Neuroanatomy of Upper Motor Neurons

The UMN is a motor neuron, the cell body of which lies within the motor cortex of the cerebrum, and the axon of which forms the corticobulbar and corticospinal tracts. The LMNs, lying in the brainstem motor nuclei and the anterior horns of the spinal cord, directly innervate skeletal muscles. The UMNs are rostral to the LMNs and exert direct or indirect supranuclear control over the LMNs (Box 74.1).

Signs and Symptoms of Upper Motor Neuron Involvement

Laboratory Evidence of Upper Motor Neuron Involvement

Several promising imaging and electrophysiological techniques are under investigation as potential markers of UMN involvement in neurological disease. However, a thorough bedside examination is the easiest and most effective means to detect UMN disease.

Primary Lateral Sclerosis

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.

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).

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

Neuroanatomy of Lower Motor Neurons

Clinical Features of Lower Motor Neuron Involvement

Laboratory Evidence of Lower Motor Neuron Involvement

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.

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).

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.

Benign Focal Amyotrophy

The terms benign focal amyotrophy, brachial monomelic amyotrophy, benign calf amyotrophy, Hirayama disease, or juvenile segmental muscular atrophy are used to describe disorders characterized by LMN disease clinically restricted to one limb. The etiology is unknown. Autopsy studies have shown the affected region of spinal cord flattened, the anterior horn markedly atrophied and gliotic, and a reduction in the numbers of both large and small motor neurons. Based upon neuroradiological studies, Hirayama, who established the disease entity, has proposed a mechanically induced limited form of ischemic cervical myelopathy, being the result of local compression of the dura and spinal cord against vertebrae during repeated neck flexion/extension, in turn due to disproportionate growth between the contents of the dural sac and the vertebral column (Hirayama, 2008; Hirayama and Tokamaru, 2000). However, surgical decompression has not altered the course of the disease, and this theory is no longer widely held. Another school of thought is that this is a segmental, perhaps genetically determined, SMA, but the actual cause is still unknown.

The disease usually begins in the late teens, but many cases can present in the fourth decade. More than 60% of patients are men. Although originally described in Indian and Japanese patients, the disorder is now recognizable around the world. The most common presentation is one of an idiopathic, slowly progressive, painless weakness and atrophy in one hand or forearm. The distribution of muscle weakness varies markedly from case to case, but a characteristic feature is that the condition remains limited to only a few myotomes in the affected limb. The most common pattern is unilateral atrophy of C7-T1 innervated muscles, with sparing of the brachioradialis (the “oblique atrophy” pattern). Muscle stretch reflexes are invariably hypoactive or absent in the muscles innervated by the involved cord segment but are normal elsewhere. UMN signs are not present, and if they are, one should consider the onset of ALS instead. Approximately 20% have hyperesthesia to pinprick and touch, usually located on the dorsum of the hand. The cranial nerves, pyramidal tracts, and the autonomic nervous system are normal. Weakness and atrophy may progress steadily for the initial 2 to 3 years, but most patients have stabilized within 5 years. The arm is the affected limb in approximately 75% of the patients and the leg in the remaining 25% (benign calf amyotrophy). Spread may occur to the contralateral limb in about 20% of cases (Gourie-Devi and Nalini, 2003), and rare patients later develop an ALS-like picture.

No pathognomonic laboratory or electrodiagnostic tests exist for this condition; their main purpose is to exclude alternative diagnoses. Motor nerve conduction studies are either normal or reveal only reduction in the maximum CMAPs; a modest reduction in SNAPs occur in up to one-third of patients. The EMG examination may show some fibrillation and fasciculation potentials, and chronic neurogenic motor unit changes are prominent. The C5-T1 myotomes are most commonly involved when the arms are affected. Careful EMG examination may reveal mild neurogenic changes on the asymptomatic contralateral side. The serum creatine kinase (CK) concentration may be modestly elevated, but other routine laboratory test results are normal. Cervical MRI may reveal segmental spinal cord atrophy or occasionally an area of increased signal on T2-weighted scans of the cervical spinal cord enlargement. “Incidental” spondylosis and cervical spinal canal stenosis detected by MRI require careful evaluation before the diagnosis of benign focal amyotrophy is established.

Spinal Muscular Atrophy

The SMA are a group of disorders caused by degeneration of anterior horn cells and, in some subtypes, of bulbar motor neurons. Almost all cases are genetically determined, with most being autosomal recessive due to homozygous deletions of the survival motor neuron (SMN) gene on chromosome 5. Traditionally, SMA is classified as one of the four types based on the age at onset: SMA type 1 (infantile SMA or Werdnig-Hoffmann syndrome), SMA type 2 (intermediate SMA), SMA type 3 (juvenile SMA or Kugelberg-Welander disease), and SMA type 4 (adult-onset SMA, pseudomyopathic SMA). A very severe prenatal form of SMA (type 0 SMA) can manifest prenatally with reduced fetal movements and respiratory distress at birth. It is also important to consider the maximum function that a child achieves in terms of sitting and walking; this is of prognostic significance. In the less severe forms of the disease, there can be periods where the child will improve or plateau, but long-term studies have demonstrated a net deterioration (Russman, 2007) (Table 74.2). The estimated incidence of infantile and juvenile recessive SMA is 1 in 6000 live births, with an approximate carrier frequency of 1 in 35 of the general population, making it a leading genetic cause of infant mortality. True adult-onset disease accounts for probably less than 10% of all cases of SMA, with an estimated prevalence of 0.32 in 100,000. The mean age at onset is the mid-30s but ranges from 20 to the late 40s. Up to 95% of all childhood cases are due to deletion of the survival motor neuron (SMN1, telomeric SMN, SMNT) gene located on chromosome 5q11.2-13.3. The remaining cases are due to small SMN mutations (rather than full deletions). SMN1 is located within an inverted gene duplication, the other half of which is occupied by the almost identical SMN2 (centromeric SMN, SMNC) gene. The SMN1 protein product is functionally absent in the vast majority (95%-98%) of cases of SMN-mutated SMA, and small amounts are present in the remaining few percent. The SMN2 protein is present in all patients, but the copy number can vary considerably. Only 1% to 2% of childhood-onset SMA is unrelated to the SMN locus on chromosome 5.

SMN1 protein is a 38-kD polypeptide important in the processing of the primary transcripts of other genes. Although a ubiquitous protein, expression is great within spinal motor neurons, and this may be why the disorder manifests as a motor neuron disease. It is associated with both nuclear and cytoplasmic complexes involved in messenger RNA splicing and interacts with other proteins that are important in the regulation of ribosomal RNA processing and modification. Within the nucleus, SMN1 forms macromolecular complexes with other nuclear proteins important in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). It is thus possible that SMA develops because of disruption in mRNA transport and/or SMN-dependent snRNP biogenesis. SMN2 protein is almost identical to SMN1 protein but only has about 10% of the activity of SMN1 protein because of a C-to-T transition within exon 7 that alters splicing. The full-length SMN1 transcript has all 9 exons, whereas 90% of the transcripts from SMN2 lacks exon 7. Thus, only 10% of the SMN2 output is the full-length SMN transcript, the remainder being unstable and rapidly degraded. Motor neuron health requires at least 23% full-length SMN protein. The SMN genome is rather unstable and as a consequence, increased copy numbers of SMN2 are possible through a process of gene conversion from SMN1 to SMN2. This has major implications for the clinical phenotype: the infantile form is very severe because most of these children have no SMN1 and only two copies of SMN2, thus producing about 9% of full-length functional transcript, whereas multiple copies of SMN2 (3-5) are associated with mild SMA (Hirth et al., 2005; Kostova et al., 2007; Monani, U.R., 2005).

Most (about 70%) adult-onset type 4 SMA is autosomal recessive, is allelic with SMA types 1, 2, and 3, and is due to mutations or deletions in the SMN1 gene. Gene conversion events occur in some cases with SMA-4 whereby SMN1 is “converted” to SMN2. The remaining adult-onset SMA cases are autosomal dominant, autosomal recessive (but not linked to chromosome 5), or are apparently sporadic. One rare form of adult-onset SMA described in a large Brazilian family was caused by a missense mutation in the vesicle trafficking protein, VAPB. This can present with typical ALS or with a late-onset SMA (Nishimura et al., 2004).

Clinical Features

Spinal Muscular Atrophy Type 1, Infantile Form (Werdnig-Hoffmann Disease)

SMA type 1 begins within the first few months of life. By definition, children with this disease are never able to sit without support. Symptoms include severe hypotonia, a weak cry, and respiratory distress. These children are unable to lift their heads when placed prone and demonstrate severe head lag when pulled from a supine to a seated position (Fig. 74.1). The baby’s posture at rest also takes a characteristic “frog-leg” position, with the thighs externally rotated and abducted and the knees flexed (a “floppy” baby). Limb weakness is severe, generalized, and worse proximally. The infant is unable to sit and raise its arms or legs from the examining table, but there may be antigravity movements of the hands and flickering movements of the feet. Muscle stretch reflexes are usually absent, and the sensory examination is normal. Observation of the fingers may reveal fine, small-amplitude involuntary movements called minipolymyoclonus that are due to dense fasciculations. Contractures usually do not develop in the early phases but may develop after several months of immobilization. Bulbar muscle weakness makes feeding laborious, causes a continuous gurgling, and eventually leads to aspiration pneumonia. Fasciculations of the tongue occur in about 50% of affected infants. In contrast to bulbar and extremity muscles, the facial muscles are only mildly weak, giving these children an alert expression. Extraocular movements are always normal. Intercostal muscles are severely weak, but diaphragmatic strength preserves until late in the disease. This dysequilibrium of ventilatory muscle function causes outward flaring of the lower ribcage and gives rise to a bell-shaped chest deformity. Death from respiratory failure, pneumonia, and malnutrition usually occurs before age 2 years. A rare form of atypical infantile SMA, spinal muscular atrophy with respiratory distress (SMARD), is associated with respiratory distress, cardiomyopathy, and lactic acidosis. This disorder is not due to SMN1 deletion but caused by mutations in the gene for immunoglobulin mu-binding protein 2 (IGHMBP2). It is interesting that this gene has homology to SETX, the gene responsible for ALS4, which can cause a familial form of distal amyotrophy, oculomotor apraxia–cerebellar ataxia, or juvenile ALS.

Fig. 74.1 A 6-month-old baby with Werdnig-Hoffmann disease. A, The baby has a typical “frog leg” posture; mouth is triangular, and facial expression suggests facial weakness. B, On sitting, the baby cannot sustain his head upright. C, When the baby is pulled by the arms, the head falls back. D, When the body is held supine, the head and extremities drop by force of gravity, and there is no active body motion.

(Courtesy Neil Friedman, Cleveland Clinic Foundation.)

Spinal Muscular Atrophy Type 2, Intermediate Form (Chronic Spinal Muscular Atrophy)

The signs and symptoms of SMA type 2 usually begin between the ages of 6 and 18 months. Delayed motor milestones are often the first clue to neurological impairment, with more prominent leg weakness then arm weakness. A fine hand tremor due to minipolymyoclonus suggests the diagnosis. The distribution, pattern, and progression of weakness is similar to that found in SMA type 1, but type 2 disease is quantitatively much milder, and progression is slower. Most children eventually are able to roll over and sit unsupported, but they rarely achieve independent walking. Weakness of trunk muscles produces a characteristic rounded kyphosis in the seated position, and as the shoulders weaken, the child becomes less mobile and eventually wheelchair confined. Contractures of the hips and knees, clubfoot deformities, severe scoliosis, and dislocation of the hips may eventually develop. The long-term prognosis varies markedly; some die in childhood because of respiratory failure, but many others survive into the third or fourth decade of adulthood.

Another rare childhood-onset form of SMA that is distinct from SMA type 2 is Fazio-Londe disease. This is a form of sporadic autosomal dominant or autosomal recessive progressive facial and bulbar palsy of late childhood. Affected children are normal at birth but develop progressive bulbar palsy (PBP) and eventual respiratory failure in the second decade of life, with little or no evidence of involvement of other motor neurons and with usually normal extraocular motility. The differential diagnosis includes a structural brainstem lesion, myasthenia gravis, and the Miller-Fisher variant of GBS.

Spinal Muscular Atrophy Type 3, Juvenile Form (Kugelberg-Welander Disease)

The onset of the juvenile form of SMA is typically after 18 months of age (usually between 5 and 15 years) and presents with difficulty in walking. Patients with onset before the age of 3 years are subclassified as SMA type 3a and those after age 3 years as SMA type 3b. The disorder has an appearance not unlike a limb-girdle muscular dystrophy. As weakness in hip-girdle muscles increases, the child develops a waddling (Trendelenburg) gait, with a protuberant abdomen due to an exaggerated lumbar lordosis, and trouble climbing stairs. As weakness progresses, the Gowers maneuver is used to arise from lying supine on the floor. Pseudohypertrophy of the calf muscles sometimes occurs, but this may be an illusion resulting from relative preservation of calf muscles as compared to thigh muscles. Eventually, wasting and weakness of the neck, shoulders, and arms develop, but as with SMA type 2, weakness in the lower extremities is nearly always more severe than in the upper extremities. Fasciculations are more prominent than in SMA-1 and SMA-2, and a fine action tremor is common. Tendon reflexes uniformly reduce and are lost, and the sensory examination is normal.

The clinical course of SMA-3 is one of slowly progressive limb-girdle weakness, but there may be long periods of stability that last for years. The eventual degree of disability is difficult to predict, but if onset is after the age of 2 years, it is likely that the patient will be remain ambulatory into the fifth decade of life and enjoy a normal lifespan.

Spinal Muscular Atrophy Type 4, Adult-Onset

Most cases of autosomal recessive adult-onset SMA appear to affect proximal muscles. The characteristic clinical presentation is that of a slowly progressive limb-girdle weakness leading to difficulty in walking, climbing stairs, and rising from a chair or the floor. Fasciculations are an important finding and occur in 75% of patients. Quadriceps muscle weakness is often a prominent feature. Muscle cramps occur but are not prominent. Bulbar signs, bony deformities such as scoliosis, and respiratory weakness are rare. Many cases have a distribution of weakness reminiscent of the limb-girdle muscular dystrophies, leading to the older term, pseudomyopathic SMA (Fig. 74.2). Many cases of autosomal dominant adult-onset SMA (also known as Finkel-type SMA) are clinically similar to the recessive form described earlier. Finkel-type SMA usually begins in the third decade of life, is proximal in distribution, is very slowly progressive, and involves the legs before the arms. Most patients remain ambulatory for decades after clinical onset. One of the autosomal dominant missense mutations causing adult-onset Finkel-type SMA affects a vesicle trafficking protein called VAPB. It is interesting that some patients with this mutation develop the clinical features of ALS rather than SMA (Nishimura et al., 2004).

Fig. 74.2 Patient with mild adult-onset proximal spinal muscular atrophy and marked shoulder-girdle muscle atrophy. Note subluxation at both shoulder joints and marked deltoid muscle atrophy.

A new class of adult-onset SMA has recently emerged and is sometimes referred to as SMA-5 to help distinguish a distal rather than proximal pattern of slowly progressive muscular atrophy. The classification of these rare disorders is rather vague, and considerable overlap with distal CMT (see later discussion) exists. Several patterns of inheritance occur, including autosomal dominant, autosomal recessive, and X-linked recessive. Some lack any apparent pattern of inheritance. Distal-predominant adult-onset SMA and some of the neuronal forms of CMT disease appear to overlap both clinically and genetically: indeed, the difference may be purely semantic. Motor-predominant CMT variants such as hereditary motor neuronopathy type 5 (HMN-5), itself a heterogeneous group of conditions, present with a slowly progressive LMN-predominant disorder affecting distal limb muscles. Mutations in the glycyl-tRNA synthetase (GARS) gene, for example, were identifiable in multiple families around the world. Patients usually present with very indolent symmetrical or asymmetrical weakness, clumsiness, and wasting of intrinsic hand muscles (with a particular predilection for thenar muscles) in the absence of any proximal weakness or sensory findings. There is little functional disability (Del Bo et al., 2006; Dubourg et al., 2006). Mutations in the p150Glued subunit of the dynactin gene, a microtubule protein important in axonal transport, cause another distal-predominant atrophic disorder that also has a predilection for thenar muscles. Unlike the GARS-associated disorder, involvement of the face and vocal cords may occur (Puls et al., 2005).

Kennedy Disease (X-Linked Recessive Bulbospinal Neuronopathy)

In 1968, Kennedy and colleagues reported a new X-linked recessive SMA with bulbar involvement and gynecomastia. The primary pathology was thought to be in the LMNs, but sensory system involvement was later recognized, which led to the term bulbospinal neuronopathy. Molecular genetics research has shown Kennedy disease to be a trinucleotide repeat expansion disease. Though rare, it is more common than adult-onset SMA (Box 74.5).

Clinical Features

As is often seen in an X-linked syndrome, this is a disorder of men, who remain largely asymptomatic until after age 30 years. Hand tremor and subtle speech disturbance are early features that are followed by LMN muscle weakness, initially involving either the proximal hip extensor or shoulder girdle muscles, and associated with decreased or absent reflexes, muscle atrophy, and occasionally calf pseudohypertrophy. Kennedy disease usually causes no respiratory muscle weakness. Coarse muscle fasciculations, often with cramps, can be prominent in the extremities and trunk. Facial and perioral fasciculations are present in more than 90% of patients. The tongue shows chronic atrophy, often as a longitudinal midline furrow. However, despite weakness of facial and tongue muscles, significant bulbar symptoms are usually a relatively late feature. Neurological examination of the sensory system may reveal only modest impairment. Progression is slow, with most cases remaining independent of assist devices until late into the fifth decade of life (Atsuna et al., 2006). If bulbar dysfunction is severe, the prognosis becomes less favorable. Partial androgen insensitivity is an important element of this condition, and gynecomastia is one of the unique features of Kennedy disease that can be found in 60% to 90% of patients (Fig. 74.3). Other endocrine abnormalities include testicular atrophy, infertility (40%), and diabetes mellitus (10%-20%). It is now recognized that female carriers may manifest subtle neurological deficits such as late-onset bulbar dysfunction.

Fig. 74.3 A man with X-linked recessive bulbospinal muscular atrophy (Kennedy disease), showing gynecomastia.

This disorder often exhibits genetic anticipation—that is, the greater the number of repeats, the younger the age at onset. However, the number of repeats has no correlation with other features such as severity of weakness, serum CK level, and presence or absence of gynecomastia, impotence, or sensory neuronopathy. Furthermore, there is marked variation in phenotypical expression within and among families.

Progressive Muscular Atrophy

PMA, first described by Aran in 1850, is a clinical LMN disorder during its entire clinical course and comprises approximately 5% to 8% of all adult-onset motor neuron diseases. It is an overwhelmingly sporadic disease, but rare genetic diseases, such as those due to mutations in dynactin, VAPB, and A4V SOD1, may present with a pure LMN disorder, so a careful family history is important. Although PMA occurs in both sexes, men are more often affected than women. In a recent study, the average age of onset of PMA was about 3 years older than that of ALS, but other studies report a younger age at onset (Kim et al., 2009; Murray, B., 2006). Several studies have demonstrated that PMA progresses more slowly than ALS, so the average survival is significantly longer. The mean duration of disease was 159 months in one series of cases, and in another study, the 5-year survival was 63.7% in PMA versus 36.8% in ALS. Most of the very longest-duration cases of “ALS” have the PMA variant. Interestingly, the recent paper by Kim et al. showed that the development of UMN signs was unrelated to survival time after diagnosis (Kim et al., 2009; Murray, B., 2006).

It has been questioned whether PMA is an independent disease or represents one end of the spectrum of ALS. However, if followed over time, many patients with PMA go on to develop clinical features of upper motor neuron disease, which allows reclassification to ALS (and thus eligibility for entry into clinical trials). In a recent retrospective study of 916 cases diagnosed with ALS at a major neurological center, in 91, the original diagnosis was PMA; 20 of these developed UMN signs within 61 months of the original diagnosis. Autopsy studies have also demonstrated UMN involvement in some cases classified as PMA in life. Studies using magnetic resonance spectroscopy and/or transcranial magnetic stimulation reveal evidence for upper motor neuron involvement in PMA patients (Kim et al., 2009; Maragakis et al., 2010; Rowland, 2006).

Subacute Motor Neuronopathy in Lymphoproliferative Disorders

A subacute, progressive, and painless motor neuron syndrome may rarely develop in patients who have Hodgkin and non-Hodgkin lymphoma with or without a paraproteinemia (Rowland, 2006; Rudnicki and Dalmau, 2000). The lymphoma may or may not temporally coincide with the motor neuron disorder, and one or other disorder may present first. Although UMN signs may develop later in more than half of all cases, a LMN-onset syndrome is typical, with patchy, asymmetrical, lower extremity–predominant muscle weakness and wasting. Neuropathology shows a loss of anterior horn cells and ventral root nerve fibers; some have evidence of inflammation in the anterior horns of the spinal cord, and half have corticospinal tract degeneration. In some patients, the disease may be relatively benign. The rate of progression of muscle weakness and atrophy tends to slow down with time, and in rare instances, the motor syndrome may respond to treatment of the underlying lymphoproliferative disorder. However, the prognosis appears to be less favorable in those who develop a combined UMN and LMN disorder. Twenty percent of all cases so far reported with motor neuron presentations in the setting of lymphoproliferative disease had myeloma or macroglobulinemia. The pathogenesis of this ALS-like disorder is undetermined, but an immune mechanism may be at play; small patient series and case reports reveal that some patients who develop this LMN syndrome may have various autoantibodies (such as antisulfatide antibody), paraproteinemia, increased CSF protein, and/or oligoclonal bands.

Postirradiation Lower Motor Neuron Syndrome

Radiation directed to the retroperitoneal paraaortic area for the treatment of testicular or lymphoid cancers can cause a pure LMN syndrome in the lower extremities that first appears many years after the irradiation. Sensory abnormalities and sphincter dysfunction are rare, and the EDX findings are consistent with a disorder of the lumbosacral motor neurons or the cauda equina (the SNAPs are spared). Myokymic discharges and nonresolving conduction blocks are characteristic electrodiagnostic features. The disease usually progresses over the first few years after symptom onset but subsequently becomes stable. There is debate as to the exact mechanism.

Amyotrophic Lateral Sclerosis

ALS is a neurodegenerative disorder of undetermined etiology that primarily affects the motor neuron cell populations in the motor cortex, brainstem, and spinal cord. It is progressive, and most patients eventually succumb to respiratory failure. The first detailed description was by Jean Martin Charcot in 1869, in which he discussed the clinical and pathological characteristics of “la sclérose latérale amyotrophique,” a disorder of muscle wasting (amyotrophy) and gliotic hardening (sclerosis) of the anterior and lateral corticospinal tracts (Gordon, 2006) involving both upper and lower motor neurons. ALS is known by several other names including Charcot disease, motor neuron disease, and in the United States, “Lou Gehrig disease” in remembrance of the famous “Iron Horse” of baseball who was diagnosed with ALS in 1939.

The World Federation of Neurology Research Group on Neuromuscular Disorders has classified ALS as a disorder of motor neurons of undetermined cause, and several variants are recognized. Included in this group are PLS and PBP. As previously mentioned, PMA is also thought to be a variant of ALS, despite its exclusion from current clinical research trial criteria. It is important to recognize that ALS is a progressive dynamic disorder. Some cases present with the classic combination of UMN and LMN signs, but others may have UMN onset, LMN onset, bulbar onset, or dyspnea at onset and only later develop signs of involvement of the other parts of the motor system (Box 74.6).

Between 5% and 10% of ALS is familial rather than sporadic, the most common inheritance pattern being autosomal dominant. Thus one comes across the terms sporadic ALS (SALS) and familial ALS (FALS). A few other conditions have a phenotypical expression similar to that of ALS, including Western Pacific ALS-parkinsonism-dementia complex (PDC) (or Guamanian ALS) and juvenile ALS.

The incidence and prevalence rates for sporadic ALS are surprisingly uniform throughout the world. The estimated incidence in North America and Europe is about 2 per 100,000, and the prevalence is about 6 per 100,000. In sporadic spinal ALS, the male-to-female ratio is 1.2 to 1.4 : 1, but a slight female predominance exists in the bulbar-onset variety. ALS may occur as early as in the second decade of life, but the peak incidence is in the 65- to 74-year-old age bracket (McGuire and Nelson, 2006). The mean disease duration from symptom onset to death is approximately 3 years, but roughly 1 in 5 patients survive to 5 years, and 1 in 10 patients survive to 10 years (Murray B., 2006). No specific environmental, occupational, or physical factors link with absolute certainty to an increased risk of ALS. Areas of interest include chronic exposure to electromagnetic fields, high levels of physical activity, high dietary intake of glutamate, environmental toxins, and a history of military service in the Persian Gulf War. Smoking appears to be an independent risk factor for sporadic ALS, with a higher risk for those who have smoked for many years (Armon, 2009; Gallo et al., 2009). Several environmental trace elements have been evaluated as potential causative agents for ALS, including selenium, aluminum, iron, manganese, copper, zinc, cadmium, and lead, but there is no convincing evidence that any one of these plays a major part in ALS pathogenesis.

Clinical Features

The typical clinical picture in ALS is that of a patient with a progressive motor deterioration manifesting with both UMN and LMN symptoms and signs. Thus, one should consider this diagnosis when a patient presents with a combination of marked weakness and wasting but with brisk reflexes, spasticity, and pathological reflexes. Of course, not all patients present with this classic pattern: muscle weakness in ALS usually begins in a focal area, first spreading to contiguous muscles in the same region before involvement of another region. The first presentation may appear very similar to a focal mononeuropathy, sometimes called the pseudoneuritic or flail leg presentation (Wijesekera et al., 2009). More commonly, however, single-limb weakness appears to occur in muscles derived from more than one peripheral nerve and/or nerve root distribution; this is a monomelic presentation. Onset of muscle weakness is more common in the upper than the lower extremities (classic, spinal ALS), but in approximately 25% of patients, weakness begins in bulbar-innervated muscles (bulbar-onset ALS). On rare occasions (1% or 2% of patients, more often male), the weakness starts in the respiratory muscles (dyspnea or respiratory-onset). Some patients present with weakness that is restricted to one side of the body (Mills hemiplegic variant), and up to 10% of patients appear with bilateral upper-extremity wasting, which is known as the flail arm or flail person in the barrel variant. The latter is more commonly seen in males and typically presents in proximal muscles of the upper limb before spreading distally into the hands, and then much later (one study used a 12-month interval) into other regions. Reflexes may be retained or even brisk in the markedly atrophic limbs.

Symptoms of muscle weakness vary, depending on which motor function is impaired. For example, when weakness begins in the hand and fingers, patients report difficulty in turning a key, buttoning, opening a bottle cap, or turning a doorknob (Fig. 74.4). When weakness begins in the lower leg, foot drop may be the first symptom, or the patient may complain of instability of gait, falling, or fatigue when walking (Fig. 74.5). When bulbar muscles are affected, the first symptoms may be slurred speech, hoarseness, or an inability to sing or shout, soon followed by progressive dysphagia (Fig. 74.6). Patients with bulbar-onset ALS often initially consult ENT specialists and not only experience progressive impairment in bulbar function but also excessive drooling (sialorrhea) and weight loss. Pseudobulbar palsy may present with inappropriate or forced crying or laughter (see Signs and Symptoms of Upper Motor Neuron Involvement, earlier in this chapter), which is often a source of great emotional distress for patients. Excessive forced yawning may also be a manifestation of pseudobulbar palsy. In the rare patient who presents with progressive respiratory muscle weakness, the first consultation may be with a pulmonologist or even admission to the intensive care unit; the diagnosis of ALS may be established when the patient fails weaning from the ventilator. Head drop (or droop) may be a feature in ALS, caused by weakness of cervical and thoracic paraspinal muscles (Fig. 74.7). Fasciculations are not commonly the presenting feature of ALS, but they develop in almost all patients soon after onset, and their absence should prompt one to reconsider the diagnosis. In some patients, waves of fasciculations spread across the chest or back. Muscle cramps are one of most common symptoms in patients with ALS and often precede other symptoms by many months. In ALS they can occur in unusual muscles such as in the thigh, abdomen, back, or tongue. Spasticity develops in wasted muscles, and patients may suffer painful flexor spasms in limbs.

Fig. 74.4 A-B, Severe intrinsic hand muscle atrophy in a patient with amyotrophic lateral sclerosis. Note the “claw hand” and atrophy of muscles innervated by both ulnar and medial nerves.

Fig. 74.5 Typical left foot drop in a 45-year-old patient whose amyotrophic lateral sclerosis began 2.5 years earlier with bulbar symptoms. When asked to dorsiflex both feet, she was able to move her right foot only. Foot drop developed 6 months before the photo was taken, and the patient wears a left ankle-foot orthosis.

Fig. 74.6 Atrophy of the tongue in amyotrophic lateral sclerosis.

Fig. 74.7 Patient with amyotrophic lateral sclerosis, showing head droop caused by weakness of the thoracic and cervical paraspinal muscles.

As dysphagia worsens, reduced caloric intake worsens fatigue and accelerates muscle weakness. Aspiration of liquids, secretions, and food becomes a risk. Patients may complain that they produce copious amounts of abnormally thick oral secretions, which may drool excessively from the mouth. This sialorrhea is made worse as perioral muscles weaken and/or head drop develops. Weight loss is often rapidly progressive; this does not simply reflect poor caloric intake but represents a form of ALS cachexia. Marked loss of muscle bulk exposes joints and associated connective tissues to abnormal mechanical stresses that can lead to joint contractures, joint deformities, painful shoulder pericapsulitis, and bursitis. Sleep disturbances in the form of increased awakenings from hypopnea and hypoxia are common in ALS and contribute to daytime sleepiness, morning headaches, and fatigue. As respiratory difficulty worsens, patients may be unable to lie supine because of worsening diaphragmatic weakness and thus compensate by using multiple pillows. In more advanced stages, patients are unable to lie in bed at all. Other manifestations of ventilatory failure include dyspnea on exertion and eventually dyspnea at rest. As the disease advances, motor function is progressively impaired, and activities of daily living (e.g., self-hygiene, bathing, dressing, toileting, walking, feeding, and verbal communication) become difficult. Accordingly, a patient’s quality of life progressively deteriorates. It may be difficult to distinguish daytime fatigue, broken sleep, affect lability, and sighing from depression, but it is vitally important to be aware of the latter, as both fatigue and depression may occur in ALS (McElhiney et al., 2009).

Frontotemporal-type dementia (FTD) and/or cognitive impairment is present in many patients with ALS, albeit on a spectrum from apparently normal to a florid FTD. These observations lend support to the notion that ALS is not a pure disorder of motor neurons, but rather a disorder that primarily affects motor neurons, with the potential to involve nonmotor systems. The presence of ubiquitinated TDP43 inclusions in ALS patients with and without FTD supports the idea that ALS and ALS-FTD may be a continuum. One needs to be cautious when assessing apparently cognitively normal patients with ALS because the deficits may be so subtle as to require specific assessments of personality, behavior, praxis, verbal fluency, visual attention, and verbal reasoning. Dysarthria may mask language disturbances (especially anomia). With appropriate testing, cognitive deficits may be found in about 50% of patients with ALS, but the full clinical (Neary) criteria for a diagnosis of FTD are met in only about 20% of cases (Lomen-Hoerth and Strong, 2006; Murphy, J., 2007). Conversely, subclinical motor neuron degeneration may be found in up to 50% of patients who have FTD (Lipton et al., 2004; MacKenzie and Feldman, 2005).

Familial Amyotrophic Lateral Sclerosis

Between 5% and 10% of all ALS is an inherited trait, in which case it is termed familial ALS (FALS). It is quite possible that the true frequency of FALS is higher, because anything less than a detailed family history may fail to identify an affected family member, and reduced penetrance may account for some apparently sporadic disease. There are autosomal dominant, autosomal recessive, and X-linked dominant forms, some being juvenile onset and others being adult onset (see Box 74.6). The clinical presentation varies considerably, not just in terms of age and site of onset but also in terms of disease duration. FALS is currently classified from ALS1 to ALS11. X-linked dominant ALS, featuring a combination of both UMN and LMN signs, has been reported, the gene locus being on chromosome Xp11-Xq12 (Siddique and Dellefave, 2006).

ALS1 is a form of late-onset (usually >age 30) motor neuron disorder that accounts for 15% to 20% of all cases of FALS (and thus 1%-2% of all ALS). It is associated with mutations in the gene that encodes superoxide dismutase 1 (SOD1) located on chromosome 21q21 (Rosen et al., 1993). Inheritance in most is in an autosomal dominant pattern, but a recessive variant occurs (Andersen et al., 1996).

SOD1 is a 32-kD homodimeric protein encoded by a gene containing 5 exons located on chromosome 21. Each monomer contains one atom of copper and one of zinc. The zinc moiety maintains the dimer formation, which doubles the dismutase activity. However, it is the copper within the active site that is important in catalyzing the conversion of O₂⁻ to H₂O₂ and O₂. SOD1 expresses ubiquitously in every cell of every eukaryotic organism, and its sequence and structure are highly conserved. The biological importance of this protein is also evident in its great abundance within some cells; it accounts for as much as 1% of all protein of the CNS.

To date, more than 120 distinct point mutations have been found in all 5 exons of the SOD1 gene, the majority of which are missense mutations that usually result in the incorporation of a wrong amino acid into the gene product. A simple pattern of loss of enzyme function is not demonstrable in SOD1-associated FALS. Mutant SOD1 proteins are often unstable, but total SOD1 enzyme activity correlates poorly with the severity of FALS and SOD1-knockout mice (animals genetically engineered to be born with no SOD1 proteins) do not have motor neuron disease.

The absence of an association between enzyme activity and disease occurrence has led to an alternative hypothesis that there is a toxic gain of function in mutated SOD1. Toxic gained properties in human disease may arise from oxidative stress through an interaction with aberrant substrates. Mutant SOD1 proteins clump together as intracellular aggregates that may interfere with proteosomal breakdown of ubiquitinated proteins or impair axonal transport of various substances. SOD1 mutations may catalyze the inactivation of GLT1 and thus cause excitotoxic cell injury via excessive influx of calcium into motor neurons or disturb calcium homeostasis through disruption of mitochondrial function. Both in vitro and in vivo research shows that mutant SOD1 protein is associated with enhanced programmed cell death (apoptosis).

There is a large degree of phenotypical variability in the expression of SOD1-associated FALS, not only between different families but also between individual members of the same family. Furthermore, penetrance is rather variable and age dependent. Generally, establishing the diagnosis of FALS is only by the fact that other family members in successive generations are, or were, affected by ALS. The clinical features of individual FALS patients overlap considerably with those of patients with SALS, but there may be subtle differences between the two. For example, lower-limb onset is more common in FALS, whereas bulbar onset is rare. The age at onset for FALS averages at about 46 years, which is earlier than that of SALS (65-74 years); the male-to-female ratio is 1 : 1 in FALS but about 1.2 to 1.4 : 1 in SALS.

ALS2 is a rare recessively inherited disorder mapped to a gene on chromosome 2q33 that encodes a novel protein called alsin. Analysis of the original families revealed that all were due to truncated protein product from frameshift or nonsense mutations, but missense mutations occur. This juvenile ALS, originally described in consanguineous families from Tunisia, was also discovered in families from Saudi Arabia and Kuwait. The phenotype of this disorder varies according to the family of origin; in the Tunisian family, it presents as a slowly progressive ALS-like disorder with mean age of onset at age 12 years; in the Kuwaiti family, the phenotype is similar to early-onset PLS. Sequence homology analysis of this protein suggests that it is a guanine-nucleotide exchange factor for Rab 5 and is thus important in intracellular cell signaling, endosomal dynamics, mitochondrial trafficking, and cytoskeleton organization. In contrast to the toxic gain-of-function theory of pathogenesis in ALS1, it appears that loss of function of the gene product is responsible for the selective injury to, and dysfunction of, the corticospinal tract in ALS2. Alternate splicing of the alsin gene results in both long and short transcripts. Frameshift and nonsense mutations cause an ALS phenotype when there is homozygous loss of both the short and long forms, whereas the PLS presentation occurs with homozygous loss of the long form alone. Missense mutations may cause an unstable protein product or lead to a protein product that is directly toxic to the cell via aberrant regulation of the apoptotic pathway. Certain mutations in the alsin gene also give rise to an infantile ascending hereditary spastic paraparesis, which demonstrates the link between ALS and related motor neuron diseases (Eymard-Pierre et al., 2006; Panzeri et al., 2006).

ALS3 describes a large European family with adult-onset autosomal dominant ALS linked to chromosome 18q21 (Hand et al., 2002). The gene for this disorder has not yet been identified. ALS4 is a juvenile-onset, slowly progressive, dominantly inherited distal amyotrophy with UMN signs but sparing bulbar features. It is caused by mutations in the senataxin gene (SETX) on chromosome 9q34, which has a DNA/RNA helicase domain suggesting a role in DNA repair and RNA processing. SETX has homology to IGHMBP2, the gene responsible for SMARD1, a rare form of SMA. Mutations in SETX also cause a recessively inherited disorder called oculomotor apraxia and cerebellar ataxia. A recent paper expanded the phenotype by describing a novel senataxin mutation presenting as a classical case of sporadic ALS (Zhao et al., 2009). ALS5 is a recessive juvenile ALS described in North African and European families. The clinical syndrome is similar to SALS except for a younger age at onset. It links to chromosome 15q15-q22, but the pathogenic gene is unidentified. ALS6 is an autosomal dominant ALS that can also be associated with frontotemporal dementia and hallucinations. Mutations on the FUS/TLS (fused in sarcoma/translocated in liposarcoma) gene on chromosome 16q12 have the pathological characteristic of FUS-immunoreactive skein-like cytoplasmic inclusion bodies. FUS is normally a nuclear protein, so this is yet another example of protein mislocalization in neurodegenerative disease. FUS mutations have a worldwide distribution and account for about 5% of FALS; they are also detectable in about 1% of SALS (Lai et al., 2010). Furthermore, it has recently been shown that FUS-immunoreactive cytoplasmic inclusions are common in both SALS and non-SOD1 FALS and are also immunoreactive to TDP 43 and ubiquitin (Deng et al., 2010). ALS7 is a rare, late-onset, autosomal dominant disorder linked to chromosome 20ptel. The cause for ALS8 is a mutation in a vesicle trafficking protein gene called VAPB (vesicle-associated membrane protein/synaptobrevin-associated membrane protein B) on chromosome 20q13.3. The clinical presentation displays quite marked heterogeneity: some patients develop a slowly progressive ALS-like picture with prominent tremor and onset between the ages of 31 and 45 years, whereas others present with a late-onset SMA or a severe, rapidly progressive ALS (Nishimura et al., 2004). ALS9 results from mutations on the angiogenin gene on chromosome 14q. This is an autosomal dominant disorder of adults (from the fourth to the eighth decade). Angiogenin may help protect motor neurons from excitotoxic- and hypoxia-induced injury, but it may also play an important role in RNA transcription as well as interact with cellular cytoskeletal proteins. ALS10, which accounts for 2% to 5% of FALS, is caused by mutations in the TDP43 gene on chromosome 1 and presents clinically as ALS with either limb or bulbar onset. Despite the association of TDP inclusions with some forms of FTD, cognitive deficits do not occur in TDP43 mutation–associated ALS. TDP43 immunoreactive ubiquitinated inclusions are present in degenerating neurons and glial cells just as they in sporadic ALS (Kuhnlein et al., 2008; Van Deerlin et al., 2008). The TDP43 gene product is a dual DNA/RNA binding protein mainly expressed in the nucleus and may play an important part in the regulation of RNA trafficking and translation. TDP43 can modulate human low-molecular-weight neurofilament messenger ribonucleic acid (mRNA) stability, which in turn underlies neurofilament aggregates, sometimes seen in ALS (Strong et al., 2006). TDP43 inclusion bodies are in fact seen in several disorders apart from ALS, including FTD, frontotemporal lobar degeneration with motor neuron degeneration, corticobasal degeneration, Guamanian ALS-PD complex, and hippocampal sclerosis. While this might suggest that TDP43 inclusion bodies are a nonspecific marker of neuronal injury or indeed representative of a physiological cell response to injury, the frequency of TDP43 mutations (30 to date) in both SALS and FALS suggests a pathogenic role.

ALS11 is due to mutations of the FIG4 gene on chromosome 6q21, which encodes a phosphoinositide 5-phosphatase, a regulator of a signaling lipid on the surface of endosomes. Mutations in this gene are known to cause a recessively inherited severe axonal sensorimotor form of Charcot-Marie-Tooth known as CMT4J, which is usually early onset (although one family presented with an adult disorder resembling ALS). FIG4 mutations can cause an ALS or PLS presentation, and additional personality changes were noted in two cases. Of the nine cases with FIG4 mutations, only three were FALS, the rest apparently being sporadic (Chow et al., 2009). Although not formally classified as a familial ALS (it has been described as a spinal and bulbar muscular atrophy), it is apparent that mutations in the p150Glued subunit of the dynactin gene may cause ALS-like presentations. Furthermore, a family history is not always evident (Munch et al., 2004). Dynactin 1 is a vital component of the dynein-dynactin motor complex and is important in retrograde axonal transport. Puls et al. have described a particular LMN disorder caused by a mutation in the p150Glued subunit of dynactin 1. The clinical phenotype is distinctive, with early bilateral vocal cord paralysis followed by prominent involvement of intrinsic hand muscles (especially those of the thenar eminence), the legs, and the face (Puls et al., 2005). The recent paper by Maruyama and colleagues described ALS in unrelated Japanese families caused by mutations in the OPTN gene for optineurin, a negative regulator of tumor necrosis factor alpha (TNF-α)–induced activation of NF-κB. OPTN may also play a role membrane trafficking, exocytosis, and maintenance of the Golgi apparatus. Mutations in this gene are known to cause primary open angle glaucoma. For patients presenting with ALS, the inheritance patterns were both autosomal recessive and autosomal dominant, with onset between the ages of 30 and 60 years and long disease duration. One case which came to autopsy showed optineurin-positive cytoplasmic inclusion bodies in anterior horn cells; the investigators also showed that TDP43- and SOD1-positive inclusions in SALS and SOD1 FALS were co-labeled with optineurin, suggesting a broader role for this protein in the pathogenesis of ALS (Maruyama et al., 2010).

Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex (Western Pacific Amyotrophic Lateral Sclerosis)

In 1954, Mulder and colleagues described an unusually high incidence of ALS in the adult native Chamorro population on the Western Pacific island of Guam. Soon afterwards, a related disorder of high incidence characterized by dementia and parkinsonism was also found in this population, with some patients displaying overlap features between ALS, parkinsonism, and dementia. A similar disorder was subsequently described in western New Guinea and the Kii peninsula of Japan, with an ALS incidence between 50 and 150 times higher than elsewhere. Clinically, about 5% of patients develop a predominantly ALS type of disorder, whereas 38% manifest principally with a combination of parkinsonism and dementia. The pathology of this unusual disorder bears similarities to that of Alzheimer disease, with prominent loss of CNS neurons and the presence of abundant tau-immunoreactive neurofibrillary tangles. However, the characteristic pathology of Guamanian ALS and PDC is by TDP43-positive inclusions in neurons and glial cells. α-Synuclein pathology also is detectable in the amygdala of affected brain tissue (Forman et al., 2002). Multiple members of a single family may be affected, and it has recently been shown that first-degree relatives of patients with ALS-PDC have a significantly higher risk of developing the disease than controls. Despite these observations and a genetic association study implicating the tau gene as a susceptibility gene for ALS-PDC, accumulated epidemiological evidence strongly suggests that an environmental factor rather than a genetic factor is more important in disease pathogenesis. Various environmental toxins have been implicated in the pathogenesis of ALS-PDC, chief among them being neurotoxins derived from the native cycad seed. This seed contains β-methylamino-l-alanine (BMAA), an amino acid that is toxic to cortical and spinal motor neurons and thought to be the product of cyanobacterial activity in the roots of the cycad palm. Cycad seed also contains a carcinogenic substance called cycasin that may act either alone or in concert with BMAA to damage motor neurons. Toxic sterol glucosides have also been isolated from washed cycad flour, and they can cause the release of glutamate (Khabazian et al., 2002). However, the role of cycad seeds in neurotoxicity is still subject to debate (Snyder et al., 2011). The cyanobacteria/BMAA hypothesis has wider implications for research in SALS worldwide. It has been recently shown that protein-bound BMAA is present in the brains of North American patients dying with ALS and Alzheimer disease and it has been hypothesized that such patients may be genetically susceptible to BMAA-induced neurodegeneration (Bradley and Mash, 2009). The cycad seed has many uses: in West Papua and Guam as a topical medicine for skin lesions and in Japan as an oral medicine (Spencer et al., 2005). Cox and Sacks (2002) proposed a process of biomagnification of cycad toxins in Guam through the Chamorro practice of eating flying foxes, which themselves feed on cycad seeds. The incidence of the Guamanian ALS variant has rapidly declined over the past several decades, a process thought to reflect the Westernization of the region. The decline in the incidence of ALS-PDC in Guam may reflect the dwindling flying fox population on Guam through a massive increase in commercial hunting using firearms introduced to the island in the decades following World War II. However, other social and dietary shifts have occurred in Guam that might be responsible for the decrease.

Spinocerebellar Ataxia Type 3 (Machado-Joseph disease)

Machado-Joseph disease is an autosomal dominant syndrome with onset varying from the third to seventh decade of life. Although cerebellar ataxia is the predominant clinical feature, patients often present with slowly progressive generalized spasticity, cramps, muscle wasting, and fasciculations of the face and tongue. Other characteristic findings include extrapyramidal signs such as dystonia and rigidity, protuberant eyes, and progressive external ophthalmoparesis. Affected patients have a twofold to threefold expansion of a CAG trinucleotide repeat on the ataxin-3 gene on chromosome 14q32.1. The expanded triplet repeat results in a mutant gene product containing an expanded polyglutamine tract. This appears to aggregate into intranuclear neuronal inclusion bodies and may interfere with the function of the cellular proteosome in degradation of proteins (Schmidt et al., 2002). The Machado-Joseph disease phenotype may also occur in SCA-2, with slowly progressive ataxia, eyelid retraction, and facial fasciculations. Patients often have slow saccades or ophthalmoparesis and may have reduced or absent deep tendon reflexes. The cause of SCA-2 is an expanded polyglutamine-encoding CAG triple repeat sequence on chromosome 12q.

Adult Hexosaminidase-A Deficiency

Adult Hex-A deficiency is an autosomal recessively inherited late-onset GM2 gangliosidosis (the other subtypes being infantile and juvenile). All three subtypes are caused by an abnormal accumulation of GM2 ganglioside in neurons due to a deficiency in the activity of the lysosomal enzyme. Hex-A is encoded by a gene on chromosome 15q23-q24 and normally degrades GM2 ganglioside. Only about 10% of Hex-A activity is required for normal health, but in the severe infantile form of this disorder, also known as Tay-Sachs disease, mutations in the α subunit of Hex-A result in complete deficiency of enzyme activity. Juveniles and adults with Hex-A deficiency, however, are compound heterozygotes with varying degrees of residual enzymatic activity and thus have a later-onset disorder with considerable variability in the phenotype. It is more common in males and those of Ashkenazi Jewish ancestry, but females and non-Jewish persons can also develop this disorder.

The adult form has a mean of onset of about 18 years and usually presents as slowly progressive weakness of predominantly proximal muscles of the upper and lower extremities (Neudorfer et al., 2005). In some patients, severe cramps may present in association with muscle weakness, mimicking SMA. In others, however, a combination of dysarthria, spasticity, and LMN signs may resemble ALS. Additional sensory, cerebellar, cognitive, psychiatric, and extrapyramidal features may later develop. The EDX may reveal prominent complex repetitive discharges and abnormal SNAPs. Generally, this constellation of symptoms and signs is not easily mistaken for ALS, but in the relatively early stages, patients with Hex-A deficiency may not manifest many features other than motor system dysfunction. Genetic counseling is important before assaying a patient’s serum or leukocytes for deficiency of Hex-A activity.

Allgrove Syndrome (Four-A Syndrome)

Four-A syndrome (Allgrove syndrome) is a very rare autosomal recessive disorder that derives its name from the combination of achalasia, alacrima, adrenocorticotrophic insufficiency, and amyotrophy. The AAAS gene is located on chromosome 12q13 and encodes a ubiquitous protein called aladin which heavily expresses in the neuroendocrine system and may be important in regulation of the cell cycle, cell signaling, intracellular transport, and the cell cytoskeleton. The syndrome can manifest from the first decade of life with dysphagia and adrenocortical insufficiency, but a wide a range of neurological problems can arise later in life, including cognitive deterioration, optic atrophy, seizures, autonomic disturbance (dry mouth, postural hypotension, and syncope), and bulbospinal amyotrophy (amyotrophy of limbs and tongue, with tongue fasciculations and pyramidal signs) (Kimber et al., 2003).

Autosomal Dominant Frontotemporal Dementia with Motor Neuron Disease

For more than half a century, various observers have pointed out that symptoms and signs of ALS and FTD appear to occur together in some families with increased frequency. One such disorder, disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), is an autosomal dominant FTD due to a mutation on the microtubule-associated protein tau gene on chromosome 17. This disorder, first described in a large Irish-American family (family Mo) in the United States, is characterized clinically by disinhibited behavior (including excessive eating and inappropriate sexual behavior), personality changes, dementia, parkinsonian manifestations, and in two cases, amyotrophy with fasciculations. Autopsy studies showed widespread neuronal loss in the substantia nigra, cerebral cortex, and anterior horn of the spinal cord, together with extensive spongy degeneration in the temporal and frontal lobes and tau-immunoreactive inclusion bodies in affected regions of the CNS (Lynch et al., 1994). In 2006, it was discovered that mutations in the progranulin gene, also on chromosome 17, can cause frontotemporal degeneration. Progranulin is a growth factor with important functions in inflammation, wound repair, tumorigenesis, and cell development. Most cases with this mutation develop a late-onset progressive disorder of personality, behavior, and especially language, without clinical features of motor neuron disease. However, TDP43-positive, tau-negative ubiquitinated inclusions are present in neurons and glial cells of affected individuals, thus linking this form of frontotemporal dementia to the pathology of ALS (Baker et al., 2006; Cruts et al., 2006; Gass et al., 2006; van Swieten and Heutink, 2008). Mutations in the TDP43 gene itself have been shown to be a rare cause of ALS, but cognitive impairment is not seen (Kuhnlein and Sperfeld, 2008; Van Deerlin et al., 2008).

Analysis of multiple pedigrees identified a locus for autosomal dominant ALS and FTD on chromosome 9q21-22. The mean age at disease onset in these families was about 54 years (range 40-62 years). Some patients developed symptoms and signs of ALS alone, but others also developed inappropriate behavior, impulsiveness, and eventually impaired memory. Both neuroimaging and pathological studies revealed frontotemporal atrophy, and histology identified gliosis, vacuoles, rare Pick bodies, and some neurofibrillary tangles and senile plaques (Hosler et al., 2000). Another familial ALS and FTD locus has been described on chromosome 9p13.2-21.3, but the cause of this disorder is unknown (Vance et al., 2006). Mutations in the p150 subunit of dynactin gene cause a LMN spinal and bulbar syndrome, but one of the mutations can cause either an autosomal dominant ALS or an FTD (Munch et al., 2005).

Adult Polyglucosan Body Disease

Polyglucosan body disease is a very rare, late-onset, slowly progressive disorder characterized by a combination of UMN and LMN signs, cognitive decline, distal sensory loss, and disturbances of bladder and bowel function. MRI of the brain may reveal diffuse white-matter signal increase on T2-weighted images. The diagnosis is clinched by the finding of characteristic pathological changes in tissue from peripheral nerve, cerebral cortex, spinal cord, or skin. Axons and neural sheath cells contain non-membrane-bound cytoplasmic periodic acid–Schiff-positive polyglucosan bodies. Ultrastructural examination shows that the inclusions consist of 6- to 8-nm branched filaments and are most abundant in myelinated nerve fibers. In Ashkenazi Jewish patients (and one reported non-Ashkenazi Jewish patient), the disorder was caused by mutations of the glycogen-branching enzyme (GBE) gene, with subsequent deficiency of the protein product. However, adult polyglucosan body disease (APBD) occurs in many different populations, and considerable molecular heterogeneity has been noted, with otherwise typical cases lacking GBE mutations despite deficiency of enzyme activity (Klein et al., 2004). The recent (albeit inadvertent) generation of muscle polyglucosan bodies in a transgenic mouse engineered to overexpress glycogen synthase in the presence of normal levels of glycogen-branching enzyme suggests that an imbalance in the activities of these two enzymes is the possible molecular mechanism underlying this unusual disorder (Raben et al., 2001). It is interesting to note that two types of polyglucosan body may be seen in ALS—Lafora bodies and corpora amylacea—although neither is considered a characteristic pathological feature.

Paraneoplastic Motor Neuron Disease

There is evidence that motor neuron disease may rarely be a paraneoplastic phenomenon, though the possibility that the ALS and the neoplasm are chance associations is still possible. Patients may present with features that are rather typical of pure “spinal” ALS or manifest in a manner akin either to PMA or to PLS. Other motor neuron manifestations may represent only one part of a larger paraneoplastic syndrome, such as anti-Hu antibody associated encephalomyelitis, with atypical features such as dysautonomia or ataxia. Unfortunately, most paraneoplastic motor disorders are unresponsive to treatment of the underlying tumor. Rare motor disorders have been described in association with other paraneoplastic antibodies, including anti-Yo antibody in a patient with ovarian carcinoma and a novel antineuronal antibody in a patient with breast cancer. A subacute painless and progressive LMN-predominant disorder has been well characterized in lymphoma (both Hodgkin and non-Hodgkin types, see earlier discussion). Patients may eventually develop UMN signs, and some may improve either with treatment of the cancer or spontaneously. Elevated CSF protein levels or the presence of a paraprotein in the blood should prompt a detailed investigation for lymphoma. Although there is insufficient evidence to conclude that there is increased risk of cancer in ALS, a combination of UMN and LMN signs has been well described in patients with breast, uterine, ovarian, and non–small-cell cancer. This ALS-like disorder is quite rapidly progressive and does not appear to respond either to treatment of the underlying cancer or to immune therapies. UMN signs and symptoms that mimic PLS may rarely occur in patients with breast tumors and may in fact precede the cancer diagnosis by a few months. In general, one should investigate for a paraneoplastic disorder if there are atypical features such as ataxia, sensory loss, and dysautonomia, and it would seem to be prudent to carry out breast screening on women with a PLS presentation.

Human Immunodeficiency Virus Type 1–Associated Motor Neuron Disorder

A retrospective review of 1700 cases of HIV-1-infected patients with neurological symptoms identified 6 cases presenting as a reversible ALS-like syndrome (Moulignier et al., 2001), representing a 27-fold increased risk of developing an ALS-like disorder in that particular HIV-1 patient population. Overall, patients were somewhat younger than the normal ALS population, all but one being younger than 40 years at the time of diagnosis. Onset was characteristically in a monomelic pattern followed by a very rapid spread to other regions over a period of weeks. There were clinical features of both UMN and LMN involvement, with fasciculations, cramps, and bulbar symptoms. Two patients also had rapidly progressive dementia, with other features suggesting an additional diagnosis of AIDS-dementia complex. Sensory and sphincter disturbances were not apparent. CSF protein levels were sometimes mildly increased, and a lymphocytic pleocytosis was evident in three patients, but all remaining laboratory results (HIV-1 seropositivity apart) were negative. EDX revealed a widespread disorder of anterior horn cells in the absence of demyelinating conduction block, and MRI in one patient showed diffuse white-matter signal increase suggestive of AIDS-dementia complex. In each case, antiretroviral therapy was beneficial either in stabilizing or (in two instances) curing the disease. No similar cases have been identified in this particular study population since the introduction of highly active antiretroviral combination chemotherapy in the management of HIV infection. Another case report found similar clinical features in a 32-year-old HIV-positive patient who also enjoyed a complete response to antiretroviral therapy. MRI of brain showed increased T2-weighted signal in the brachium pontis with some minimal contrast enhancement. The resolution of motor symptoms coincided with a lack of detectable HIV in plasma and CSF. In addition, the abnormal MRI signal almost completely resolved (MacGowan et al., 2001). Flail-arm ALS-like variants have also been described, with MRI signal changes in the anterior cervical spinal cord (Henning and Hewlett, 2008; Nalini et al., 2009). Other forms of HIV may also relate to the pathogenesis of motor neuron disease; a pure LMN syndrome occurred in a woman who was seropositive for HIV-2. Overall, there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have true sporadic ALS.