD has been reported to occur in as many as 48% of PBP cases if carefully sought for.^73–76 One report suggests that there is an increased incidence of language-dominant FTD in patients with bulbar-onset disease.⁷¹

ALS beginning as an UMN exclusive (PLS) or dominant (UMN-D) process is less common than phenotypes dominated by LMN or bulbar dysfunction.^77–81 Approximately 2–5% of ALS cases begin with a PLS phenotype.⁷⁸ The average age of onset in virtually every series is about 50 years, approximately 10 years younger than typical ALS.⁷⁸ Three-quarters of PLS cases involve the legs, initially creating an inability to effectively run or hop. In most cases, the onset is asymmetric and at times may be hemiparetic, referred to as the Mills variant.⁷⁸ In approximately 15% of cases, PLS affects the bulbar muscles initially. In 10% of cases, the upper extremities are the first region to become symptomatic.^5,6 It is commonly held that ALS spares the anterior horn of the sacral segments. As a result, it is commonly held that genitourinary symptoms do not occur in this disease. In our experience, PLS is an exception to this rule as urinary urgency and urgency incontinence may occur. Presumably this results from detrusor–sphincter dyssynergia. To further cement the biological relationship between PLS and ALS, PLS patients also appear susceptible to frontotemporal dysfunction and FTLD.^81,82

The distinction between PLS from UMN-D ALS is based on whether LMN signs are absent (PLS) or present.^4,5 In the aforementioned reports, the authors defined the threshold for LMN involvement by EMG as abnormalities in more than two muscles (minimal number of muscles studied not defined). These abnormalities could include fibrillation potentials/positive waves, fasciculation potentials, or evidence of mild MUAP enlargement consistent with denervation and reinnervation. Presumably, these limits were defined so as to not exclude patients with minor EMG abnormalities secondary to a separate, unrelated, neurogenic injury. It has been suggested that focal weakness, bulbar symptoms at onset, or later development of weight loss and declining ventilatory function predict transition to ALS.⁵

The natural history of PLS is more favorable than PMA or ALS. In nine reported series, mean disease duration ranged between 7 and 14 years.⁸⁰ The majority (80%) of individuals with PLS who evolve into ALS do so within the first 4 years of their disorder.⁵ Conversely, development of LMN features, either clinically or electrodiagnostically, may not develop until 20 or more years after the initial symptoms at which time the distinction between ALS and PLS becomes moot. The natural history of patients who do not have clinical or electrodiagnostic evidence of LMN involvement during the first 4 years of their illness is statistically superior to those who do. ALS may not be initially considered in the differential diagnosis when the initial manifestations are dominated by UMN features. Presumably, this results from the relative rarity of this condition in comparison to the other more common causes of progressive UMN disease. Typically, PLS is considered, and appropriately diagnosed, only after imaging, CSF and other investigations fail to provide an alternative explanation for a patient’s worsening spasticity.

In up to 2.7% of cases, ALS may initially present with symptoms attributable to ventilatory muscle weakness.^83,84 These may escape initial detection due to their sometimes protean clinical manifestations including disordered sleep, early morning headache, fatigue, or altered sensorium. Involvement of ventilatory muscles may not be recognized until the more classic manifestations of dyspnea on exertion or orthopnea occur. It is not rare for patients to notice dyspnea for the first time after meals or while bending over to tie their shoes which restrict movement of weak diaphragms. On occasion, ALS may be first recognized in an individual who cannot be weaned from the ventilator following elective intubation. Paradoxical abdominal movements or a drop in vital capacity of more than 10% in the supine position indicates diaphragmatic weakness in patients with a suspected neuromuscular cause of ventilatory symptoms.

ALS and frontotemporal dysfunction represent overlapping disorders which exist in a continuum.^2,31–34 This association is important for a number of reasons including insight into a potential common biology. In addition, a reduced life expectancy in ALS patients with concomitant frontotemporal dysfunction has been suggested.^2,71,85 Alternative management strategies may be required when ALS and FTD coexist.² Both ALS and FTD may occur on either a sporadic or hereditary basis. Although it has been previously suggested that FTD may be more prevalent in patients with familial disease, others feel that the prevalence of cognitive impairment is similar in both sALS and fALS.⁸⁶ Both ALS and FTD may exist as individual disorders or develop collectively, either on a clinically evident or strictly a pathological basis. In the latter circumstance, the second disorder may or may not become clinically manifest during the lifetime of the patient.

It is estimated that 15% of patients who present with apparent sporadic FTD will have ALS and another 30% will have features suggestive of MND.³³ Conversely, 30–50% of ALS patients in most series and up to 75% in some who undergo careful testing will be identified as having some alteration in behavior, executive function, or language.^{2,31,72,74,85} Estimates of dementia fulfilling Neary criteria are estimated between 15% and 41% in ALS patients.^2,29,76,87 ALS and FTD may precede the development of the other, or both may present concomitantly.³³ On occasion, patients with FTD and ALS will be found to have concomitant Parkinsonism as well.³³ The concurrence of ALS, a movement disorder, and dementia should raise the consideration of one of the known genetic causes of this triad (see above) (Table 6-2).

Minor cognitive and behavioral changes in MND patients may be overlooked for a number of reasons. They may be subtle and therefore escape detection unless appropriate screening instruments are utilized. The detection of these changes may also be obscured by the patient’s writing and speaking difficulties. Behavioral changes, when recognized, may be misattributed to known consequences of ALS such as hypercapnia, depression, or pseudobulbar affect.

A nomenclature for frontotemporal dysfunction, with or without ALS, has been established and continues to evolve.² Patients may have a behavioral syndrome characterized by apathy, altered social and interpersonal conduct, emotional blunting, and loss of insight.⁸⁷ Alternatively, the primary deficit may be one of expressive language with speech that is dysgrammatical, associated with paraphasic errors and word-finding difficulties. Frontotemporal dysfunction may also manifest as a semantic, predominantly receptive language disorder in which the significance of words and objects lose meaning. Executive dysfunction, which is the loss of the ability to plan and organize tasks by maintenance of attention or the ability to shift sets to accomplish a goal-directed task, represents a significant component of frontotemporal dysfunction as well. Executive dysfunction has been estimated to occur in anywhere between 22% and 35% of ALS patients who do not fulfill the criteria for overt dementia.^2,34,88

Tests of verbal fluency provide a sensitive screening method for FTD patients with cognitive impairment.^2,74 Normal values are 8 and 13 respectively for number of words generated in 1 minute beginning with the letter D and names of animals.^2,74 Another strategy that may be even more sensitive for detecting set-shifting difficulties is to ask the patient to provide a word beginning with a specific letter alternating with a different category, for example, men’s first names. Normative values for this task are seven or more pairs in 1 minute. Perseveration may be readily detected if two consecutive responses belonging to the same category are provided. A potentially useful screening test in individuals with unintelligible speech is “antisaccade” testing (the ability to look in the opposite direction in response to a lateralized visual stimulus). A patient should make no more than two errors in 10 attempts to be considered normal. There are numerous standardized tests that can be efficiently administered during a routine clinic visit. It should be pointed out that the mini-mental state examination is not a particularly sensitive test for detection of early frontotemporal dysfunction. The authors prefer the Montréal cognitive assessment (MOCA) as their standardized screening instrument of choice due to its availability, ease of use, and ability to assess frontotemporal function.⁸⁹ Behavioral abnormalities are best assessed by specific behavioral inventories.

sALS remains a clinical diagnosis supported by the exclusion of potentially mimicking disorders for which testing exists. In cases where the clinical diagnosis of ALS is indisputable, it can be argued that the predominant goal of testing is to validate the credibility of the diagnosis in the eyes of the patient and their family. There are a number of suggested algorithms for the evaluation of the ALS suspect based on differential diagnostic considerations.^59,100,132 It is our practice to perform limited “routine” testing in ALS suspects. It is our opinion that testing should be done on a case-by-case basis as the differential diagnostic emphasis differs depending on whether it is a UMN-D, LMN-D, or bulbar-onset phenotype (Table 6-4). Disorders that are dominated by LMN features provide the largest number of differential diagnostic considerations.