The view of amyotrophic lateral sclerosis (ALS) has changed drastically over the past decade. Originally considered a pure motor neuron disorder (MND), ALS is now viewed as a heterogeneous disorder with regard to site of onset, rate of progression, etiologic cause and pathogenesis. Survival in ALS has significantly improved due to multidisciplinary care, in large part, with earlier recognition and treatment.
The estimated incidence of sporadic ALS is 4 to 6 per 100,000, with a male-to-female ratio of 1.5:1, and combined average age at onset of 56 years, with fewer patients presenting before age 40 years. The duration of disease varies from 3 to 5 years, but rare patients survive decades and others expire shortly after diagnosis.
The World Federation of Neurology El Escorial Conference provide a useful clinical benchmark for the diagnosis and classification of ALS. For classification purposes, lower motor neuron (LMN) signs (weakness, wasting and fasciculation) combine with upper motor neuron (UMN) (overactive deep tendon reflexes, spasticity, clonus, Hoffmann, Babinski) signs collectively indicate a likely case. However, it should be stated that an unequivocal diagnosis can only be established with certainty at postmortem examination.
Genetic factors are implicated in about 10% of cases termed familial ALS (FALS). Several mutated genes including those in the copper/zinc superoxide dismutase (Cu/ZnSOD) gene located on chromosome 21 displays autosomal dominant (AD) inheritance and similar age at onset and clinical course in successive generations. AD-FALS and frontotemporal dementia (FTD/ALS) are linked to a heterozygous expanded hexanucleotide repeat (GGGGCC) located at the 9p21.2 locus, between the noncoding exons 1a and 1b of the C9ORF72 gene. Three pathogenic mutations notably lead to AD-FALS. One missense mutation occurs at the 1p36.22 locus of the TARDBP gene encoding the 43kd TAR DNA binding protein, originally identified as a transcriptional repressor binding to TAR-DNA of human immunodeficiency virus type-1 (HIV-1). A second missense mutation occurs at the 16p11.2 locus of the FUS gene in FALS with or without FTD, encoding the FUS protein involved in the regulation of transcription and RNA splicing and transport with functional homology to TARDBP. A third mutation found in dominantly inherited X-linked ALS and ALS/dementia maps to the Xp11.21 locus of the UBQLN2 gene encoding the ubiquitin-like protein ubiquitin 2, associated with abnormal protein degradation, aggregation, and CNS neurodegeneration. The gene most commonly associated with an increased susceptibility to sporadic ALS is ATXN2 which mapped to the 12q24 locus in association with an expanded CAG tri-nucleotide repeat.
The evaluation of patients suspected of ALS starts with screening autoimmune, metabolic, and infectious serology. Examination of cerebrospinal fluid (CSF), while not ordinarily necessary, is warranted in patients with atypical findings such as diminished tendon reflexes, sensory involvement, or other laboratory indices pointing to a systemic inflammatory or paraneoplastic process. Skeletal muscle biopsy of an involved limb region confirms the presence of neurogenic denervation of that region. Magnetic resonance imaging of the brain and spinal cord are indispensable in excluding a lesion in the brain or spinal cord.
The relation of ALS to Lyme disease has been a subject of debate. In favor of a relationship between the two disorders is the improvement with treatment for Lyme, and increased frequency of positive serologic testing for Lyme disease in many so studied indicating prior exposure. In 56 patients with MND from a highly endemic area for Lyme disease at Stony Brook University, almost one-half of patients tested positive for Lyme compared to 11% without MND. However a study by investigators at Massachusetts General Hospital noted that <1% cases of ALS cases tested positive by screening Lyme serology. Most authorities agree that it would be appropriate to consider Lyme disease in patients with atypical presentations of ALS, particularly those accompanied by rash, headache, stiff neck, fever, reversible facial nerve palsy, pain and sensory loss, especially those who reside in Lyme-endemic areas. Compelling arguments can be proposed for two other relatively uncommon disorders that may coexist with Lyme disease without true causality including Parkinson disease and multiple sclerosis.
A role for immune-mediated mechanisms in human ALS and transgenic SOD1 mice is suggested by the observation of increased microglial activation, CD8+ and CD4+ T-cells inflammation, and brain microglia that potentiate inflammatory responses. Regulatory T-cells are increased during the early phase of an ALS mouse model. Injury and stress induced by the presence of misfolded mutant SOD1 leads to release of reactive oxygen species and pro-inflammatory CNS cytokines with further motor neuron stress, culminating in a self-propagating cycle of injury and cell death. Immunosuppressive therapy is rarely if ever employed empirically in a given patient in the absence of disease-evident autoimmunity. The salutary benefit of immune-modulatory therapy may be considered in selected patients who demonstrate evidence of concomitant peripheral demyelinating neuropathy or vasculitis.