BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing stereotypic motor impairment, commonly known in the United States as Lou Gehrig’s disease, after the famous baseball player stricken with ALS in the 1930s.¹ Jean-Martin Charcot’s 1874 description of clinical and pathological features of ALS remains largely accepted today.² Clinical and basic research since Charcot’s time have further refined the clinical features in ALS and provide evidence that ALS has multiple causes.³ Also apparent is that a number of neurological disorders share certain features with ALS, complicating the diagnostic evaluation of suspected ALS in some patients. Epidemiological aspects of ALS are summarized in Table 66-1.

TABLE 66-1 Epidemiology of Amyotrophic Lateral Sclerosis

Data from Kondo K: Epidemiology of motor neuron disease. In Leigh PN, Swash M, eds: Motor Neuron Disease: Biology and Management. London: Springer-Verlag, 1995, pp 19-33; and from Mitsumoto H, Chad D, Pioro E: Epidemiology. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 18-33.

ALS is by definition a progressive motor disorder affecting upper motor neurons (UMNs) and lower motor neurons (LMNs), typically culminating in life-threatening complications of respiratory muscle weakness within 3 to 4 years after onset.⁴ However, the relative extent of UMN and LMN involvement differs among patients. Individual variation in rate of progression also is seen in ALS, from rapid decline over a period of months in a small proportion of patients to slow progression over 20 to 30 years in rare cases. Current pharmacotherapy at best yields only modest increase in survival.⁵ Management remains mainly supportive, but the effect of these interventions on quality of life can be significant.⁶

Nomenclature

Classic ALS is a mixed UMN and LMN disorder, but the term may also be applied to incomplete manifestations with only LMN or UMN signs or solely bulbar features. In “pure” form, however, these partial presentations also are recognized as disorders separate from ALS (Fig. 66-1).⁷ A proposed solution was to apply the general term motor neuron diseases to this range of presentations, ALS being one manifestation in the spectrum of adult motor neuron diseases (Table 66-2).⁸ Of the others, motor neuron disease with exclusively LMN features is classified as progressive muscular atrophy (PMA)⁹; generalized, purely UMN disease is classified as primary lateral sclerosis (PLS); and progressive bulbar palsy (PBP) is a UMN and/or LMN disorder restricted to the bulbar region. Most patients presenting with these syndromes eventually develop the full clinical picture of ALS, but approximately 10% of patients with adult motor neuron disease retain the diagnosis of PMA, PLS, or PBP.¹⁰ In life, these diagnoses are established on clinical grounds, because no confirmatory supportive test other than postmortem examination is available.¹¹ The diagnostic challenge is exemplified by PMA, in which autopsy studies demonstrate UMN pathology, establishing the correct diagnosis of ALS. Diagnostic distinction is more than academic, inasmuch as prognosis differs for the various syndromes.¹²

Figure 66-1 Theoretical relationships between amyotrophic lateral sclerosis (ALS) and other forms of idiopathic adult motor neuron disease: progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Indistinct boundaries between these entities reflect the possibility that these disorders may represent varied expression of the same underlying disease process. Most patients presenting with features of PBP, PMA, or PLS progress to develop the full clinical picture of ALS, although “pure” presentations of these conditions may occur. Lower motor neuron (LMN) signs predominate at one end of the spectrum, and upper motor neuron (UMN) signs predominate at the other.

(Data from Desai J, Swash M: Essentials of diagnosis. In Kuncl RW, ed: Motor Neuron Disease. Philadelphia: WB Saunders, 2002, pp 1-20; and from Mitsumoto H, Chad D, Pioro E: History, terminology, and classification of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 3-17.)

TABLE 66-2 Nomenclature of Idiopathic Adult Motor Neuron Disease

Condition	Acronym	Features
Amyotrophic lateral sclerosis	ALS	Upper and lower motor neuron signs in limbs, trunk and bulbar regions
Progressive bulbar palsy	PBA	Upper and/or lower motor neuron signs in bulbar region only
Progressive muscular atrophy	PMA	Lower motor neuron signs of limb and trunk musculature; bulbar involvement late if at all; no upper motor neuron signs
Primary lateral sclerosis	PLS	Upper motor neuron signs in bulbar, limb and trunk regions; no lower motor neuron signs

From Strong M, Rosenfeld J: Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:136-143.

The guidelines divide the central nervous system into 4 regions: bulbar, cervical, thoracic, and lumbosacral.

EMG, electromyography; PBP, progressive bulbar palsy; PLS, primary lateral sclerosis; LMN, lower motor neuron; UMN, upper motor neuron.

Data from Brooks BR: El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical Limits of Amyotrophic Lateral Sclerosis” workshop contributors. J Neurol Sci 1994; 124(Suppl):96-107; and from Brooks BR, Miller RG, Swash M, et al: El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1:293-299.

The El Escorial criteria in clinical practice can provide a framework for establishing the diagnosis of ALS, but they remain arbitrary guidelines. Patients’ conditions do not necessarily follow stepwise progression from the lower levels of diagnostic certainty to clinically definite ALS.¹⁵ Those without features required for a clinically definite diagnosis at presentation may die of the disease without developing signs that allow classification as clinically probable or definite ALS.

Internet Resources

The knowledge base for ALS is rapidly evolving. Sources of current information on the diagnosis and management of ALS and ongoing research trials include several internet sites, some of which offer downloadable patient information. A selection of these is listed in Table 66-4.

TABLE 66-4 Internet Resources for Information on Amyotrophic Lateral Sclerosis (ALS)

CLINICAL FEATURES

Weakness with related symptoms and signs in ALS reflects loss of cortical, brainstem, and spinal motor neurons.¹⁶ Cortical, or UMN, pathology results in characteristic weakness and in UMN signs such as weakness, hyperreflexia, and pathological reflexes such as Hoffmann and Babinski signs. Anterior horn cell loss produces weakness, atrophy, and fasciculations.¹⁰

Involvement of the corticobulbar tract produces UMN-type orofacial weakness and associated signs and symptoms, such as sialorrhea, dysphagia, and dysarthria. These symptoms, in addition to muscle atrophy, accompany involvement of brainstem motor nuclei. Dysarthria in ALS may have mainly spastic and/or flaccid qualities in relation to the degree of UMN and/or LMN dysfunction. Patients may gradually lose functional speech and become mute before or after significant respiratory muscle weakness develops. Airway protection may be compromised by impaired glottic closure. Glottic spasm may also occur.

Initial motor deficits in ALS tend to arise focally, involving a single limb or orofacial muscles, and gradually extend to adjacent body regions.⁸ The ratio of patients with limb onset to those with bulbar onset is approximately 3:1.^12,17,18 Diffuse onset of weakness is less common. With focal onset, deficits tend to progress to the corresponding opposite side of the body and ipsilaterally in a rostral or caudal direction.¹⁹ Rostral-caudal extension appears to occur more rapidly than caudal-rostral extension. Extension to a nonadjacent body region, such as from left lower limb to right upper limb, is atypical. Disease onset may be in the thoracic region, leading to stooped posture as a result of paraspinal muscle weakness and weakness of abdominal wall muscles.^10,20

Fasciculations are characteristic of ALS but may be difficult to detect in some patients. Fasciculations appear to arise in the axon of diseased motor neurons in ALS but are not specific for the disorder; they are present in other chronic neurogenic disorders, endocrine/metabolic conditions, and in some normal persons.^21–23 Those in normal persons, so-called benign fasciculations, tend to have restricted distribution, repetitively occurring in a single muscle rather than diffusely as in ALS. Exercise, stress, and fatigue may promote benign fasciculations in some healthy subjects. Normal neurological examination and electromyographic findings can provide assurance that fasciculations in this setting are benign.²⁴ EMG may help identify fasciculation potentials that are not apparent on physical examination: for example, in obese patients.¹⁰

Dysphagia

Nutritional compromise and weight loss can occur in patients with ALS as a result of oropharyngeal weakness and dysphagia. UMN and/or LMN involvement may occur in the distributions of cranial nerve nuclei V, VII, IX, X, and XII. Dysphagia is an early or presenting symptom in 10% to 30% of patients with ALS.¹⁰ Nearly all such patients eventually experience dysphagia.²⁵ Recognition of this complication is important in avoiding weight loss, possible malnutrition, and aspiration. Nutritional balance and composition with adequate fluid intake should match estimated dietary needs and swallowing ability.

Aspiration is a significant complication of oropharyngeal weakness, potentially leading to avoidance of certain foods or liquids and interfering with administration of oral medications.¹⁰ Symptoms of oropharyngeal weakness include fatigue with chewing, lodging of food in the gingival-buccal mucosa, sensation of food sticking in the throat when swallowing, coughing or choking during meals, sialorrhea, and leaking of liquids from the mouth during swallowing. Patients with severe oropharyngeal weakness may become at risk for aspiration of their own secretions.

Pseudobulbar affect refers to recurrent, involuntary outbursts of laughter or crying triggered by circumstances that normally would not provoke an overtly emotional response. This symptom can be distressing for patients and caregivers. The cause appears to be bilateral interruption of pathways between UMNs and bulbar nuclei, possibly including the cerebellum.²⁶ The incidence of pseudobulbar affect increases gradually during the course of the disorder. In a study of 73 patients with a relatively long mean duration of disease (8.5 years), 49% exhibited pseudobulbar affect.²⁷

Respiratory dysfunction in ALS tends to develop insidiously, although relatively rapid development of respiratory failure is reported in some cases. In rare cases, respiratory failure is the presenting sign of ALS.^28–30 Respiratory impairment in ALS stems mainly from LMN weakness of the diaphragm and respiratory accessory muscles (Table 66-5). Exertional dyspnea and fatigue can be early symptoms, although patients may be asymptomatic despite respiratory muscle weakness demonstra ble on pulmonary function testing.³¹ Symptoms may be mitigated by reduced activity level.³² Dyspnea during conversation, frequent sighing, reduced speech volume, orthopnea, and weak cough can be indicators. Dyspnea with mild exertion or in association with meals is suggestive of significant respiratory muscle weakness. Postprandial dyspnea and orthopnea are attributable to pressure against the diaphragm from the abdominal contents.³³

TABLE 66-5 Respiratory Muscles Affected by Amyotrophic Lateral Sclerosis

Rights were not granted to include this table in electronic media. Please refer to the printed book.

From Krvickas L: Pulmonary function and respiratory failure. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 382-404.

Physical signs of respiratory compromise include tachypnea, use of accessory muscles, and dyssynchrony of chest/abdominal muscle movement, including paradoxical inward abdominal movement during chest expansion.³⁴ Changes in laboratory tests such as increased hematocrit and respiratory acidosis with reduced serum chloride levels are relatively late indicators of severe respiratory compromise in ALS.¹⁰

Significant respiratory muscle weakness can be overlooked if not sought in the history and pulmonary function testing. Early identification of clinically significant respiratory muscle involvement in ALS is important in order to allow the patient adequate time to make decisions regarding potential use of mechanical ventilatory support.¹⁰

Sleep disturbance in ALS can be exacerbated by depression, limited mobility interfering with comfortable positioning, and respiratory muscle weakness. Mechanisms of weakness-related sleep disturbance include paresis of respiratory muscles, mechanical obstructive sleep apnea caused by pharyngeal muscle weakness and resulting hypopharyngeal collapse, and/or weakness of vocal cord abduction.^10,35,36 Specific inquiry regarding changes in sleep habits, ability to sleep comfortably supine, and recurrent morning headache may be needed to identify these conditions.

DIFFERENTIAL DIAGNOSIS

A large number of disorders may enter into the differential diagnosis of suspected ALS.¹⁰ Differential diagnosis can be considered in terms of symptoms and by anatomical localization. An approach to a symptom-based differential diagnosis is shown in Table 66-6. Specific disorders in relation to anatomical localization are discussed as follows.

Patients with suspected ALS who have LMN signs but borderline or no UMN signs can be grouped by the anatomical level of primary pathology: anterior horn cell, peripheral motor axon, neuromuscular junction, and muscle.

Several primary anterior horn cell diseases may resemble ALS with mainly LMN signs. All are less common than ALS. PMA, a sporadic LMN disorder, is one of these, occurring in about 10% of patients with motor neuron disease.³⁷ ALS lacking UMN signs is clinically indistinguishable from PMA. Case series suggest that there are a higher male-to-female ratio in PMA and a better prognosis than in ALS, with longer survival and lower frequency of progression to significant bulbar dysfunction and respiratory compromise in PMA than in ALS. Ultimately, the determination that a patient with LMN disease has ALS rather than PMA can be made during the patient’s life only if UMN signs develop or at postmortem study through identification of pyramidal tract pathology.^38–40

Adult-onset forms of the hereditary spinal muscular atrophies (SMA) may present diagnostic uncertainty of the type encountered with PMA.⁴¹ Several forms of adult-onset SMA are reported with autosomal recessive or autosomal dominant inheritance.^42–44 Adult-onset SMA becomes apparent generally after age 20 years. Progression is slow, and the prognosis is better than that of ALS. Initial involvement typically is in the limbs. Generalized weakness may develop, but significant bulbar or respiratory weakness is rare.

Kennedy’s disease, or spinobulbar neuronopathy, is an X-linked inherited disorder in which LMN signs predominate.^45,46 Progressive weakness affects bulbar and limb muscles with atrophy and fasciculations, the latter particularly in the orofacial muscles. Progression is slow and potentially compatible with a normal life span, but significant dysarthria, dysphagia, and respiratory impairment can develop. Gynecomastia and impotence may occur. Primary pathology involves LMNs, but sensory neurons also are involved. Sensory and other nonmotor abnormalities may be asymptomatic, however, and Kennedy’s disease is an important consideration in the differential of LMN presentations of ALS in men. Kennedy’s disease is caused by a trinucleotide (cytosine-adenine-guanine) repeat expansion in the X-linked androgen receptor gene.⁴⁷ Needle electromyographic findings in Kennedy’s disease are similar to those of ALS, but in contrast to ALS, nerve conduction studies tend to show reduced sensory nerve action potential amplitudes.⁴⁸ DNA testing for the trinucleotide mutation that causes the disorder can establish diagnosis of Kennedy’s disease.

Other uncommon LMN disorders that may resemble ALS include brachial amyotrophic diplegia, a progressive LMN condition of the upper limbs, and monomelic amyotrophy, a progressive LMN disorder affecting a single extremity, usually an upper limb.^37,49–53 These conditions tend to progress over a few years and then stabilize, without spread to other body regions. Natural history data suggest that progression of disease outside of the initially involved limb or limbs is unlikely if spread is not evident within a few years after onset.

In rare cases, paraneoplastic motor neuron disease or motor neuronopathy occur with lymphoma.^54,55 Weakness in most cases is exclusively LMN type, although some patients demonstrate probable or definite UMN signs that are compatible with ALS.⁵⁶ Identification of lymphoma in this syndrome may be difficult. Paraproteinemia is a useful marker and, if present, should prompt cerebrospinal fluid examination. Increased cerebrospinal fluid protein and/or oligoclonal bands warrant consideration of bone marrow examination. The neurological disorder may stabilize with treatment of the lymphoma.^56,57

Postpolio syndrome is the recurrence of weakness in patients with a history of poliomyelitis a decade or more after the initial infection.^58,59 New or ongoing instability and degeneration of previously affected motor units is suspected, but the primary cause is not established.⁶⁰ Involved muscle groups tend to be those originally affected, but previously unaffected muscles may be included. Progression is slow; periods of stabilization may be interspersed. Bulbar and respiratory function can be affected. Fatigue and musculoskeletal pain are significant in many patients. UMN signs generally are not found, although Babinski’s sign may be present. EMG shows chronic and active neurogenic changes. No specific diagnostic test is available for postpolio syndrome; distinction from LMN-type ALS is based on slow progression, absence of UMN signs, and history of poliomyelitis.

Hexosaminidase A deficiency, a form of GM₂ gangliosidosis, is an autosomal recessive condition with a range of neurological phenotypes, depending on the degree of residual enzyme activity.⁶¹ Complete absence or profound deficiency of hexosaminidase A results in the fatal infantile disorder Tay-Sachs disease. Less severe deficiency of hexosaminidase A can produce various childhood, juvenile, or adult-onset phenotypes, including one resembling a progressive LMN disease.^62,63 Onset in the latter is typically in childhood, but clinical manifestation may be delayed until adulthood. Hexosaminidase A deficiency with prominent LMN features can suggest a sporadic LMN disorder. Clinical features such as childhood onset, slow progression, and associated signs such as tremor or developmental delay readily distinguish hexosaminidase A deficiency from ALS. EMG shows signs of chronic motor denervation, but nerve conduction studies usually show sensory nerve involvement, and brain computed tomography or magnetic resonance imaging (MRI) reveals cerebellar atrophy, at variance with ALS.

Multifocal motor neuropathy (MMN) with conduction block is a rare, immune-mediated disorder with a male-to-female ratio of 3:1 and mean age at onset of 40 years.^64,65 The estimated incidence is 1 to 2 per 1,000,000, much lower than that of ALS. MMN can be an important consideration in the differential diagnosis ALS because of clinical overlap and the observation that up to 80% of affected patients respond to treatment. Weakness in MMN may be asymmetrical, beginning distally in the upper limbs. Tendon reflexes are usually reduced but may be retained and seem inappropriately brisk; pathological reflexes are not present. Nerve conduction studies show evidence of demyelination and conduction block in multiple motor nerves, generally not solely at common sites of entrapment. Needle electromyographic abnormalities may be similar to those of ALS but are found only in the territory of involved nerves, not diffusely.⁶⁶ Approximately 50% of patients have serum immunoglobulin M antibodies that react with GM₁ and other gangliosides.^67,68 Elevated titers of ganglioside antibodies are found in some patients with ALS, but their presence nevertheless warrants thorough evaluation for possible motor conduction block.

Monoclonal gammopathy may be associated with peripheral neuropathy or polyradiculoneuropathy with mainly motor features, resembling the LMN presentation of ALS.⁶⁹ Affected patients may have a lymphoproliferative disease potentially amenable to treatment.⁷⁰ This syndrome can be difficult to distinguish from primary LMN disorders if sensory symptoms/signs are minimal or lacking. Muscle atrophy and fasciculations may be present, but UMN signs are not.⁷¹ Associated systemic features may be present and, when fully established, constitute the syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS). The monoclonal protein in these disorders usually is immunoglobulin G or A_κ, associated with one or more bony lesions (osteosclerotic or sclerotic/lytic). Nerve conduction studies compatible with demyelination and cerebrospinal fluid protein elevation potentially exceeding 100 mg/dL facilitate the distinction from ALS.⁷⁰ Pathological significance of a monoclonal gammopathy in ALS can be difficult to establish, inasmuch as paraproteinemia is reported in nearly 10% of patients with motor neuron disorders in general, including clinically definite ALS.⁷²

Other peripheral neuropathies that may resemble the LMN presentation of ALS include chronic inflammatory demyelinating polyneuropathy and unusual manifestations of Guillain-Barré syndrome with minimal paresthesia or sensory signs.^73,74 Elevated cerebrospinal fluid protein, evidence of demyelination on nerve conduction studies, and nerve biopsy, if indicated, readily distinguish these conditions from ALS.⁷⁵

Neuromuscular junction disorders that share certain features with ALS include the autoimmune diseases myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS). Diffuse weakness may occur in both disorders, but myasthenia gravis has a predilection for ocular and bulbar muscles.⁷⁶ Fasciculations are not a hallmark of either myasthenia gravis or LEMS. Motor nerve conduction studies of clinically weak muscles in myasthenia gravis tend to show a decrement on slow (2- to 3-Hz) repetitive stimulation. This may occur in ALS, but denervation on EMG distinguishes the latter. Unlike patients with ALS, approximately 85% of patients with myasthenia gravis have serum antibodies to the acetylcholine receptor, and approximately 40% of seronegative patients have antibodies that react with muscle-specific kinase.^77,78

LEMS tends to produce limb girdle weakness with milder, if any, bulbar weakness. Increase in strength after repetitive use and autonomic dysfunction also are features of LEMS but not of ALS.⁷⁹ Patients with LEMS tend to show an electromyographic decrement on slow repetitive stimulation. Motor amplitudes generally are low, and increase by more than 100% on stimulation immediately after brief (10- to 15-second) exercise. LEMS may occur as a primary autoimmune condition, but more often is associated with underlying cancer, particularly small cell lung carcinoma. A high proportion of patients with LEMS carry serum antibody against P/Q-type calcium channels.⁸⁰

Inclusion body myositis (IBM), polymyositis, and dermatomyositis are inflammatory muscle diseases that in adults produce gradually progressive weakness without fasciculations or UMN signs.^81,82 Clinical findings in IBM in particular may superficially resemble ALS with LMN features. IBM affects particularly knee extensors and flexor forearm muscles; neck muscle weakness and dysphagia also may occur. Polymyositis and dermatomyositis cause mainly proximal weakness. Characteristic skin rash is typical of dermatomyositis. Weakness may be asymmetrical, especially in IBM. EMG in these inflammatory myopathies typically reveals fibrillation potentials and myopathic motor unit potentials. In IBM, chronic neurogenic motor unit potential abnormalities are not uncommon. Muscle biopsy demonstrates inflammatory changes in all three, with rimmed vacuoles, amyloid deposition, and filamentous intranuclear inclusions in IBM. If inflammatory myopathy is a diagnostic consideration, muscle biopsy is indicated.

Other muscle disorders that may superficially resemble predominantly LMN presentations of ALS are listed in Table 66-7. Absence of fasciculations, myopathic features on EMG, and findings on muscle biopsy readily distinguish these from possible ALS.⁸³

TABLE 66-7 Muscle Disorders in the Differential Diagnosis of Suspected Amyotrophic Lateral Sclerosis (ALS) with Lower Motor Neuron Features^*

* Electromyography and muscle biopsy are generally useful in distinguishing these disorders from ALS.

† Fasciculations and upper motor neuron signs are not found in these disorders.

‡ As in ALS, mild creatine phosphokinase elevation may be present.

Modified from Mitsumoto H, Chad D, Pioro E: The differential diagnosis of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 87-121.

Neurological disease manifesting solely with UMN signs and no associated evidence of LMN pathology may indicate the initial stages of ALS. However, the differential diagnosis of this syndrome includes other forms of motor neuron disease, such as PLS, and conditions dominated by UMN weakness and spasticity, such as hereditary spastic paraparesis.

PLS is a rare sporadic disorder affecting corticobulbar and corticospinal neurons, found in 2% to 4% of patients in larger motor neuron disease series.^84,85 The age at onset is similar to that of ALS.⁸⁶ Spasticity and weakness may begin in the bulbar region or lower limbs, usually the latter. Physical findings may initially be asymmetrical (i.e., hemiparesis).⁸⁶ Gradual progression to initially uninvolved regions is typical. The concept of PLS as a specific disease entity is supported by autopsy data demonstrating solely UMN pathology in patients given this diagnosis while alive.^85,87 However, natural history data include reports of patients with an initial diagnosis of PLS who after years of follow-up developed LMN signs compatible with ALS.⁹ Furthermore, mild creatine kinase elevation is reported in some patients who otherwise meet criteria for diagnosis of PLS; needle EMG may reveal signs of active and chronic motor denervation; and muscle biopsy may demonstrate neurogenic changes.^84,88 Also, patients given a diagnosis of PLS while alive may at postmortem demonstrate anterior horn cell disease.⁸⁹ Nosology aside, it is clear that the diagnosis of PLS, even if LMN signs eventually develop, tends to progress more slowly than in patients meeting diagnostic criteria for ALS.^84,85 Like that of ALS, diagnosis of PLS rests on history, clinical findings, and periodic reassessment.

Hereditary spastic paraparesis causes a progressive spastic weakness of the lower limbs, rarely extending to the upper limbs and bulbar region.^90–92 Inheritance may be autosomal dominant, autosomal recessive, or X-linked; more than 20 genetic loci are identified.⁹³ Onset usually occurs in childhood or early adulthood, earlier than expected for ALS. Bulbar or significant upper limb involvement generally is not a feature of hereditary spastic paraparesis. Urinary symptoms and large fiber sensory involvement may occur, readily distinguishing hereditary spastic paraparesis from ALS.

Mixed UMN and LMN or mainly UMN disorders resembling ALS are uncommon but are important to consider in the workup of patients with possible ALS. Spondylotic cervical spinal stenosis may produce myelopathy and associated LMN signs in the upper limbs.^94,95 Thyrotoxicosis can produce a syndrome with mixed UMN and LMN signs attributed to combined myopathy, myelopathy, and motor neuropathy.⁹⁴ Vitamin B₁₂ deficiency, multiple sclerosis, syringomyelia, adrenal leukodystrophy, human T cell lymphotropic virus I myelopathy, and human immunodeficiency virus myeloneuropathy may superficially suggest ALS with UMN signs.^96–102 Identification of these conditions is aided by signs and/or symptoms of neurological involvement beyond solely UMN and anterior horn cell pathology.

Neurological disorders with motor features confined to the bulbar region may resemble a bulbar presentation of ALS. PBP, by definition a UMN and/or LMN disorder limited to bulbar muscles, is included in this differential diagnosis.¹⁰³ Distinction of PBP from ALS with bulbar onset is established by the presence of LMN and/or UMN signs outside the bulbar region. Physical findings establishing the diagnosis of ALS usually develop in PBP.

Disorders suggestive of bulbar-onset ALS that potentially cause mixed UMN/LMN signs include structural lesions such as tumors in the brainstem or foramen magnum.¹⁰⁴ Cerebrovascular disease and demyelinating disease such as multiple sclerosis may produce similar signs and symptoms. Associated symptoms may help rule out ALS, but brain imaging, particularly MRI, as a rule is indicated.⁸³ Cerebrovascular events can generally be ruled out on the basis of their acute onset and nonprogressive course, but some ALS patients report acute symptom onset, and early on it may be unclear whether the disorder is progressive.

Exclusively bulbar weakness may occur in myopathic conditions, neuromuscular transmission disorders, cranial neuropathies, and brainstem structural or demyelinating diseases. Ptosis is characteristic of myopathies such as oculopharyngeal dystrophy and of neuromuscular transmission disorders such as myasthenia gravis.^76,105 Ophthalmoparesis, similarly, is not present in ALS except in advanced disease, generally in ventilator-dependent patients approaching a locked-in state.^106,107

A variety of conditions have been reported in rare instances to produce an ALS-like disorder. These include lead exposure or other heavy metal exposure, connective tissue disease such as Sjögren’s disease, Lyme disease, and hyperparathyroidism.¹⁰⁸ Data supporting these associations are limited, and investigation of these diagnoses seems warranted only in the event of associated clinical or laboratory indications or, in the case of heavy metal toxicity, a history of exposure.

AMYOTROPHIC LATERAL SCLEROSIS WITH ATYPICAL FEATURES

Patients with ALS occasionally have neurological findings in addition to UMN and LMN involvement, also referred to as ALS-plus.¹⁴ These findings include dementia, extrapyramidal signs, autonomic features, and sensory signs and/or symptoms. Diagnosis of these syndromes as variants of ALS requires exclusion of potential causes for the variant features. Two of these, dementia and extrapyramidal features, are mentioned briefly here. Clinical management of motor aspects of the syndromes is similar to that of classic ALS.

Dementia, characteristically a frontotemporal type, is reported in about 5% of patients with ALS, although data suggest that the incidence may be higher.^18,109,110 Clinically similar familial and sporadic forms occur; one phenotype is linked to chromosome 9.¹¹¹ Associated cognitive dysfunction includes impaired executive function, emotional lability, decreased speech output, perseveration, and disinhibition. These may develop before or concurrently with motor abnormalities in ALS or manifest after motor deficits are established.

Extrapyramidal signs, including bradykinesia, rigidity, tremor, and postural instability may be present with features of ALS.^112,113 One such ALS variant is the ALS-parkinsonismdementia complex of Guam, largely confined to western Pacific islands (Guam, New Guinea, and the Kii Peninsula of Japan).^114,115 Patients with this form of ALS often have parkinsonismdementia. Its occurrence outside of this geographic distribution has been reported,^116–118 and its incidence on the western Pacific islands may be declining.¹¹⁹ The pathogenesis is not established; dietary exposure to a cycad-derived toxin may contribute. Other forms of ALS with extrapyramidal involvement include rare familial extrapyramidal syndromes.^120,121

PATHOGENESIS

The cause of sporadic ALS is unknown, although data are suggestive of an interaction of genetic and acquired mechanisms leading to neuronal death.^1,122 Causative genes are identified for some inherited forms of ALS, but the molecular pathogenesis is not understood. ALS appears to be a multisystem disorder with selective vulnerability of UMNs and LMNs.

Pathology of ALS is characterized by loss of LMNs in bulbar motor nuclei and the spinal anterior horn.¹⁶ UMN changes include myelin pallor in the corticospinal tract and variable pathological changes in motor cortex, such as loss of pyramidal neurons, including Betz cells, and motor cortex gliosis. LMN nuclei characteristically spared are those innervating external ocular muscles (cranial nerves III, IV, and VI) and those innervating pelvic floor/sphincter muscles (Onuf’s nucleus).