DDx: See charts below for dzs affecting UMN, LMN, & both. Chronic motor peripheral neuropathies, Charcot-Marie-Tooth dz, cervical spondylosis or disc dz/cervical spine pathology, muscular dystrophies, myasthenia gravis, myopathies such as polymyositis, inclusion body myositis, pseudobulbar palsy secondary to vascular dz, chronic Lyme dz, spinal muscular atrophies, multifocal motor neuropathy w/conduction block.

Workup: Labs (chem 10, CBC, coags, CK, Lyme, ESR, CRP, HIV, SPEP, UPEP, IFE, B₁₂, TSH); EMG/NCS; MRI brain or spine depending on clinical history & distribution of sx; consider CT chest/abdomen/pelvis or PET scan to evaluate for malignancy; genetic testing, depending on clinical history. Send anti-GM1 antibody if lower motor neuron predominant, evidence of conduction slowing.

Rx: For many of these illnesses, no Rx to slow progression of dz. For amyotrophic lateral sclerosis (ALS), riluzole shown to prolong survival by months, & dextromethorphan/quinidine (Nuedexta) approved for emotional lability (see below in “Amyotrophic lateral sclerosis” section for details). Supportive care: PT, OT, speech
therapy, walking assist devices, walking aids (cane, walker, or wheelchair), braces, early nutritional support (PEG), trach (if pt wishes), genetic counseling in appropriate cases, support groups. Agents for spasticity, medications to reduce drooling. Important to diagnose or exclude dzs w/available Rx.

Clinical features: 2%-4% cases of ALS; onset typically in 50s. Gradual spastic paraparesis spreading to UE, weakness, & unstable gait; may cause pseudobulbar affect, urinary urgency, subtle cognitive deficits. Tends to have slower progression (if it doesn’t progress to ALS), dz duration average >7 yr.

Dx/Rx: Dx of exclusion; pure PLS defined by isolated UMN si/sx >4 yr (Neurology 2006;66:647). Exclude other causes of UMN sx: Chiari malformation, spinal cord lesions, myelopathies such as MS, HTLV, HIV, Lyme, syphilis, or adrenomyeloneuropathy. Family history to r/o HSP, spinocerebellar ataxia (SCA), familial ALS (FALS), hexosaminidase A, adrenomyeloneuropathy. Supportive Rx, no proven benefit from riluzole (in contrast to ALS; see below).

Clinical features: HTLV-1 rarely may cause tropical spastic paraparesis in Caribbean or HTLV-1-associated myelopathy in Japan. HTLV-2: Similar to HTLV-1, may also cause myelopathy. Chronic, slowly progressive myelopathy beginning after age 30. Spastic paraparesis, paresthesias, painful sensory neuropathy, bladder dysfunction.

Dx/Rx: HTLV-1 & HTLV-2 serology in blood & CSF. Combination of PCR, HTLV-1 antibody, & oligoclonal bands (Lancet 2006;5:1068). Supportive Rx.

Clinical features: Clinically & genetically diverse disorder, which can be AD, AR, or X-linked. Progressive spasticity of LE. Complicated form may also exhibit optic neuropathy, deafness, ataxia, ichthyosis, amyotrophy, peripheral neuropathy, dementia, autoimmune hemolytic anemia, thrombocytopenia (Evan syndrome), extrapyramidal dysfunction, mental retardation, bladder dysfunction.

Dx/Rx: Family history; if no family history, then differential dx is same as PLS. 40% AD cases w/mutation in spastin on 2p22-21 (Arch Neurol 2009;66:509). Supportive Rx, especially baclofen, tizanidine, oxybutynin for urinary symptoms.

Clinical features: X-linked recessive mutation in ABCD1 gene on Xq28 → very long chain fatty acid (VLCFA) accumulation; most common phenotype affects young boys 4-8 yr of age. Adrenal insufficiency, progressive cognitive decline, seizures, blindness, deafness, & spastic quadriparesis. Milder cases: Slowly progressive spastic paraparesis & mild polyneuropathy in adult men w/or w/o sensory disturbances.

Dx: Family history. EMG/NCS: Primarily axonal sensorimotor polyneuropathy w/lesser component of demyelination. Increased VLCFA levels in plasma, RBCs, or cultured skin fibroblasts. Sural nerve biopsy: Loss of both myelinated & unmyelinated axons w/onion bulb formation. EM: Lamellar inclusions in cytoplasm of Schwann cells (J Neuropathol Exp Neurol 1995;54:740).