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A. Summary of Characteristic Symptoms and Signsnavigator

CharacteristicsMyopathyPeripheral Neuropathy
DistributionProximal/SymmetricalDistal
StrengthWeakImpaired
ReflexesUsually PreservedLost Early
SensationIntactImpaired
CPK (Serum)High (most)Normal
EMGMyopathicFasciculations,Sharps,Giants
Nerve ConductionNormalDecreased Speed and Amplitude
BiopsyMyopathicAtrophy

B. Overview of Peripheral Neuropathy navigator
  1. Demyelinating
    1. Acute - Guillain Barre Syndrome (GBS)
    2. Chronic - chronic inflammatory demyelinating polyneuropathy (CIDP)
    3. Hereditary
  2. Focal Neuropathy
    1. Carpal Tunnel Syndrome
    2. Ulnar Nerve Palsy (cubital tunnel syndrome)
    3. Brachial Plexus Lesions
    4. Mononeuritis Multiplex (see below)
    5. Radial (Spiral) Nerve Syndrome
    6. Tarsel Tunnel Syndrome
    7. Multifocal Motor Neuropathy (see below)
  3. CNS Disease may cause focal deficits [2]
    1. Multiple sclerosis
    2. Sarcoidosis
    3. Vasculitis
    4. Syringomyelia
  4. Radiculopathy
    1. Cervical
    2. Lumbar
  5. Generalized [15]
    1. Diabetic Neuropathy
    2. Vitamin B12 Deficiency
    3. Toxin Neuropathy - heavy metal poisoning, chemotherapy, thalidomide, others
    4. Idiopathic small fiber neuropathy
    5. Tick Paralysis
    6. Multiple myeloma and other monoclonal gammopathies
    7. Amyloidosis - primary and familial
    8. Sjogren's syndrome (sicca complex)
    9. Vasculitis
    10. HIV infection
    11. Rare hereditary neuropathies (see below)
    12. Critically ill patients, particularly on mechanical ventilation [14]
  6. Infections
    1. Poliomyelitis
    2. Leprosy
    3. Varicella Zoster
    4. Bell's Palsy
  7. Classification of Autoimmune Neuropathies [9]
    1. GBS, CIDP, multifocal motor neuropathy, paraproteinemic demyelinating neuropathies
    2. Neuromuscular junction defects (see below)
    3. Inflammatory myopathies: dermatomyositis, polymyositis, inclusion body myositis
    4. CNS Disorders: multiple sclerosis, stiff person syndrome
  8. Motor Neuron Disease (neuronopathy) [13]
    1. ALS
    2. Motor and sensory neuropathies
    3. Hereditary spinal muscular atrophy
    4. Familial ALS and ALS variants
    5. Spinal and Bulbar Muscular Atrophy
    6. Hereditary spastic paraplegia
    7. Postpolio Syndrome [1]

C. Miscellaneous Neuropathiesnavigator

  1. Mononeuritis Multiplex [16]
    1. Vascular, infectious (including HIV), paraproteinemia most common etiologies
    2. Vasculitides - including polyarteritis nodosum
    3. Cholesterol Emboli Syndrome
  2. Multifocal Motor Neuropathy [9]
    1. Slowly progressive, asymmetric, primarily distal weakness
    2. Weakness usually prominent in forearms
    3. Progression eventually to muscular atrophy
    4. Persistent motor conduction blocks with normal sensory nerve function
    5. Some patients have anti-GM1 antibodies (unclear role in pathogenesis)
    6. Does not respond to glucocorticoids (may worsen disease)
    7. Clear response to 0.4gm/kg daily intravenous immunoglobulin (IVIg) for 5 days [1]

D. Hereditary Motor and Senory Neuropathies (HMSN) navigator

  1. HMSN Types I through IV well described
  2. Peroneal Muscular Atrophy (HMSN I) / Charcot-Marie-Tooth Disease []
    1. Types 1-3 (autosomal dominant), Type 4 (autosomal recessive), and Type X (X linked)
    2. Type 1A most common form, linked to chromosome (chr) 17p11.2-12
    3. Type 1A due to mutations in peripheral myelin protein 22 (PMP22) gene [3]
    4. Mutations in genes (chr) type 1B (MPZ, chr 1q22), type 1C (LITAF, chr 16p13), type 1D (EGR2, chr 10q21)
    5. Mutations in type 2A (KIF1B or MFN2), type 2B (RAB7), type 2C (unkown), type 2D (GAR5), type 2E (NEFL), type 2F (HSPB1) [4]
    6. Mutations in type 3A (PMP22), type 3B (MPZ), type 3C (EGR2)
    7. Mutations in type 4A (GDAP1), type 4B (MTMR2 or MTMR13), type 4C (unknown), type 4D (NDRG1), type 4E (EGR2), type 4F (PRX)
    8. X-linked: gap junction protein connexin-32 (GJB1) mutations at chr Xq13.1
    9. Usually childhood onset with symptoms of axonal, demyelination, or both
    10. Gait problems, anterior and peroneal muscle atrophy; late hand involvement
    11. Slow nerve conduction velocities (NCV) in most types of HMSN I
    12. Axons have demyelination with remyelination
  3. Peroneal Muscular Atrophy, Neuronal Form (HMSN II)
    1. Autosomal Dominant
    2. Onset late childhood
    3. Little demyelination / remyelination of axons
    4. Near normal NCV
    5. Symptoms similar to HMSN I but delayed onset
  4. Dejerine-Sottas Disease (HMSN III)
    1. Autosomal Recessive
    2. Severe disruption of myelin
    3. Symptoms onset in infancy with delayed motor development
    4. Small stature and skeletal deformities
    5. Marked sensory loss
    6. Deafness
    7. Much reduced NCV
  5. Refsum Disease (HMSN IV)
    1. Autosomal Recessive
    2. Onset age 4-20
    3. Abnormal gait and sensory deficits
    4. Waxing and waning strength
    5. Progressive deafness
    6. Cardiomyopathy
    7. Retinitis pigmentosa
    8. Ichthyosis
    9. Slow NCV

E. Hereditary Motor Neuron Diseases [13]navigator

  1. Spinal Muscular Atrophy (SMA) - Types 1-4, and distal forms [20]
    1. Types 1-4 due to abnormalities in SMA1 gene on chr 5q11.2-13.3
    2. SMA1 protein found in cytoplasm and nucleus in all somatic tissues
    3. Particularly high levels of SMA1 in motor neurons of spinal cord
    4. SMA1 protein in nucleus associated with coiled (Cajal ) bodies, called gems
    5. SMA1 is required for proper assembly of spliceosomes along with Smith class proteins
    6. SMA1 mutations to reduced numbers of gems and abnormal spliceosomes
  2. SMA Type 1 (Werdnig-Hoffmann Disease; Severe)
    1. Inheritance: autosomal recessive
    2. Lower motor neuron signs prominent
    3. Linkage: chr 5q11.2-13.3, survival motor neuron 1 (SMA1) gene deletion or conversion
    4. Onset: birth to 6 months; death before age 2 years
    5. >50% of cases of SMA
  3. SMA Type 2 (Intermediate)
    1. Inheritance: autosomal recessive
    2. Lower motor neuron signs prominent
    3. Linkage: chr 5q11.2-13.3, survival motor neuron 1 (SMA1) gene
    4. Onset: 7-18 months; children cannot stand; death by adolescence (often respiratory failure)
  4. SMA Type 3 (Wohlfart-Kugelberg-Welander Disease)
    1. Inheritance: autosomal recessive or dominant
    2. Lower motor neuron signs prominent
    3. Linkage: chr 5q11.2-13.3, survival motor neuron 1 (SMA1) gene abnormality
    4. Onset: childhood to adolescence, course varies, often mild
  5. SMA Type 4 (Adult Onset)
    1. Inheritance: autosomal recessive or dominant
    2. Lower motor neuron signs prominent but very heterogeneous symptoms
    3. Linkage: 5q11.2-13.3, survival motor neuron protein
    4. Onset: >25 years, mild course
  6. Distal Spinal Muscular Atrophy
    1. Neuronal form of Charcot-Marie-Tooth Disease (see above)
    2. Inheritance: autosomal recessive or dominant
    3. Lower motor neuron signs prominent
    4. Linkage: 5q11.2-13.3, survival motor neuron protein
    5. Onset: adolescence
    6. Distal weakness with normal nerve conduction velocities
  7. Spinal and Bulbar Muscular Atrophy [7]
    1. Kennedy's Disease
    2. X-linked disorder with onset in adolescence or later
    3. Linked to Xq21-22, androgen receptor gene
    4. Increased numbers of CAG repeats in androgen receptor gene
    5. Affected patients have symptoms of pure lower motor neuron loss
    6. Fasciculations prominent, often with gynecomastia; slow progression
    7. Likely due to affects of androgens on neurons rich in androgen receptors
  8. Familial ALS
    1. Inheritance of adult forms: autosomal dominant or X-linked
    2. Inheritance of juvenille forms: autosomal recessive or dominant
    3. Both upper and lower motor neuron signs prominent
    4. Variety of linkages, mainly unknown genes
    5. Adult autosomal dominant ALS alone linked to chrom 21q22.1, superoxide dismutase
    6. ALS with parkinsonism and dementia linked to tau mutations chrom 17q21
    7. Onset: adult form >40 years in most cases
  9. Hereditary Spastic Paraplegia
    1. Inheritance: autosomal dominant or recessive, X-linked
    2. Upper motor neuron signs prominent
    3. Linkage: >15 loci including paraplegin, cellular adhesion molecule, spastin
    4. Onset: spastic paraparesis
  10. Hereditary Neuropathy Associated with Biochemical Abnormalities
    1. Acute intermittant porphyria
    2. Krabbe's Disease
    3. Leukodystrophy (various types)
    4. Fabry's Disease (alpha-galactosidase A deficiency)
    5. Tangier Disease (a-lipoprotein deficiency)
    6. Abetalipoproteinemia (Bassen-Kornzweig Disease)

F. Overview of Muscle Diseases [17,18] navigator

  1. Inflammatory
    1. Polymyositis
    2. Dermatomyositis
    3. Juvenile Myositis Forms
    4. Inclusion Body
    5. Myositis associated with neoplasm
    6. Overlap syndromes: lupus, scleroderma, rheumatoid arthritis, Sjogren Syndrome
  2. Endocrine / Metabolic
    1. Thyroid disorders
    2. Cushing's Syndrome
    3. Hypokalemia
    4. Hypophosphatemia
    5. Disorders of carbohydrate, lipid or purine metabolism
  3. Drugs
    1. Alcoholism - usually severe
    2. Drug Abuse: cocaine, heroin
    3. Pharmaceuticals: statins, niacin, glucocorticoids, colchicine, chemotherapy, zidovudine
  4. Toxins
    1. Botulism
    2. Tetanus
    3. Shellfish (Siguatoxin)
    4. Pufferfish
    5. Other natural toxins and venoms
  5. Active Infections
    1. Viral: influenza, parainfluenza, coxackievirus, HIV, CMV, echovirus, adenovirus, EBV
    2. Bacterial: pyomyositis (mainly streptococcal, staphylococcal, mixed infections)
    3. Parasitic: trichinosis, toxoplasmosis
  6. Rhabdomyolysis
    1. Crush injury
    2. Hyperthermia
    3. Prolonged seizures
    4. Drugs (listed above)
  7. Hereditary
    1. Muscular Dystrophies
    2. Hypertrophic Peroneal Muscular Atrophy (HMSN I), Charcot-Marie-Tooth Disease
    3. Serum cholinesterase deficiency
    4. Hereditary Myotonias

G. Diseases of the Neuromuscular Junctionnavigator

  1. Myasthenia gravis (post-synaptic)
  2. Eaton-Lambert Syndrome (presynaptic)
  3. Botulism (presynaptic)
  4. Electrolyte Abnormalities: hypocalcemia, hypermagnesemia (presynaptic)
  5. Snake bite (presynaptic)
  6. Nerve gases - irreversible cholinesterase inhibitors
  7. Tick Paralysis

H. Tick Paralysis [11]navigator

  1. Caused by a neurotoxin secreted by ticks
  2. Neurotoxin Effects
    1. Reduces nerve conduction velocity
    2. Inhibits terminal-nerve conduction and acetylcholine release (presynaptic junctions)
    3. Causes total blockade of transmission at myoneural junctions
  3. Dermacentor and Amblyomma ticks cause disease in Northwest and South
  4. Much more common in children with ticks
  5. Adults appear less susceptible to neurotoxin and are heavier
  6. Can cause severe, permanent ascending paralysis
  7. However, if tick is removed early in disease course, complete recovery is possible
  8. Differential diagnosis includes variety of paralytic syndromes
    1. GBS
    2. Acute spinal cord lesion
    3. Cerebellar ataxia
    4. Poliomyelitis
    5. Botulism
    6. Myasthenia gravis
    7. Electrolyte disorder
    8. Periodic paralysis
    9. Diphtheria
    10. Heavy metal intoxication
    11. Insecticide poisoning
    12. Porphyria
    13. Glue sniffing / solvent inhalation
    14. Hysterical paralysis

I. Muscle and Nerve Conduction Studiesnavigator

  1. EMG (Electromyography)
    1. Spontaneous muscle activity
    2. Morphology of voluntary motor unit activity
    3. Recruitment of new motor units with exertion
    4. Single Fiber EMG
  2. Nerve Conduction
    1. Sensory - conduction in both directions. Antidromic larger than orthodromic
    2. Motor
    3. Repetitive nerve stimulation
  3. Motor Unit Studies [6]
    1. Normal duration <10ms, Amplitude <5mV (single motor units)
    2. Normal velocity ~50meters/second (nerve conduction velocity)
    3. Frequency: 50-60 Hz
    4. Normally there is no spontaneous activity
  4. Neuropathic Disease
    1. Abnormal spontaneous activity occurs: fibrillations and sharp waves
    2. Fibrillations represent spontaneous contractions of single muscle fibrils
    3. Fibrillations require 2-3 weeks to appear
    4. Spontaneous activity seen in disorders of:
    5. Failed conection with motor neurons (found in neuropathy and pure muscle disease)
      1. Disoders of denervation (transected nerves)
    6. Reinnervation: increased duration and amplitude of motor potentials
    7. Neuropathic changes can occur in diseases that exclusively affect the muscle
    8. In neuropathic disease, reflexes are lost out of proportion of effects on the muscle
  5. Myopathic Disease [17]
    1. Reduced amplitude and duration of motor unit potentials
    2. Excess of phases (due to reduction in muscle fiber density in motor unit)
    3. These "myopathic" changes appear whenever inactivation of portion of muscle fibers that consitute a motor unit occur and can include neuropathic diseases
    4. Myopathies characterized by decreased production of force despite normal, complete recruitment of motor units
    5. In pure muscle disease, reflexes are reduced comensurate with the loss of muscle strength
    6. In mixed neuropathic-myopathic disease, reflexes are lost out of proportion to muscle loss
  6. Sensory Unit Studies
    1. Velocity normally 40-50 meters/second
    2. 5-15µV potentials
  7. Hoffman Reflexes - sensitive indces of detection of early polyneuropathies [17]

J. Stiff Person (Man) Syndrome (SPS) [8] navigator

  1. Progressive rigidity with pain in neck, trunk, and lower extremity muscles
  2. Etiology
    1. Origin of problem is central nervous system (CNS)
    2. Reduced levels of inhibitors neurotransmitters gamma-aminobutyric acid (GABA)
    3. May also have reduced function or levels of inhibitory neurotransmitter glycine
    4. Lack of inhibition causes chronic (intermittent) contraction of muscles and/or skin
    5. Opposing muscle groups are often firing in parallel, leading to marked stiffness
    6. May be associated with cancer (paraneoplastic syndrome)
    7. ~10% of patients have seizures, consistent with CNS hyperactivity
  3. Autoantibodies [12]
    1. Strongly associated (>50%) with auto-Abs to 65K glutamic acid decarboxylase (GAD)
    2. Anti-GAD Abs also found in Type I Diabetes mellitus (DM1)
    3. Titers of anti-GAD are ~100 fold lower in DM1 than in SPS
    4. Helper T lymphocytes are required for generation of anti-GAD Abs in SPS
    5. Antibodies and T lymphocytes both directed against different epitopes in SPS and DM1 [12]
    6. Paraneoplastic SPS associated with autoantibodies to synaptic protein amphiphysin [19]
    7. Increased frequency of certain HLA-DR and -DQ phenotypes present
  4. Accompanying endocrine disorders, including polyendocrine failure, may be found [10]
  5. Treatment
    1. GABA enhancing drugs such as valproate, diazepam, tiagabin, or vigabatrin help
    2. Doses of diazepam required for treatment are usually poorly tolerated
    3. Therefore, the newer anti-epilepsy medications are recommended
    4. Immunomodulators: intravenous Ig, plasmapheresis, and/or glucocorticoids

References navigator

  1. Thorsteinsson G. 1997. Mayo Clin Proc. 72(7):627 abstract
  2. Siao PTC, Cros DP, Lees RS. 1996. NEJM. 334(21):1389 (Case Report)
  3. Gabriel JM, Erne B, Pareyson D, et al. 1997. Neurology. 49(6):1635 abstract
  4. Saito M, Hayashi Y, Suzuki T, et al. 1997. Neurology. 49(6):1630 abstract
  5. Phillips PS, Haas RH, Bannykh S, et al. 2002. Ann Intern Med. 137(7):581 abstract
  6. Bracker MD and Ralph LP. 1995. Am Fam Phys. 51(1):103 abstract
  7. Martin JB. 1999. NEJM. 340(25):1970 abstract
  8. Levy LM, Dalakas MC, Floter MK. 1999. Ann Intern Med. 131(7):522 abstract
  9. Dalakas MC. 2004. JAMA. 291(19):2367 abstract
  10. Mueller-Schoop JW and Meyer M. 1996. Lancet. 348:1420 (Case Report) abstract
  11. Felz MW, Smith CD, Swift TR, et al. 2000. NEJM. 342(2):90 abstract
  12. Lohmann T, Hawa M, Leslie RDG, et al. 2000. Lancet. 356(9223):31 abstract
  13. Rowland LP and Shneider NA. 2001. NEJM. 344(22):1688 abstract
  14. De Jonghe B, Sharshar T, Lefaucheur JP, et al. 2002. JAMA. 288(22):2859 abstract
  15. Amato AA and Oaklander AL. 2004. NEJM. 350(21):2181 (Case Record) abstract
  16. Gorson KC, Hedley-Whyte ET, Skinner MM. 2001. NEJM. 344(12):917 (Case Record)
  17. Sato O and Hedley-Whyte ET. 2003. NEJM. 349(17):1656 (Case Record) abstract
  18. Polisson RP, Crocker JT, Mueller PR, et al. 2005. NEJM. 353(12):1275 (Case Record) abstract
  19. Sommer C, Weishaupt A, Brinkhoff J, et al. 2005. Lancet. 365(468):1406
  20. Lunn MR and Wang CH. 2008. Lancet. 371(9630):2120 abstract