What conditions can mimic motor neuron disease (amyotrophic lateral sclerosis) and how should they be evaluated?

Conditions That Mimic Motor Neuron Disease

When evaluating suspected motor neuron disease, you must systematically exclude structural spinal lesions (especially cervical myelopathy), multifocal motor neuropathy, Kennedy's disease, metabolic disorders (thyroid/parathyroid), and immune-mediated conditions before confirming the diagnosis, as these mimics are treatable and have fundamentally different prognoses.

Critical Structural Mimics

Cervical spondylotic myelopathy is the most important structural mimic because it can present with both upper and lower motor neuron signs and requires surgical intervention rather than ALS management 1, 2. The key distinguishing features include:

• Sensory involvement (pain, paresthesias, proprioceptive loss) strongly suggests myelopathy rather than ALS, as motor neuron disease spares sensory pathways 3
• MRI cervical spine without contrast is essential to exclude compressive myelopathy, syrinx, or intramedullary tumors that can mimic ALS 1
• Cervical myelopathy and ALS can rarely coexist in the same patient, making diagnosis particularly challenging when postoperative improvement plateaus or reverses 2

Spinal cord lesions including syringomyelia, intramedullary tumors, and radiation myelopathy must be excluded with spine MRI, as they can produce progressive weakness with mixed motor neuron signs 1, 4.

Treatable Peripheral Nerve Mimics

Multifocal motor neuropathy (MMN) is the most critical peripheral mimic because it responds to immunotherapy and has a benign prognosis compared to ALS 5, 4. Distinguishing features include:

• Asymmetric, patchy weakness without upper motor neuron signs (no spasticity, hyperreflexia, or Babinski signs) 5, 4
• Anti-GM1 ganglioside antibodies are present in 30-80% of cases 6, 4
• Nerve conduction studies show conduction block, which is absent in ALS 4
• EMG demonstrates denervation in a non-myotomal distribution 4

Kennedy's disease (X-linked bulbospinal muscular atrophy) presents with slowly progressive lower motor neuron weakness, bulbar symptoms, and characteristic features 5, 4:

• Gynecomastia and testicular atrophy due to androgen receptor dysfunction 4
• Perioral fasciculations and tremor are prominent 4
• Genetic testing for CAG repeat expansion in the androgen receptor gene confirms diagnosis 4
• Much slower progression than ALS with near-normal life expectancy 5, 4

Metabolic and Endocrine Mimics

Hyperthyroidism and hyperparathyroidism can produce progressive weakness with hyperreflexia mimicking motor neuron disease 4. Essential screening includes:

• Thyroid function tests (TSH, free T4) to exclude thyrotoxicosis 6, 7, 4
• Serum calcium and parathyroid hormone to exclude hyperparathyroidism 4
• Vitamin B12, folate, and vitamin E levels as deficiencies can cause motor symptoms 6

Post-Infectious and Post-Radiation Syndromes

Post-polio syndrome develops decades after acute poliomyelitis with new weakness, fatigue, and muscle atrophy 5, 4. Key features:

• History of prior polio infection (often in childhood) 5, 4
• Stable period of 15+ years before new symptoms emerge 4
• Extremely slow progression compared to ALS 5

Radiation-induced myelopathy can occur months to years after spinal radiation therapy, producing progressive motor weakness 4. MRI spine shows T2 hyperintensity at the radiation site 4.

Immune-Mediated Mimics

Myasthenia gravis can mimic bulbar-onset ALS but shows 6:

• Fatigable weakness that worsens with repetitive activity 6
• Positive anti-acetylcholine receptor or anti-MuSK antibodies 6
• Decremental response on repetitive nerve stimulation 6

Paraneoplastic syndromes can produce motor neuron-like syndromes, requiring 6:

• Paraneoplastic antibody panel (anti-Hu, anti-Yo, anti-Ri) 6
• Age-appropriate cancer screening if antibodies positive 6

Systematic Diagnostic Approach

Initial Imaging Strategy

MRI brain without contrast is the first-line imaging study to exclude ALS mimics 1, 3, 7:

• T2/FLAIR sequences assess for corticospinal tract hyperintensity in the posterior limb of internal capsule and cerebral peduncles (supports ALS) 1, 3
• T2/susceptibility-weighted imaging* detects precentral gyrus hypointensity (86% sensitive, highly specific for ALS) 1
• Excludes demyelinating disease, structural lesions, and vascular pathology 1

MRI cervical and thoracic spine without contrast should be obtained when 1, 3, 7:

• Sensory symptoms are present 3
• Neck pain or radicular symptoms exist 2
• Upper extremity weakness predominates 2
• "Snake eyes" sign (bilateral anterior horn T2 hyperintensity) may appear late in ALS but is nonspecific 3, 7

Electrodiagnostic Testing

EMG and nerve conduction studies are mandatory to confirm lower motor neuron involvement and exclude mimics 3, 6, 7, 5:

• EMG findings in ALS: fibrillation potentials, positive sharp waves, fasciculations in multiple myotomes across multiple limbs 7
• Nerve conduction studies in ALS: normal or low CMAP amplitudes with preserved conduction velocities (no conduction block) 7, 4
• Conduction block on NCS indicates MMN, not ALS 4

Laboratory Evaluation

A comprehensive metabolic and immunologic workup excludes treatable mimics 6, 7:

• Complete blood count for infectious/inflammatory conditions 6
• Comprehensive metabolic panel (glucose, electrolytes, renal/hepatic function) 6
• Creatine kinase (mildly elevated in ALS, markedly elevated suggests myopathy) 7
• Thyroid function tests (TSH, free T4) 6, 7
• Vitamin B12, folate, vitamin E levels 6
• Serum protein electrophoresis for paraproteinemic neuropathy 6
• Anti-ganglioside antibodies (especially anti-GM1 for MMN) 6
• Anti-acetylcholine receptor and anti-MuSK antibodies for myasthenia gravis 6
• Paraneoplastic antibody panel if atypical features present 6

Genetic Testing

Genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP) should be considered when 3, 6:

• Family history of ALS or frontotemporal dementia exists 3, 6
• Age of onset is unusually young (<40 years) 3
• Atypical clinical features are present 3

Kennedy's disease genetic testing (androgen receptor CAG repeats) when lower motor neuron disease occurs in males with gynecomastia or family history 4.

Red Flags Against ALS Diagnosis

The following features should prompt reconsideration of the diagnosis 3, 5, 4:

• Prominent sensory symptoms (pain, numbness, proprioceptive loss) 3
• Oculomotor involvement (diplopia, ophthalmoplegia) - extraocular muscles are typically spared in ALS 5
• Bladder/bowel dysfunction early in disease 5
• Asymmetric, patchy weakness in non-anatomic distribution suggests MMN 4
• Very slow progression over many years suggests Kennedy's disease or post-polio syndrome 5, 4
• Improvement with treatment excludes ALS 4

Common Diagnostic Pitfalls

Cervical myelopathy coexisting with ALS is rare but documented, requiring high vigilance when surgical decompression fails to produce expected improvement 2. If neurological deterioration continues despite adequate decompression on repeat MRI, perform EMG to assess for concurrent motor neuron disease 2.

Pure lower motor neuron presentations (progressive muscular atrophy) may eventually develop upper motor neuron signs, but if they remain isolated for years, consider Kennedy's disease, MMN, or post-polio syndrome instead 5, 8.

Bulbar-onset weakness can mimic myasthenia gravis, especially when fatigue is prominent - always check acetylcholine receptor antibodies and perform repetitive nerve stimulation before confirming ALS 6.