Primary lateral sclerosis (PLS), first described by Erb in 1875, is a rare UMN disease variant that accounts for 2% to 4% of all cases of ALS and is traditionally distinguished by a lack of LMN involvement. The Pringle criteria for PLS stipulated that disease be restricted to the UMN system for at least 3 years from the time of clinical onset (Pringle et al., 1992), but a figure of 4 years is now proposed during which there is neither clinical nor neurophysiological evidence of LMN involvement. In a recent study comparing the evolution of disease in PLS versus UMN-predominant ALS and typical ALS, the median time to development of electromyographic (EMG) LMN features after onset in those with an evolving ALS was 3.17 years; in those patients, clinical signs of LMN disease occurred on average about 6 months later. Nonetheless, later development of LMN signs may occur and require reclassification as ALS in some cases, which therefore necessitates constant longitudinal review of each case (Gordon et al., 2009).

PLS typically presents in patients in their early 50s (about a decade younger than typical MND/ALS patients) as a very slowly evolving spastic paraparesis that spreads to the upper limbs and eventually causes pseudobulbar palsy. In rare instances, onset is in the bulbar system or follows a slowly ascending or descending hemiplegic pattern (Mills hemiplegic variant), but a bulbar-onset presentation should make the clinician wary of later LMN signs elsewhere. Other features include cramps and fasciculations, but such complaints are neither prominent nor universal. Bladder dysfunction is rare and, if it occurs at all, tends to be a late feature. Although muscle weakness is present, the main deficits are due to spasticity in dexterity and gait. The rate of progression can be exceedingly slow, often progressing over many years to the point where the patient manifests a robotic gait, debilitating generalized spasticity, and prominent pseudobulbar palsy. Muscle atrophy, if it occurs at all, is a very late feature. No clinically detectable sensory changes occur. Neuropsychological test batteries may define subtle cognitive deficits due to frontal cortical involvement, but dementia is not a prominent feature. A few patients may exhibit abnormal voluntary eye movements. Breathing is usually unimpaired in PLS, and as a consequence, forced vital capacity (FVC) is not affected (Gordon et al., 2009).

The prognosis is significantly better than for MND/ALS: one series had a median disease duration of 19 years and another series exhibited a range of survival from 72 to 491 months (Murray, B., 2006). The underlying pathogenesis of PLS remains undefined. Pathological changes include a striking loss of Betz cells in layer 5 of the frontal and prefrontal motor cortex (and other smaller pyramidal cells) together with laminar gliosis of layers 3 and 5 and degeneration of the corticospinal tracts. Spinal anterior horn cells are characteristically unaffected.

The diagnosis of PLS is essentially one of exclusion (Table 74.1). Rare reports exist of UMN-onset ALS exist where the interval between onset of UMN signs and subsequent LMN signs have been up to 27 years. As such, it is vital to reassess patients diagnosed with PLS, as late signs of LMN involvement may occur that would reclassify their disorder as UMN-onset ALS.

Table 74.1 Disorders of Upper Motor Neurons and Their Key Characteristics

Disorders	Key Characteristics
Primary lateral sclerosis	A diagnosis of exclusion
Hereditary spastic paraplegia	Heredity, usually autosomal dominant, spastin gene mutation, other mutations (see text), “sporadic”
HTLV-1-associated myelopathy	Slowly progressive myelopathy, endemic, and positive HTLV-1
HTLV-2-associated myelopathy	Amerindian, IV drug abuser, concomitant HIV
Adrenomyeloneuropathy	X-linked recessive inheritance, adrenal dysfunction, myelopathy, very long-chain fatty acid assay
Lathyrism	History of consumption of chickling peas
Konzo	Eastern African, cassava root consumption

HIV, Human immunodeficiency virus; HTLV, human T-lymphotropic virus; IV, intravenous.

Appropriate testing must exclude all definable causes for generalized UMN involvement. These include structural abnormalities (Chiari malformation and intrinsic and extrinsic spinal cord lesions) and myelopathies such as multiple sclerosis (MS) spondylotic cervical myelopathy, human immunodeficiency virus (HIV) myelopathy, human T-lymphotropic virus type 1 (HTLV-1) myelopathy, Lyme disease, syphilis, or adrenomyeloneuropathy. Spondylotic cervical myelopathy and MS are probably the most common causes among these disorders. The family history must be negative to rule out hereditary spastic paraplegia (HSP)/familial spastic paraparesis, spinocerebellar ataxia (SCA), hexosaminidase-A (Hex-A) deficiency, familial ALS (FALS), or adrenomyeloneuropathy. It is now apparent that some spastin mutation–associated HSP may lack a family history; it is worthwhile to carry out this gene test in patients presenting with symptoms and signs that are restricted to the lower extremities (Brugman et al., 2009). Paraneoplastic syndromes (especially in association with breast cancer) and Sjögren syndrome may clinically resemble PLS. Understanding of these entities is poor.

Treatment

No specific pharmacotherapy is available, and treatment therefore focuses on symptom control and supportive care. However, antispasticity drugs such as the GABA-B agonist, baclofen, and the central α₂-agonist, tizanidine, may be tried for symptomatic treatment. Severe spasticity sometimes requires the insertion of an intrathecal baclofen pump. Tricyclic antidepressants, selective serotonin reuptake inhibitors, or dextromethorphan/quinidine may control pseudobulbar affect lability (Brooks et al., 2005).

Hereditary Spastic Paraplegia

HSP (or familial spastic paraparesis) is a genetically and clinically heterogeneous group of disorders rather than a single entity. The clinical feature common to all cases is progressively worsening spasticity of the lower extremities, often with variable degrees of weakness. The characteristic pathology is retrograde degeneration of the longest nerve fibers in the corticospinal tracts and posterior columns. Its estimated prevalence is 0.5 to 11.9 in 100,000, but its worldwide prevalence may actually be underestimated because of the benign nature of the disease in many families. Although the most common mode of inheritance is autosomal dominant, it may also be inherited in a recessive or X-linked fashion, and 12% to 13% of cases with apparently sporadic spastic paraparesis have spastin mutations (Depienne et al., 2006).

Although most cases present in the second to fourth decades, onset is from infancy into the eighth decade. The clinical syndrome is broadly divisible into the pure form and the complicated form. In the pure form, patients develop only lower-extremity spasticity, but some of these cases eventually become complicated. However, the complicated form may also include optic neuropathy, pigmentary retinopathy, deafness, ataxia, ichthyosis, amyotrophy, peripheral neuropathy, dementia, autoimmune hemolytic anemia/thrombocytopenia (Evans syndrome), extrapyramidal dysfunction, mental retardation, and bladder dysfunction.

Genetic linkage studies of families around the world have mapped loci to over 40 autosomes as well as the X chromosome, with 17 distinct genes identified to date (Salinas et al., 2008). Inheritance of most pure HSP is autosomal dominant, whereas complicated forms are more often autosomal recessive. Between 40% and 45% of all families link to the SPAST gene on chromosome 2p22-21, which encodes spastin, a 616-amino acid protein. Mutations of various types (missense, nonsense, frameshift, splice site) may affect this gene (McDermott, C.J., 2006). Spastin is a highly conserved member of the AAA family of proteins (adenosine triphosphatase [ATPase] associated with various cellular activities). The exact role of mutant spastin in the pathogenesis of HSP is undefined, although a disturbance in maintenance of the microtubule cytoskeleton may exists, thus disrupting axonal transport. More than half of all cases do not manifest symptoms and signs until after age 30 years. Although this is normally a pure HSP, complicated forms occur, and some cases can develop a late-onset cognitive decline. Pathologically, degeneration of the longest corticospinal tracts and, to a lesser degree, the posterior columns of the spinal cord is seen.

Mutations in the SPG3A gene on 14q11-q21 encoding the novel protein, atlastin, give rise to an autosomal dominant often early-onset (<10 years of age) pure HSP which accounts for about 10% of autosomal dominant cases. This protein shares structural homology to guanylate-binding protein 1, which is a member of the dynamin family. Dynamins are important in intracellular trafficking of various kinds of vesicles. Mutations in KIF5A (SPG10, Chr 12q), a kinesin motor domain that is critical in intracellular transport, can cause both early- and late-onset spastic paraparesis with distal amyotrophy (Blair et al., 2006). Spastic paraplegia 11 (SPG11) is an autosomal recessive complicated HSP (thin corpus callosum, neuropathy, cognitive impairment) due to mutations in the spatacsin gene on chromosome 15q. This protein is of unknown function and does not appear to interact with the Golgi apparatus or microtubules. The cause of autosomal dominant pure HSP, linked to 2q24-34, is a mutation in the SPG13 gene, which encodes a mitochondrial heat shock protein. Recessively inherited complicated HSP links to chromosome 16q and is caused by a mutation in a gene encoding a mitochondrial protein known as paraplegin; this disorder can be ether pure or complicated (cerebellar signs, pale optic discs, and peripheral neuropathy). The genes for two different X-linked complicated HSP have been identified. In the first, mutant L1 (neural) cell adhesion molecule (L1CAM) may disrupt neuronal migration or differentiation; in the second mutant proteolipid protein (PLP1) is found in association with changes in white matter (duplication mutations in this same gene can also cause Pelizaeus-Merzbacher disease). Spastic paraplegia 17 (SPG17) is caused by mutations in the seipin gene on chromosome 11q12-q14. Also known as Silver syndrome, this disorder is an autosomal dominant complicated form of HSP with distal hand and foot amyotrophy beginning in the late teens to early 30s. Mutations in this gene are also the cause of a form of distal hereditary neuropathy (Charcot-Marie-Tooth [CMT] disease type 5).

Diagnosis

The basis for diagnosis of HSP is evidence of a family history in the setting of progressive gait disturbance, evidence of lower-extremity spasticity, and sparing of craniobulbar function. However, difficulties arise when there is no clear family history in recessive or X-linked disease and in cases of sporadic spastin mutation–associated HSP. Furthermore, considerable variation in disease expression exists between and within HSP families. In the absence of a family history or a demonstration of a known mutation, it is important to consider alternative causes for the clinical presentation, including structural disease (e.g., cerebral palsy, hydrocephalus, myelopathy), degenerative/infiltrative/inflammatory disease (e.g., MS, ALS, SCA, leukodystrophy), infections (syphilis, HIV, HTLV), levodopa-responsive dystonia, metabolic/toxic damage (vitamin B₁₂ deficiency [subacute combined degeneration of the spinal cord (SCDC)], vitamin E deficiency, copper deficiency, lathyrism), and paraneoplastic disorders. MRI may reveal that cervical and thoracic spinal cord diameters are significantly smaller in both pure and complicated HSP than in controls (Sperfeld et al., 2005). Perhaps the most important differential diagnosis is that between apparently sporadic pure HSP and PLS, especially as the later may present with a slowly evolving spastic paraparesis for many years prior to the development of upper limb or bulbar features. The only reliable way to distinguish such disorders is through genetic testing; age at onset, urgency of micturition, and signs of dorsal column involvement (clinical or abnormal somatosensory evoked potentials [SSEPs]) are not accurate indicators of HSP versus PLS (Brugman et al., 2009).

Treatment

At present, treatment of spastic paraplegia is limited to symptomatic interventions, supportive care to reduce spasticity, and appliances and orthotics such as canes, walkers, and wheelchairs. Antispasticity drugs such as baclofen, tizanidine, diazepam, or dantrolene are often suboptimal, and patients with very disabling spasticity may require intrathecal baclofen administered through an implanted pump.

Human T-Lymphotropic Virus Type 1–Associated Myelopathy, or Tropical Spastic Paraparesis

HTLV-1 causes a chronic progressive myelopathy that is referred to as tropical spastic paraparesis (TSP) in the Caribbean or HTLV-1–associated myelopathy (HAM) in Japan. This retrovirus is endemic in the Caribbean area, southwestern Japan, equatorial Africa, South Africa, parts of Asia, Central America, and South America, where it infects between 10 and 20 million people. Transmission occurs though sexual contact, intravenous (IV) drug use and also through breastfeeding. While between 2% and 3% of those infected can develop adult-onset T-cell leukemia, an estimated 2.5% to 3.8% can develop a chronic inflammatory myelopathy, with up to 20/100,000 affected in the Caribbean population and 3/100,000 in Japan. Recent evidence implicates high levels of activated HTLV-1–specific helper T cells and cytotoxic T cells in the pathogenesis of this syndrome; these immune cells appear to activate in response to interactions with retroviral env and tax proteins with greatest activity within the thoracic cord. Increased susceptibility for neurological disease appears to depend on both viral and host factors, with differences in certain HTLV-1 subgroups, proviral load, and HLA background being important. This may also explain differences in susceptibility between ethnic populations (Saito, 2010). Mode of transmission is through contaminated blood, sexual activity, breastfeeding, and very rarely in utero.

HAM/TSP is a chronic, insidiously progressive myelopathy that typically begins after age 30 years (but can occur as early as the first decade). In addition to slowly progressive spastic paraparesis, patients complain of lower-extremity paresthesias, a painful sensory neuropathy, and bladder dysfunction, and some patients may also develop optic neuropathy. Examination reveals UMN signs in the legs (weakness, spasticity, pathological reflexes, hyperreflexia), although reflexes may also be brisk in the arms. Overall, evidence of LMN involvement may be scant, and objective sensory findings may be difficult to detect. MRI may reveal increased signal on T2-weighted sequences in periventricular white matter and atrophy of the thoracic cord, but these findings may not be specific to HTLV-1. The definitive diagnosis of HAM/TSP requires HTLV-1–positive serology in blood and cerebrospinal fluid (CSF). To be sensitive and specific, CSF should reveal a combination of a polymerase chain reaction amplification of HTLV-1 deoxyribonucleic acid (DNA), together with evidence of an increased HTLV-1–specific antibody index and oligoclonal bands (Puccioni-Sohler et al., 2001). At present, no antiviral agents effectively treat HAM/TSP, but a case report showed partial benefit of plasmapheresis (Narakawa et al., 2001). As more is learned about the molecular etiology of HAM/TSP, future therapies will likely target the pathogenic effect of HTLV-1–reactive T cells.

Human T-Lymphotropic Virus Type 2–Associated Myelopathy

Though phylogenetically similar in many respects, HTLV-1 and HTLV-2 are still antigenically distinct. Nonetheless, using enzyme-linked immunosorbent assay (ELISA) and Western blot techniques, many laboratories worldwide often report the presence of sero-indeterminate HTLV-1/2. It has long been thought that myelopathy in such sero-indeterminate cases is due to HTLV-1 rather than HTLV-2, but rare cases are now being described of a syndrome characterized by spastic paraparesis, diffuse hyperreflexia, spastic bladder, and periventricular white matter changes on MRI in patients infected with HTLV-2 but not HTLV-1. This retrovirus is endemic in some Native American tribes and now often encountered worldwide among IV drug abusers. It is worthwhile to test CSF and serum for the presence of this virus in known IV drug abusers who present with a spastic paraparesis (Silva et al., 2002). However, co-infection with HIV-1 is a confounding factor in many cases of presumed HTLV-2–associated neurological disease. It has been suggested that such co-infection, rather than infection with HTLV-2 alone, increases the likelihood of neurological manifestations (Araujo and Hall, 2004; Posada-Vergara et al., 2006).

Adrenomyeloneuropathy

Adrenomyeloneuropathy is a variant of adrenoleukodystrophy, an X-linked recessive disorder caused by mutations in the ABCD1 gene on chromosome Xq28 that encodes a ubiquitously expressed integral membrane peroxisomal ATPase-binding cassette transporter protein. Mutations in this gene lead to abnormal peroxisomal β-oxidation, which results in the harmful accumulation of very long-chain fatty acids (VLCFAs) in affected cells. Excessive levels of VLCFAs may interfere with the membrane components of both neurons and axons. The most common phenotype, adrenoleukodystrophy, is an inflammatory disorder of brain and spinal cord that affects young boys 4 to 8 years of age, who develop severe adrenal insufficiency, progressive cognitive deterioration, seizures, blindness, deafness, and spastic quadriparesis. Adrenomyeloneuropathy is a noninflammatory axonopathy of the spinal cord that involves descending corticospinal tracts in the thoracic and lumbosacral regions and the ascending posterior columns in the cervical region. The characteristic clinical picture is a slowly progressive spastic paraparesis and mild polyneuropathy in adult men (in their late 20s), with or without sensory symptoms and sphincter disturbances. Adrenal insufficiency may be present and may predate onset of neurological symptoms by several years. Adult female carriers may present with slowly progressive spastic paraparesis. Approximately 20% of men with adrenomyeloneuropathy also develop cerebral changes on MRI that may accompany cognitive/language/behavioral deterioration. Rare cases may present as a spinocerebellar degeneration. Considerable phenotypic variation exists even within individual families. Female carriers may manifest more subtle symptoms such as cramps, back pain, or arthralgias. The diagnosis should be suspected in male cases with progressive sensorimotor deficits in the legs and a family history of a myelopathy (including supposed MS). Progressive sensorimotor deficits in the lower extremities with a history of memory loss or “attention deficit disorder” should also prompt testing for adrenomyeloneuropathy, as should a history of idiopathic childhood epilepsy or primary adrenal failure (Mukherjee et al., 2006). Sural nerve biopsies show loss of both myelinated and unmyelinated axons, with some degree of onion bulb formation. Ultrastructural examination may show characteristic inclusions (empty lipid clefts) in Schwann cell cytoplasm. Nerve conduction studies and needle electrode examination may reveal a predominantly axon-loss type of sensorimotor polyneuropathy with a lesser component of demyelination, and SSEPs may show reduced or absent responses. The diagnostic test of choice is to demonstrate increased VLCFA levels in plasma, red blood cells, or cultured skin fibroblasts. No specific therapy exists for adult-onset adrenomyeloneuropathy.

Plant Excitotoxins

Lathyrism

Lathyrism is a chronic toxic nutritional neurological disease caused by long-term (or subacute) ingestion of flour made from the drought-resistant chickling pea (Lathyrus sativus). It is an important example of a disease in which a natural excitotoxin causes selective UMN impairment. The responsible neurotoxin is β-N-oxalylamino-l-alanine (BOAA), an α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor agonist. Ingestion of this neurotoxin results in increased intracellular levels of reactive oxygen species and subsequent impairment of the mitochondrial oxidative phosphorylation chain. Degeneration is most prominent in those Betz cells of the motor cortex (and the longest corresponding pyramidal tracts) that subserve lower-extremity function. Lathyrism occurs in the indigenous populations of Bangladesh, China, Ethiopia, India, Romania, and Spain. It also occurred in regional concentration camps during World War II. The condition may occur in epidemic form when malnourished populations increase consumption of flour made from L. sativus chickling peas during times of food shortage due to droughts. An analysis of an epidemic of neurolathyrism in Ethiopia showed a higher incidence in boys aged 10 to 14 years. The increased risk was associated with cooking grass pea foods in traditional clay pots (Getahun et al., 2002). The onset of clinical toxicity is either acute or chronic, manifesting as muscle spasms, cramps, and leg weakness. In addition to spastic paraparesis, sensory (including leg formications) and bladder dysfunction may occur. Occasionally there is a coarse tremor of the upper extremities. Although irreversible, the disorder is not progressive (unless there is continuing intoxication), and lifespan is not affected.

Konzo

Konzo (“tied legs”) is another toxic nutritional disorder of cortical motor neurons caused by chronic dietary ingestion of a neurotoxin derived from flour made from cassava roots that have not been soaked for a sufficient time. The disorder is endemic in protein-deficient communities in Tanzania, Zaire, and Eastern Africa and in times of famine can occur in epidemic form. The neurotoxic effect of chronic cassava root ingestion likely is derived from the liberation of cyanohydrins (cyanoglucoside linamarin) from the flour, which may be further metabolized to thiocyanate. The latter in turn may excessively stimulate the AMPA glutamate receptor subtype, causing excitotoxic neuronal injury. As with lathyrism, there appears to be a selective effect on Betz cells of the cerebral cortex and the longest corresponding corticospinal tracts. Patients typically present with spastic paraparesis (although some may exhibit only lower-extremity hyperreflexia). Occasionally one may detect weakness of the upper extremities, but not to the same degree as that of the lower extremities.

Disorders of Lower Motor Neurons

Neuroanatomy of Lower Motor Neurons

Interneurons

The interneurons constitute most of the anterior horn cells of the spinal cord and determine the final output of the LMNs. The interneuron system receives supranuclear excitatory and inhibitory motor control from the brainstem descending tracts, corticospinal tracts, and limbic system; this system also receives afferent information, directly and indirectly, from the afferent peripheral nerves. The interneuron system forms intricate neuronal circuits involving automatic and stereotyped spinal reflexes to coordinate and integrate the activation of synergist muscles while inhibiting antagonist muscles, contralateral muscles, and sometimes even a distant motor pool. The same interneuron network that mediates such automatic and stereotyped reflex behavior also acts as the basic functional unit involved in highly skillful voluntary movements. Ultimately, all of the interneuronal paths converge on the LMNs that innervate skeletal muscles, which Sherrington called the final common path.

Lower Motor Neurons

LMNs are located in the brainstem and spinal cord and send out motor axons that directly innervate skeletal muscle fibers. Spinal cord LMNs, also known as anterior horn cells, cluster in nuclei forming longitudinal columns; those innervating the distal muscles of the extremities are located in the dorsal anterior horn, whereas those innervating proximal muscles of the extremities are in the ventral anterior horn. Those LMNs that innervate the axial and truncal muscles are the most medially located. The normal cervical and lumbar enlargements of the spinal cord are the result of markedly enlarged lateral anterior horns containing the LMNs for the upper and lower limb muscles.

Large spinal cord LMNs called alpha motoneurons are the principal motor neurons innervating muscle fibers. Medium-sized motor neurons (beta motoneurons) innervate both extrafusal and intrafusal (muscle spindle) fibers, and intermediate and small motor neurons (gamma motoneurons or fusimotor neurons) innervate only spindle muscle fibers. The rest of the small anterior horn cells are interneurons.

Alpha motoneurons are among the largest neurons of the nervous system. Each has a single axon that branches to its target muscles and a number of large dendrites that provide an extensive receptive field. The motor unit is the smallest unit of the motor system and consists of one alpha motoneuron, its axon, and all of its target muscle fibers.

Clinical Features of Lower Motor Neuron Involvement

Loss of Muscle Strength (Weakness)

The loss of an LMN results in denervation of its motor unit, whereas an impaired LMN may lead to abnormal or impaired activation of its motor unit. In either case, the number of fully functional motor units decreases, which reduces overall muscle twitch tension.

In a disease causing chronic motor unit depletion, neighboring axons belonging to healthy motor neurons may reinnervate denervated muscle fibers belonging to a diseased motor unit by collateral sprouting. In this way, existing motor units continually modify in the face of persistent losses of motor axons to maintain muscle strength. For example, in patients who have recovered from acute poliomyelitis, depletion of more than 50% of LMNs occurs before residual muscle weakness is clinically detectable. Healthy individuals have sufficient motor units available to offset an unexpected loss of motor neurons (Box 74.3).

Box 74.3 Signs and Symptoms of Lower Motor Neuron Involvement

Loss of muscle strength (moderate to severe weakness)

Muscle atrophy

Hyporeflexia

Muscle hypotonicity or flaccidity

Fasciculations

Muscle cramps

Muscle Atrophy and Hyporeflexia

Muscle fiber denervation causes muscle fiber atrophy, and progressive LMN involvement results in reduced overall muscle bulk. Hyporeflexia occurs with LMN involvement because the loss of active motor units reduces the overall muscle twitch tension; thus, muscle stretch reflexes elicit less tension (diminished reflexes) or no visible twitch (absent reflexes).

Muscle Hypotonicity or Flaccidity

Hypotonicity, or flaccidity, refers to the decrease or complete loss of normal muscle resistance to passive manipulation. In contrast to spasticity, the muscle tone is flaccid.

Fasciculations

Fasciculations are spontaneous contractions of muscle fibers belonging to a single (or part of a) motor unit. (A video of this disorder can be found at www.expertconsult.com) Clinically, fasciculations appear on the muscle surface as fine, rapid, flickering, and sometimes vermicular contractions that occur irregularly in time and location. The impulse for the fasciculation appears to arise from hyperexcitable motor axons anywhere in their course. Fasciculations can occur both in healthy individuals and in patients with LMN involvement, so fasciculations themselves do not indicate LMN disease.

In general, larger muscles have larger motor units and therefore larger fasciculations. In tongue muscles, fasciculations produce small vermicular movements on the tongue surface. Fasciculations usually do not cause any joint displacement but when they occur in muscles moving the fingers, joint movements can occur (mini-polymyoclonus) (see video). Large fasciculations may occur in muscles undergoing extensive chronic reinnervation, such as chronic spinal muscular atrophy (SMA), Kennedy disease, and the postpoliomyelitis syndrome.

Muscle Cramps

Muscle cramps are common in the general population and are a common symptom of LMN involvement and many chronic neuromuscular diseases. The pathogenesis of cramps in all these diseases, as in normal individuals, is poorly understood. Cramps and fasciculations are likely to share a common pathogenic mechanism such as hyperexcitability of the motor neurons. Muscle cramps are an abrupt, involuntary, and painful shortening of the muscle, accompanied by visible or palpable knotting, often with abnormal posture of the affected joint. Relief of cramps is by stretching or massaging.

Laboratory Evidence of Lower Motor Neuron Involvement

Electrodiagnostic Examination

The electrodiagnostic examination (EDX) consists of nerve conduction studies and needle electrode examination (see Chapter 32B). The loss of motor units reflects in the loss of the amplitude of the maximal compound muscle action potential (CMAP). In a primarily demyelinating process, conduction velocity slows, and in severe cases, block. In a primarily axon loss process, there is usually only a modest degree of conduction velocity slowing commensurate with dropout of large myelinated axons. Sensory nerve conduction studies are normal in pure LMN disorders.

The needle electrode examination EMG is crucial in obtaining electrophysiological evidence of abnormal motor units in LMN disorders. Actively denervated muscle fibers discharge spontaneously, producing fibrillation potentials and positive sharp waves. Fasciculation potentials may also be detectable, but as an isolated EDX finding, they are not sufficient evidence to diagnose an axon-loss disorder. The recruitment pattern during voluntary muscle activation is also altered in neurogenic disease, with a reduced number of motor units that have an increased firing rate; this reflects a compensatory effort on the part of surviving motor units to maintain a particular force. Because denervation of muscle fibers triggers a reinnervation process, motor units continuously remodel. Early in the reinnervating process, newly formed neuromuscular junctions are electrically unstable, and thus an individual motor unit action potential will vary in amplitude during repeated firing. Furthermore, newly regenerated axons that reinnervate denervated muscle fibers tend to have slow conduction velocities, causing a prolonged conduction time within one motor unit. All these changes alter the configuration of the motor unit potential so that it becomes irregular and polyphasic. In a chronic reinnervating process, surviving motor units may reinnervate a greater number of muscle fibers, resulting in a potential that is broader in duration and higher in amplitude. Therefore, the shape of a typical chronic neurogenic motor unit potential is polyphasic, broad, and high in amplitude.

Motor unit number estimation (MUNE) and similar techniques are specialized neurophysiological tools that can estimate the number of functioning motor units that remain in a progressive neurogenic process.

Muscle Biopsy

Although EDX usually provides sufficient evidence of LMN involvement, muscle biopsy may also reveal early evidence of muscle fiber denervation and rule out other causes of muscle weakness. Denervated muscle fibers are small, angular, and stain darkly by oxidative enzyme and nonspecific esterase stains. As the denervation process progresses, small groups of atrophied muscle fibers (group atrophy) may appear. In normal human muscle, the different muscle fiber types that are distinguished using myosin ATPase stain appear in a random distribution, sometimes mistakenly termed a “checkerboard pattern.” In chronic denervating disease, repeated denervation and reinnervation eventually results in loss of this random pattern, and in very chronic neurogenic disease (such as SMA), large areas of the biopsy consist of just one muscle fiber type, a process called fiber type grouping. However, in a relatively rapid disorder of motor unit loss such as ALS, there is insufficient time to develop marked fiber type grouping.

Acute Poliomyelitis

Poliomyelitis (acute anterior poliomyelitis) is one of the most dramatic disorders causing acute LMN dysfunction. The disease is caused by poliovirus, a single-stranded ribonucleic acid (RNA) enterovirus belonging to the picornavirus family. Three subtypes exist, with type I being responsible for most cases of the epidemic paralytic disease. Before the introduction of poliovirus vaccine in the late 1950s, epidemics of acute paralytic poliomyelitis were relatively common in temperate zones and primarily affected children and young adults (infantile paralysis). In 1988, the World Health Organization resolved to eradicate poliomyelitis worldwide, but this remains unachieved. The mode of spread is via the fecal-oral route, the virus first entering pharyngeal and intestinal lymphoid tissue before being borne in the bloodstream to the CNS. The live oral polio vaccine can itself rarely cause poliomyelitis and other non-polioviruses can cause a paralytic polio-like syndrome. Thus, even in the developed world, it is still important that physicians be acquainted with this syndrome.

Clinical Features

After a brief 3- to 6-day incubation period, a viremia occurs, during which approximately 90% of individuals remain asymptomatic. Most of the remaining individuals develop an acute flulike illness with cough, malaise, diarrhea, myalgia, headache, and fever. This self-limited “abortive” polio usually lasts 2 to 3 days, and patients do not progress to develop acute muscle weakness. Between 2% and 3% of acutely infected patients develop aseptic meningitis characterized by severe headache due to meningeal irritation. This is typically self-limited and resolves within 7 to 14 days. Less than 1% of infected patients who ingest poliovirus develop the acute paralytic syndrome, characterized by localized fasciculations, severe myalgia, hyperesthesias, usually fulminant focal and asymmetrical paralysis, and fever. Any skeletal muscle can weaken, including bulbar muscles and muscles of respiration, but the leg muscles are the most commonly affected (Howard, 2005).

Physical examination reveals severe LMN-type muscle weakness with hypoactive or absent deep tendon reflexes, decreased muscle tone, and fasciculations. With time, muscle atrophy occurs (usually beginning about 3 weeks after onset). Objective signs of sensory loss are not characteristic. The risk of paralytic disease seems to increase with patient age and with the level of virulence of the virus. Most patients with paralytic disease recover significant strength. Improvement may begin as early as the first week after the onset of paralysis, and estimates are that 80% of recovery occurs by 6 months. Further improvement may be modest, but it may continue over the ensuing 18 to 24 months. Up to two-thirds of patients have some degree of functional impairment.

Laboratory Features

Motor nerve conduction studies performed 21 or more days after the onset (see Chapter 32B) may reveal low-amplitude maximum CMAPs. No evidence of significant demyelination-related motor conduction slowing or block exists. Sensory nerve action potentials (SNAPs) are normal. EMG examination in the acute phase shows profuse axon loss in the form of positive sharp waves and fibrillation potentials. In addition, fasciculations may be prominent. As motor axon loss progresses, evidence of neurogenic motor unit potential changes may be detected. The CSF typically shows increased protein content with normal glucose and a pleocytosis, with polymorphonuclear cells predominating during the acute stages and lymphocytes predominating later in the disease. Identification of CSF poliovirus-specific immunoglobulin M (IgM) antibody allows a specific diagnosis. Stool or nasopharyngeal cultures are positive for poliovirus in nearly 90% of patients by the 10th day of illness. The diagnosis may also be established by documenting a fourfold or greater increase in serum antibody titer against poliovirus from the acute as compared to the convalescent phase. Polymerase chain reaction (PCR) is now the best technique to diagnose poliovirus subtype as well as determine if the illness is related to wild-type versus Sabin oral polio vaccine–induced disease.

Differential Diagnosis

Acute paralytic disease caused by other viruses such as West Nile flavivirus (see later discussion), Japanese encephalitis flavivirus, enterovirus 71, and coxsackievirus A7 is very similar to acute poliomyelitis. The documentation of an increase in neutralizing antibody titers of these other viruses from acute compared to convalescent sera, or isolation of the virus in culture, is the only way to make a correct diagnosis. Although acute paralytic poliomyelitis has a distinct clinical presentation, other conditions such as Guillain-Barré syndrome (GBS), acute motor axonal neuropathy (AMAN), acute spinal cord injury and botulism may resemble acute paralytic polio. One must also consider myasthenia gravis, neuralgic amyotrophy, acute intermittent porphyria, HIV neuropathy, periodic paralysis, tic paralysis, and acute rhabdomyolysis.

Treatment

The treatment of acute paralytic poliomyelitis consists of aggressive general supportive care. Most patients will require hospitalization in an intensive care unit to optimize close monitoring of ventilatory and cardiovascular function. After the acute illness, aggressive rehabilitation is the mainstay of continued treatment. All healthcare staff treating patients with acute paralytic poliomyelitis require prior immunization.

Vaccination

The best treatment for polio is prevention. Two vaccines are available, the Sabin (live-attenuated) and the Salk (inactivated). The Sabin trivalent oral poliovirus vaccine, in widespread use since the early 1960s, contains all three live attenuated serotypes of poliovirus. It is almost 100% effective in preventing acute paralytic poliomyelitis. Adults who plan to travel to areas where poliomyelitis is prevalent should receive an extra dose of this vaccine. However, the oral poliovirus vaccine itself is responsible for very rare cases of acute paralytic poliomyelitis in the developed world, with an estimated risk of 1 case in 2.5 million vaccines ingested.

Immunocompromised individuals and their unimmunized direct household contacts are at particular risk for this rare complication. Consequently, in Northern America, Japan, Europe, New Zealand, and Australia, where wild viral infection is almost completely eradicated, policy shifted to use of the Salk inactivated vaccine in immunization schedules (Alexander et al., 2004).

Postpolio Syndrome/Progressive Postpoliomyelitis Muscular Atrophy

In the United States alone, it is estimated that 250,000 to 640,000 people survived acute paralytic poliomyelitis; the last epidemic was in 1952. Many years after recovery from acute poliomyelitis, some patients experience progressive functional impairment, with muscle fatigue, pain, sleep disturbances, cold intolerance, depression, dysphagia, and dysarthria, called the post-polio syndrome. If progressive muscle weakness and wasting occurs in this setting, the term progressive postpoliomyelitis muscular atrophy (PPMA) is used. The reported incidence of postpolio syndrome/PPMA among polio survivors ranges from 28.5% to 64%; no accurate estimate of the incidence exists. By definition, patients with postpolio syndrome/PPMA have recovered from acute poliomyelitis, and the disease course has been stable for at least 10 years after the recovery (Box 74.4).

Etiology

The etiology of postpolio syndrome/PPMA is not established. Numerous studies have failed to identify chronic persistent poliovirus in PPMA, and solid evidence is lacking to implicate a persistent immune-mediated mechanism, although CSF and muscle biopsy samples show some chronic inflammation. The “peripheral disintegration model” is the most widely held theory. This theory proposes that an oversprouting of new axon terminals from surviving LMNs occur in the immediate aftermath of the acute paralytic poliomyelitis. This compensatory distal reinnervation expands the size of motor units and provides effective motor function; this stabilizes muscle strength for many years. However, this extensive nerve sprouting also increases the metabolic burden of surviving LMNs, so after many years, an unidentified process first causes nerve terminal dysfunction presenting as fatigue and then nerve terminal disintegration presenting as muscle weakness and atrophy. It is possible that normal age-related neuronal loss may be the process causing this late degeneration.

Clinical Features

Patients who develop postpolio syndrome/PPMA previously had a stable course for many years after the acute poliomyelitis infection. These patients then experience progressive symptoms of new muscle weakness and new atrophy in previously affected muscles or sometimes in muscles apparently not affected by the original poliomyelitis. EMG examination reveals that muscles thought to be clinically unaffected by acute poliomyelitis often have evidence of previous disease (characterized by chronic neurogenic MUP changes with or without some acute denervation). Muscle cramps and fasciculations may accompany new weakness, but they are often present in stable muscles also. Generalized fatigue is characteristic and can be the most disabling accompaniment, often called the polio wall. Other common symptoms include pain, sleep disturbances, cold intolerance, depression, hypoventilation (manifesting as dyspnea), dysphagia, and dysarthria. The proposal is that these new symptoms should have persisted for a full year if one is to consider the diagnosis of postpolio syndrome. The neurological examination reveals focal and asymmetrical muscle weakness and atrophy, but it may be difficult to determine whether the weakness and atrophy is new and progressive or remote and static. Fasciculations can be unusually coarse and large in keeping with the giant motor units detectable during EMG examination.

Laboratory Features

Because EMG provides definitive evidence of remote poliomyelitis and can help exclude diseases mimicking PPMA, it is an indispensable test when suspecting PPMA, though it cannot confirm the diagnosis. In patients with PPMA, the motor nerve conduction studies may be abnormal (low maximum CMAP amplitudes) when recorded from affected muscles. The needle electrode examination of affected weak muscles typically shows a reduced number of motor units and chronic neurogenic motor unit potentials. Giant motor units may be present, indicative of chronic denervation and reinnervation. Modest numbers of fibrillation potentials and occasional fasciculations may occur in affected muscles, but such electrophysiological evidence of acute muscle fiber injury is not necessary to make the diagnosis. Sensory nerve conduction studies are normal. The muscle biopsy specimen usually shows acute and chronic neurogenic atrophy and often marked group muscle fiber atrophy and fiber type grouping; however, these biopsy findings are not diagnostic of PPMA.

Diagnosis

A history of clinical stability for at least 10 years after recovery from acute poliomyelitis is a prerequisite for considering the diagnosis of PPMA. When this requirement is satisfied, PPMA is then a diagnosis of exclusion. Exclude all potential diseases causing progressive, focal, and asymmetrical weakness. Myelopathy, radiculopathy, electrolyte abnormalities, endocrine diseases, diabetic amyotrophy, connective tissue disorders, entrapment neuropathies, inflammatory myositis, inflammatory neuropathy, and vasculitis are among the diseases to exclude by appropriate laboratory studies. The symptoms of progressive focal muscle weakness in PPMA may raise the possibility of the progressive muscular atrophy (PMA) variant of ALS. Approach this diagnosis with great caution in the setting of a history of prior paralytic polio.

Treatment

No specific pharmacotherapy for postpolio syndrome exists. Care focuses on symptom relief (Gonzalez et al., 2010). A randomized controlled trial of intravenous immunoglobulin (IVIG; 2 courses of IVIG at a dose of 90 g per course over 3 days, with a 3-month interval) reported a significant improvement in muscle strength but not quality of life in 135 patients (Gonzalez et al., 2006). A need for further trials in larger patient groups exists.

The care plan should focus on avoiding fatiguing activities that aggravate symptoms, modifying activities to conserve energy, weight reduction for those who are overweight, and treating underlying medical disorders that reduce overall well-being. Careful screening and treatment for possible sleep apnea and depression are important. Those patients who have worsening of preexisting ventilatory muscles may require noninvasive positive-pressure ventilation (NIPPV) or noninvasive bilevel positive airway pressure (BiPAP) ventilation.

Physical therapy should focus on nonfatiguing aerobic exercise, modest isometric/isokinetic exercise, and range-of-motion stretching maneuvers. The goal should be to maintain exercise in affected muscles but not to the point of overuse, while also limiting the disuse of unaffected muscles. Low-impact exercise in warm water can be particularly helpful and also appears to help control fatigue and pain. In patients with more serious functional decline, prescribe appropriate assistive devices to maintain activities of daily living. Pulmonologists must evaluate those who develop respiratory insufficiency to rule out primary pulmonary disease and to prevent/treat chest infections. Patients whose employment or lifestyle involves significant physical exertion need to modify their work duties and other activities.

West Nile Virus

West Nile virus (WNV) is an arthropod-borne flavivirus that cause epidemics of meningitis, encephalitis, and in some instances an acute polio-like flaccid paralysis. Approximately 80% of those who are infected are asymptomatic, and 20% develop a flulike illness (termed West Nile fever). Less than 1% present with neuroinvasive disease. Following the 1999 outbreak in New York, an epidemic spread across the North American continent and peaked in 2002/2003. Between 1999 and 2008, almost 29,000 confirmed and probable cases of WNV infection were received in the United States, and over 40% of cases were of the neuroinvasive type. The highest incidence of neuroinvasive WNV occurred in the western north-central United States and mountain states between the months of July and September (Lindsey et al., 2010). Epidemics also occurred in Israel, Italy, Russia, Romania, Hungary, Tunisia, the Sudan, the Caribbean, and Latin America. WNV is now endemic in North America and is the leading cause of arboviral encephalitis in the United States. WNV is a zoonotic pathogen that has crossed over from birds to humans, the latter serving as incidental hosts. The prime bridge vector is the Culex mosquito, and the spread of disease appears to have followed the migration patterns of bird populations (Kilpatrick et al., 2006). Human-to-human transmission can occur via blood transfusion, organ transplant, intrauterine exposure, and breastfeeding, hence the need to screen for the virus amongst blood donors. One of the most dramatic presentations is an acute asymmetrical flaccid paralysis in a febrile patient with or without meningitis, encephalitis, and cranial neuropathies (including hearing loss). Aching pains in affected limbs often accompany the paralysis, but actual sensory loss is not a feature. Respiratory failure and death may occur, and up to one-third of cases suffer bladder and bowel dysfunction. Recovery is very slow, and from the available evidence, incomplete. Other presentations include a GBS, multifocal chorioretinitis, pancreatitis, hepatitis, myocarditis, nephritis, and splenomegaly. Risk factors for death from WNV infection include chronic renal disease, an immunosuppressed state (e.g., in organ transplant recipients), the presence of encephalitis (versus meningitis) and old age (Murray, K., et al., 2006; Tyler et al., 2006). Detection of WNV-specific IgM antibody in the serum of a patient with abnormal CSF and acute neurological illness confirms the diagnosis. The diagnosis can also be confirmed by WNV-specific IgM antibody capture ELISA in CSF. PCR has also been developed to detect the virus (Tang et al., 2006). CSF protein is typically elevated (100 mg/dL or more and often higher in encephalitis versus meningitis), glucose is typically normal, and there are increased numbers of white cells (mean of about 220/mm³ with ≈ 45% neutrophils). The number of red cells is variable and may be higher in encephalitis (Tyler et al., 2006). Neuroimaging of the brain is usually normal, but that of the spinal cord may reveal increased signal in the anterior horns. Electrodiagnostic studies reveal an acute disorder of anterior horn cells, with acute loss of motor units in affected myotomes.

Treatment is symptomatic and supportive. Although a vaccine is available for horses and also for birds in zoos, no vaccine for humans exists. The best way to prevent this condition is to avoid mosquito bites through judicious use of appropriate clothing and insect repellants.

Multifocal Motor Neuropathy

A complete description of multifocal motor neuropathy is in Chapter 76. The condition is believed to be autoimmune in nature, and most cases have evidence of focal demyelination in the peripheral nerves (multifocal motor neuropathy with conduction block [MMNCB]) similar to that in chronic inflammatory demyelinating peripheral neuropathy. The clinical presentation, however, is with pure LMN involvement. The condition enters into the differential diagnosis of benign focal amyotrophy and the progressive muscular atrophy variant of ALS. It is important to search for this condition, since it is treatable by high-dose immunoglobulin infusions or other immunotherapy.