Differential Diagnosis in Neurology

Topic 3. Anterior Horn Cell Disease that Affects Adult Patients

3.3. Immune Mediated and Genetic Lower Motor Neuron Syndrome

  • Multifocal motor neuropathy with conduction block (MMN); less than 50% CMAP is required with specific conduction blocks
  • Differential diagnosis of low titer IgM anti GM1 antibodies (less than 1–400 μg/liter) is:
    • GBS
    • ALS
    • Sensorimotor neuropathy
    • CIDP
    • MG
    • SLE
    • Normal patients
  • High titers (greater than 1 to 6400 μg/dl) of GM1 antibodies have 80–90% specificity for clinical disease
  • High titers of IgG anti-GM1 antibodies are found in lower motor nerve syndromes and acute axonal neuropathy secondary to Campylobacter jejuni

Differential Diagnosis of Immune Mediated Motor Neuropathies

The major clue to this diagnosis is upper extremity asymmetric distal weakness with no sensory loss or upper motor neuron features. The onset may be rather sudden, but progression is insidious. The distal adult SMAs are autosomal dominant and are less asymmetric. Progressive muscular atrophy is proximal rather than distal, monomelic amyotrophia is primarily a disease of Indian and Japanese patients and affects the intrinsic muscles of the hand (more wasting) than immune processes. It is associated with MRI evidence of an atrophic lower cervical and upper thoracic spinal cord. Brachial amyotrophic diplegia affects proximal muscles more than distal and is symmetrical to a large degree. Hereditary sensory motor neuropathy Type II may involve individual upper extremity muscles, but these are usually proximal rather than distal. Distal myopathies that affect the upper extremity can be distinguished by genetic patterns, symmetry of upper extremity involvement, associated features (myotonia) and relative preservation of reflexes.

EMG establishes a neurogenic or myopathic process (hexosaminidase A deficiency in the former and glycogen storage disease type 6) in the latter. Muscle biopsy rules out specific forms of congenital myopathy and storage syndromes. Conduction block, significant titers of GM1 antibodies and other signs of demyelination secure the diagnosis of a demyelinating process.

  • Immune neuropathy is differentiated from early ALS on clinical grounds by:
    • Onset prior to age 35
    • An indolent course
    • Absence of significant wasting in the hand (ALS frequently involves the first dorsal interosseus and the 4th and 5th intrinsic hand muscles)
    • Non myotomal pattern of weakness
    • Absence of upper motor signs and no bulbar involvement

Other Immune Mediated Lower Motor Nerve Syndromes

  • General considerations:
    • Many of these patients have high titers of anti-GM1 antibodies
  • Clinical features:
    • Most have distal presentation
    • Patients with proximal presentation:
      • Later age of onset
      • Men > women
      • LMN atrophy of extremities that is static for 3–5 years
  • Laboratory evaluation:
    • High titers of IgM or IgG or asialo antibodies are present

Genetic Lower Motor Nerve Syndromes

  • Spinal muscular atrophies (chromosome 5q linked and non-linked)
  • Kennedy's syndrome (X-linked recessive bulbospinal neuropathy)
  • Monomelic amyotrophy
  • Brachial amyotrophic diplegia
  • Progressive muscular atrophy (ALS variant)
  • Progressive bulbar palsy (ALS variant)
  • Fazio–Londe Disease (ALS variant)

Multiple System Disorders with Anterior Horn Cell Involvement

  • Hereditary spastic paraparesis (HSP) (I-20) complicated and uncomplicated variants
  • Adult hexosaminidase A deficiency
  • Spinocerebellar degeneration:
    • OPCA variants
    • SCA III (Machado Joseph Disease)
      • AD
      • AR

Adult Polyglucosan Body Disease

  • General considerations:
    • Sporadic and familial cases; high proportion of patients are Ashkenazi Jews
    • In Jewish patients a mutation of the glycogen branching gene is noted but may have more than one basis as non-Jewish patients, have an identical phenotype without the mutation
    • Polyglucosan bodies are also seen in glycogenosis type IV and Lafora body disease
      • Noted in astrocytes, subpial and subependymal layer as well as the cerebellum and myelinated nerves; systemically in liver, heart, lung, smooth and skeletal muscle; loss of anterior horn cells
  • Clinical features:
    • Onset in the 5th or 6th decade
    • Sensory peripheral neuropathy
    • Abnormal gait
    • Dementia
    • Urinary incontinence
    • Corticospinal tract dysfunction
    • Severity of disease various amongst patients
    • All features are not present in every patient
    • Normal pressure hydrocephalus presentation without other upper or lower motor signs
    • An ALS presentation with only corticospinal and anterior horn cell signs
  • EMG evaluation:
    • Slowing of motor NCVs; low amplitude or absent SNAP's (sural nerve biopsy demonstrates intra-axonal polyglucosan bodies
  • MRI evaluation:
    • Periventricular and subcortical white matter abnormalities on T2 weighted images; no anterior or posterior predilection

Differential Diagnosis of Adult Polyglucosan Body Disease

Primary lateral sclerosis has severe spasticity affecting extremities and cranial nerves. ALS has no sensory loss and in 60% of patients no dementia. There are rarely bladder abnormalities with ALS. Severe demyelinating disease has optic atrophy, an intranuclear ophthalmoplegia and bilateral severe cerebellar ataxia. B12 deficiency has cranial nerve I abnormalities, a frontal lobe affect and active paresthesias in upper and lower extremities. Dorsal column dysfunction predominates the sensory symptoms. Metachromatic leukodystrophy at the age of presentation of APBD has more spasticity and intact u fibers on MRI. ALD is X-linked recessive, has a much earlier onset, and no peripheral neuropathy. Adrenomyeloneuropathy starts in middle age, there is no bladder symptomatology and mentation is much better preserved.

The difficult differential diagnosis to make is that of NPH. Prominent features in this entity not noted with APBD are falling backward and gait apraxia. Ventricular enlargement and the temporal horn out of proportion to the lateral ventricles with a mostly intact cortex are distinguishing features. Olivopontocerebellar degeneration, including retinal, dorsal column and brainstem variants have much more ataxia.

Rare MSA with Anterior Horn Cell Involvement

  • Hallervorden Spatz disease (PANK-2)
    • Akinetic rigid syndrome
    • "Eye of the tiger" in GPi by MRI
  • Guamanian–Parkinsonian – ALS (Lubag)
    • Severe dystonia (particularly of the mouth)
    • Lubag (Dystonia 7)
    • Dementia
    • X-linked
  • Huntington's disease
    • Choreoathetosis of body; choreatic eye movements
    • Dementia
    • Amyotrophy
  • Creutzfeldt–Jacob
    • Classic disease has prominent fasciculations
    • Speed of the dementing process plus the myoclonus makes the diagnosis
  • Alzheimer's variant
    • Spastic paraparesis
    • Anterior horn cell involvement
  • Pick's disease
    • Broca's aphasia in a patient with otherwise ALZ phenotype
  • HSP
    • Spasticity and lower motor neuron features
  • Shy Drager
    • Akinetic rigid dementing illness
    • Autonomic dysregulation is seminal feature
    • Some amyotrophy

Paraneoplastic Motor Neuron Disease

  • General considerations:
    • Occurs with multiple cancers; most often small cell carcinoma of the lung
    • Rarely removal of the tumor stabilizes the MND; most often there is no change
    • Antigenic overlap between tumor cells and motor neurons ( molecular mimicry)
    • MND occurs with other well established paraneoplastic syndromes

Antibodies Associated with MND

  • Anti-Hu with small cell lung cancer; antinuclear neuronal antibody1; ANNA1
  • MND may be associated with encephalomyelitis; dorsal root ganglionitis and large fiber sensory neuropathy
  • The motor neuron disease may precede the cancer by 4–10 months
  • In general, both removal of the tumor and immune treatment fail to reverse the neurological signs and symptoms

Hodgkin's and Non-Hodgkin's Lymphoma

  • Subacute painless lower motor neuron syndrome
  • Rare sensory symptoms
  • Anti-MA antibodies
  • Variable progression
  • Upper motor neuron symptoms develop over time similar to ALS

ALS Like Syndrome from Multiple Cancers

  • Hodgkin's lymphoma, breast, uterine, ovarian, non-small cell lung cancer
  • Both upper and lower motor neuron symptoms and signs
  • LMN > UMN manifestations
  • Neurologic symptoms may precede or follow the diagnosis

Primary Lateral Sclerosis Syndrome with Breast Cancer

  • Neurologic manifestations occur prior to the diagnosis
  • Slowly progressive course
  • Upper motor neuron signs are usually first which then evolve into a lower motor neuron syndrome

Specific Antibodies Identified with Motor Neuron Syndromes

  • Anti-Yo-cerebellar degeneration, primarily Purkinje cell; few patients with MND
  • Anti-Hu-limbic encephalitis, dorsal root ganglionitis, rarely MND
  • M proteins with lymphoproliferative disease
  • GDlb with thyroid adenoma; most often this is correlated with Campylobacter jejuni and CM Fisher syndrome or motor axonopathy
  • Breast cancer patients may have a motor axonopathy and antibodies to nodes of Ranvier; anti-Ri antibodies
  • Testicular-anti Ta antibodies
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