ABSTRACT
A. Complete Transaction of Spinal Cord 1. Causes: trauma, tumor, hematoma, abscess, infectious
or inflammatory transverse myelitis 2. Absence of reflexes, lower motor neuron paresis, atro-
phy, and fasciculations at level of the lesion
3. Early period of “spinal shock”: early stage of flaccid paralysis, absence of reflexes, autonomic hypoactivity below level of the lesion
4. Spastic paraparesis or quadriparesis (depending on level of the lesion) occurs in the subacute to chronic stage following early “spinal shock” phase (rest of the discussion below refers to this chronic stage)
5. Sensory level: panmodality sensory loss at and below level of the lesion
6. Anhidrosis or hypohidrosis (as seen on thermoregulatory sweat test) and diminished piloerection below level of the lesion; hyperhidrosis above level of the lesion
7. Horner’s syndrome if lesion above level of segment T1: interruption of descending sympathetic pathways
8. Preserved phrenic nerve function for lesions below segment C5 (innervation is C3-C5, “C3,4,5 keep the diaphragm alive”)
9. Lesions below level of segment T1 spare upper extremities
10. Lesions above midthoracic segment, episodic autonomic dysreflexia: diaphoresis, flushing, hypertension, and reflex bradycardia induced by stimulus (e.g., bladder distention)
11. Lesions above segment T6, loss of superficial abdominal reflexes (deep abdominal reflexes are often increased)
12. Lesions below segment T12 spare upper superficial abdominal reflexes
13. Lesions at level of segment T10, Beevor’s sign: intact upper abdominal reflexes and weakened lower abdominal reflexes cause cephalad pulling of umbilicus when patient’s head is flexed against resistance by the examiner in attempt to contract the abdominal muscles
14. Lesion at segment L1: weakness of all lower extremity muscles and panmodality sensory loss involving entire lower extremity bilaterally; brisk patellar and Achilles reflexes
15. Lesion at segment L2, absence of cremasteric reflex 16. Lesion at segment L2, L3, or L4, reduced or absent
patellar reflexes 17. Lesion at segment S1, absence of Achilles reflex 18. Lesion above sacral segments
a. Intact reflex emptying of bladder and urinary urgency and urge incontinence
b. Priapism c. Bowel function: increased rectal tone and “anal wink”
reflexes, constipation, sexual dysfunction in chronic stage
B. Conus Medullaris Syndrome 1. Early sphincter dysfunction
2. Urinary retention with absence of urinary sensation, loss of voluntary initiation of micturation, urinary retention, and (later) overflow incontinence
3. Pain: uncommon, may be symmetric or vague in distribution
4. Saddle anesthesia: symmetric 5. Variable presence of reflexes
C. Cauda Equina Syndrome 1. Late sphincter dysfunction 2. Pain: common, often asymmetric, may follow der-
matomal distribution 3. Exacerbation of pain with lying supine, percussion ten-
derness over vertebral bodies, paravertebral swelling: suggestive of malignancy or infection
4. Weakness: flaccid, hypotonic, follows multiple myotomal distribution (often asymmetric)
5. Saddle anesthesia: may be asymmetric 6. Reflexes: absence of Achilles reflex, variable presence of
patellar reflex (areflexic with extensive lesions)
D. Brown-Séquard Syndrome: hemisyndrome of spinal cord
1. Contralateral loss of pain and temperature sensation: involvement of crossed lateral spinothalamic tract
2. Ipsilateral loss of pain and temperature of a short segment at level of the lesion: involvement of ipsilateral dorsal roots, dorsal horns and/or the spinothalamic tracts (before crossing)
3. Ipsilateral loss of vibration and proprioceptive sensation below level of the lesion: involvement of posterior columns caudal to level of the lesion
4. Ipsilateral pyramidal weakness (spastic weakness): involvement of corticospinal tracts below level of the lesion
5. Ipsilateral lower motor neuron paresis with atrophy, fasciculations: involvement of anterior horn cells at the level of the lesion
6. Differential diagnosis: trauma; extramedullary compression by tumor, hematoma, abscess; intramedullary processes such as vascular insult, syrinx, myelitis due to inflammatory or demyelinating disease, radiation myelopathy
E. Central (intramedullary) Spinal Cord Lesions 1. First sign: involvement of anterior commissure of
spinal cord and crossing spinothalamic fibers, resulting in segmental distribution of “dissociated,” selective sensory loss of pain and temperature (capelike distribution if it occurs in cervical spinal cord)
2. With expansion, ventral horns are involved, and there may be weakness and atrophy of corresponding myotomes
3. With further expansion, lateral spinothalamic tracts are involved: sacral fibers lie peripherally and are often spared until late in the course of the expansion (sacral sparing)
4. With further expansion, lateral corticospinal tracts may be involved, producing upper motor neuron signs below level of the lesion
5. Involvement of sympathetic pathways in cervical cord can produce Horner’s syndrome
6. Posterior columns may be relatively preserved (especially with spinal cord infarction, most of which occurs in the distribution of anterior spinal artery)
7. Differential diagnosis: trauma, demyelination, inflammatory myelitis, intramedullary tumors, syrinx, spinal cord infarction (in the distribution of anterior spinal artery)
A. Hereditary Spastic Paraparesis (HSP) (also called spastic paraplegia [SPG])
1. Genetics (Table 20-1) 2. Uncomplicated (“pure”): most common form
a. Classification of uncomplicated HSP based on inheritance 1) Autosomal dominant variants (2/3 of cases)
a) Most common (40% of cases): SPG4 associated with mutation of gene on chromosome 2p22-p21 encoding protein spastin (age at onset varies, may range from 2 to 75 years)
b) Second most common (9% of cases): SPG3A linked to chromosome 14q11-q21, encoding atlastin
2) Autosomal recessive variants (1/3 of cases): SPG11 (chromosome 15q13-q15) accounts for half of autosomal recessive cases
3) X-linked inheritance (rare) b. Clinical manifestations
1) Slowly progressive spastic paraparesis 2) Spasticity: most common feature, more disabling
than weakness, most predominant in legs, symmetric 3) Weakness: often less prominent than spasticity, often
in distal lower extremities 4) Hyperreflexia (legs > arms), extensor plantar responses
common 5) Hypertonic urinary bladder (urgency progressing into
urge incontinence): early bladder disturbance occurs with SPG19
6) Mild vibratory and sometimes joint position sensory loss (usually later in course of the disorder)
7) Skeletal deformities such as pes cavus 8) Cognitive decline described in SPG4
c. Pathology: axonal wallerian degeneration involving corticospinal tracts, dorsal columns (fasciculus gracilis > cuneatus), and (to a lesser extent) spinocerebellar pathways
3. Complicated a. Classification of complicated HSP based on inheritance
1) Autosomal dominant variants a) SPG9 (linked to chromosome 10q23.3-q24.1) b) SPG17 (linked to chromosome 11q12-q14):
Silver syndrome, characterized by slowly progressive spastic paraparesis with distal amyotrophy of hands and feet and pes cavus
c) SAX1 (linked to chromosome 12p13) 2) Autosomal recessive variants
a) SPG7 (linked to chromosome 16q24.3, gene encoding mitochondrial protein paraplegin): bulbar involvement (dysarthria, dysphagia), optic atrophy, cortical and cerebellar atrophy, and axonal neuropathy
b) SPG20 (linked to chromosome 13q12.3, gene encoding spartin): Troyer syndrome, characterized by early childhood onset of mild developmental delay (motor and speech), late walking, followed by gradual worsening of learned milestones, pervasive developmental problems, progressive spastic quadriparesis, dysarthria, distal amyotrophy, and choreoathetosis (when advanced)
c) SPG21 (linked to chromosome 15q, gene encoding maspardin protein, which localizes to intracellular vesicular system): Mast syndrome, characterized by slowly progressive young adult onset of spastic paraparesis (legs > arms), bulbar involvement (dysarthria, dysphagia), cognitive decline, psychiatric symptoms, and late cerebellar and extrapyramidal deficits; early childhood may be marked by delayed motor milestones
3) X-linked a) SPG1 (linked to chromosome Xq28, encoding L1
cell adhesion molecule): characterized by spasticity, ataxia, mental retardation, and adducted thumbs; mutations of this gene can cause hydrocephalus, CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis, hydrocephalus) or MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs)
b) SPG2 (caused by point mutation of gene on chromosome Xq22 encoding myelin proteolipid protein, allelic with Pelizaeus-Merzbacher disease): characterized by progressive paraparesis, congenital nystagmus, optic atrophy, sensory loss, delayed motor milestones, and white matter changes on magnetic resonance imaging (MRI)
b. Clinical manifestations: features of uncomplicated HSP plus optic neuropathy, retinopathy, deafness, cerebellar features, ichthyosis, amyotrophy, peripheral neuropathy, cognitive deficits, seizures, autoimmune hemolytic anemia,
thrombocytopenia (Evans syndrome), extrapyramidal dysfunction, and bladder dysfunction
4. Diagnosis: exclusion of mimicking disorders and positive family history
5. Treatment: symptomatic treatment
B. Hereditary Sensory Neuropathy With Spastic Paraparesis (Cavanagh’s variant)
1. Predominantly small-fiber neuropathy 2. Spasticity 3. Mutilating acropathy of lower limbs
Table 20-1. Classification of Hereditary Spastic Paraparesis (HSP)
Subtype Locus Gene product Unique feature
C. Adrenomyeloneuropathy 1. Variant of adrenoleukodystrophy 2. Inheritance: X-linked recessive (linked to chromosome
Xq28) 3. Clinical phenotype milder than adrenoleukodystrophy
(which afflicts young boys presenting with severely progressive cognitive and psychomotor deterioration, progressive visual loss, and adrenal insufficiency)
4. Typical presentation: slowly progressive spastic paraparesis and mild peripheral neuropathy in adult men
5. Hypogonadism: mild 6. Female carriers may be asymptomatic or develop late-
onset myelopathy (may present as late as fifth decade) 7. Spasticity (spastic paraparesis) predominantly affects
lower limbs 8. Sensory loss involving all modalities, including proprio-
ceptive loss 9. Abnormalities of sphincter control 10. Pathophysiology related to increased saturated,
unbranched very long-chain (>24 carbon) fatty acids (VLCFAs)
11. Diagnostic evaluation a. Electrodiagnostic evaluation: predominantly axonal neu-
ropathy on electromyography (EMG) and nerve conduction studies, and abnormal brainstem auditory and somatosensory evoked potentials
b. Increased plasma VLCFAs, confirmed by assays of VLCFA concentrations in cultured skin fibroblasts
12. Treatment: symptomatic treatment of spasticity, physical therapy, and steroid replacement for adrenal insufficiency
D. Sporadic Primary Lateral Sclerosis (PLS): adultonset
1. Clinical presentation a. Slowly progressive, often symmetric, spastic paraparesis
(legs before arms), may progress to involve upper limbs and cranial nerves
b. Patients eventually develop pseudobulbar palsy (there may be some asymmetry of deficits, especially early)
c. Important features: spasticity, hyperreflexia, extensor plantar responses, upper motor neuron pattern of weakness
d. Patients may also have cramps, fasciculations, and (less commonly) urinary urgency
e. No sensory loss, but somatosensory evoked potentials are not always normal
f. By definition, no lower motor neuron signs (it is debatable whether this is a subtype of amyotrophic lateral sclerosis [ALS], and some patients with ALS have prominent
upper motor neuron signs reminiscent of PLS and later develop lower motor neuron syndrome)
g. Progression: often quite slow, may last up to 3 decades 2. Pathology
a. Spinal cord: rarefaction and atrophy of corticospinal tracts, with neuronal loss and gliosis (Fig. 20-1)
b. Degenerative changes also involve precentral gyrus (Betz cells in layer V) and possibly prefrontal gyrus (sensory cortex may be involved in some cases)
c. Anterior horn cells are spared 3. Diagnosis of exclusion: must rule out other mimicking
disorders with similar presentation; cortical motor evoked potentials often demonstrate absent or prolonged latencies
4. Treatment: primarily symptomatic treatment (e.g., antispastic agents such as baclofen)
E. Progressive Muscular Atrophy (PMA) 1. Pure lower motor neuron syndrome: progressive weak-
ness and atrophy involving upper and lower limbs and bulbar and respiratory muscles
2. Most cases evolve into ALS (eventually develop upper motor neuron manifestations): diagnosis of PMA should not be made until 3 years after onset of symptoms
F. Familial Childhood Primary Lateral Sclerosis 1. Autosomal recessive (linked to chromosome 2q33,
encoding alsin protein): deletion in exon 3 or 4 causes ALS phenotype (ALS2, discussed below), whereas deletions in exons 9 and 5 cause PLS phenotype
2. Characterized by childhood onset of spastic paraparesis, bulbar involvement, and gaze paresis
G. Sporadic Amyotrophic Lateral Sclerosis 1. Progressive neurodegenerative disorder of motor
systems 2. Prevalence: 4.09/100,000 population 3. Mean age at onset of sporadic ALS: about 56 years
(mean age at onset of familial ALS, 46 years) 4. Mean duration of disease in sporadic ALS: about 3
years 5. Sporadic ALS most frequently afflicts men, with
M:F=3:2 (unlike familial forms) 6. Familial in 10% of cases (discussed below) 7. Pathogenesis
a. Excitotoxicity (induced by glutamate) 1) Glutamate: major excitotoxic neurotransmitter 2) Reduced sodium-dependent glutamate reuptake and
increased glutamate-induced excitotoxicity (AMPA/ kainate receptor) increased permeability to calcium and increased intracellular calcium
3) Reduced expression of excitatory amino acid transporter type 2 (EAAT2)
b. Oxidative stress 1) Highly reactive free radicals can injure cells through
oxidation or peroxidation of proteins, lipids, and nucleic acids
2) Superoxide radicals produced as by-products of oxidative phosphorylation
3) SOD1 mutations cause a toxic gain of function, enhance free radical formation as well as abnormal copper metabolism, and catalysis of tyrosine residue nitration by peroxynitrite
c. Mitochondrial dysfunction: possibly provokes oxidative stress and mediates neuronal injury by excitotoxic and apoptotic pathways
d. Neurofilament dysfunction and aggregation 1) Axonal spheroidal inclusions containing aggregates of
ubiquinated filaments and abnormal phosphorylated neurofilament proteins present in anterior horn cells because of oxidative stress-induced neurofilament injury
2) Phosphorylation of neurofilaments alters their function and induces their aggregation as spheroidal inclusions
3) Alterations in axonal transport a) Increased fast axonal transport b) Decreased retrograde slow transport
e. Alteration in intracellular calcium levels: the common final pathway of most of the proposed mechanisms of injury 1) Inability to handle increased intracellular calcium levels
by poor expression of calcium-binding proteins parvalbumin and calbindin-D28k likely also has
important role in the pathogenesis of ALS and contributes to selective vulnerability of motor neurons in ALS
2) Relative resistance to degeneration of subset of motor neurons (i.e., extraocular motor neurons and Onuf’s nuclei) until late in disease is likely due to high expression of calbindin-D28k or parvalbumin (or both) in these motor neurons
8. Pathology (Fig. 20-2) a. Neuronal loss of anterior horn cells and rarefaction of
ventral horns (sparing of sacral anterior horn cells in nuclei of Onuf)
b. Bunina bodies: dense cytoplasmic granular inclusions best observed with electron microscopy to contain amorphous granular material accompanied by vesicular structures and neurofilaments
c. Spheroids: axonal aggregations of neurofilaments 9. Clinical presentation
a. Early symptoms of limb-onset presentation: muscle cramps, fasciculations, weight loss, fatigue
b. Patients may present with monomelic weakness (involving multiple peripheral nerve distribution in one limb), with spread to contiguous limbs and anatomic segments
c. Limb weakness: initial manifestations usually distal; occasionally patients may present with predominantly proximal, symmetric upper or lower limb weakness
d. Upper limb weakness: difficulty with grip, holding or turning keys, opening bottle tops, buttoning clothes
e. Lower limb weakness: footdrop (most common), gait instability, effort-dependent fatigue, and leg weakness with walking
f. Bulbar involvement: dysarthria (often mixed spastic and flaccid); brisk jaw jerk; atrophied, fasciculating, weak, and spastic tongue; sialorrhea; dysphagia
g. Respiratory involvement with diaphragmatic weakness presenting with dyspnea (on exertion initially, then at rest with progression)
h. Weight loss: rapidly progressive (cachexia, likely more than what can be attributed to poor caloric intake)
i. Other symptoms (indicative of upper motor neuron involvement): forced yawning, labile emotional affect
j. Some patients may have cognitive impairment in pattern consistent with frontotemporal dementia (up to 1/3 of patients, according to recent data)
k. Relative sparing of bowel and bladder function, extraocular muscles, and sensory systems
l. Examination findings 1) Lower motor neuron signs: fasciculations (eventually
develop in all patients), atrophy, weakness 2) Upper motor neuron signs: spasticity and hyper-
reflexia, including exaggerated Hoffmann sign, pathologic jaw jerk, pathologic gag reflex, extensor plantar responses (usually develop later in disease course)
3) Hyperreflexia and spasticity of amyotrophic limb: suggestive of ALS
m. World Federation of Neurology (WFN) diagnostic criteria 1) Clinical and electrodiagnostic evidence for upper and
lower motor neuron loss (with evidence of spread within a segment or to other segments of central nervous system)
2) Evidence of subclinical lower motor neuron involvement may be provided by electrodiagnostic studies
3) Four segments of neuroaxis may be involved: bulbar, cervical, thoracic, and lumbosacral
4) Definite ALS: upper and lower motor neuron clinical signs in bulbar plus two spinal segments or in three spinal segments
5) Probable ALS: upper and lower motor neuron signs in at least two segments, with some upper motor neuron signs rostral to lower motor neuron signs
6) Probable laboratory-supported ALS: upper and lower motor neuron signs in one segment or upper motor neuron signs in one segment and lower motor neuron signs by electrophysiologic criteria in at least two limbs
7) Clinically possible ALS: upper and lower motor neuron clinical signs in one segment or upper motor neuron clinical signs in two or more regions or lower motor neuron clinical signs rostral to upper motor neuron clinical signs
10. Electrodiagnostic findings a. Performed to confirm lower motor neuron dysfunction
in clinically involved segments, to detect lower motor
neuron abnormalities in clinically uninvolved segments, and to exclude other diagnoses
b. Sensory conduction studies 1) Expected to be normal 2) Any detected abnormality should be incidental 3) If pronounced abnormalities, an underlying sensory
axonopathy or neuronopathy may be present and diagnoses other than ALS are entertained (e.g., polyradiculoneuropathy or Kennedy’s syndrome)
c. Motor conduction studies 1) Normal or mildly reduced (CMAP) amplitudes in
early stages, with normal distal latencies and conduction velocities
2) With ongoing uncompensated denervation and disease progression, CMAP amplitudes steadily decrease, and conduction velocities may slow down as the rapidly conducting myelinated fibers are involved
3) Absence of conduction block (caution: phase cancellation and mild slowing of the conduction velocities may resemble partial conduction block)
4) Reduced F wave response frequency and repeated F wave responses (due to decreased number of anterior horn cells)
d. Repetitive stimulation 1) May be mild decrement (often <10%) 2) Due to impaired neuromuscular transmission between
immature nerve terminals of the sprouting axonal collaterals and newly reinnervated muscle fibers
3) Greater decrement in rapidly progressive disease e. Single fiber EMG: increased jitter, blocking, and
increased fiber density f. Motor unit number estimate (MUNE)
1) Quantitative estimate of number of functioning motor units
2) Quantitative follow-up of progression 3) Reduced in ALS
g. Needle examination 1) Signs of active denervation (fibrillation potentials,
positive sharp waves, fasciculation potentials): may be limited and sparse early in disease course due to active, compensatory reinnervation
2) Signs of chronic denervation and reinnervation: large-amplitude, long-duration motor unit potentials with reduced recruitment
3) Increased polyphasia and instability of motor unit potentials indicate active reinnervation: impaired neuromuscular transmission of new collateral axons and slowed conduction of immature (yet unmyelinated) axon terminals are responsible for instability of motor unit potentials
4) Early in disease course: evidence of chronic, compensated reinnervation with motor unit potential remodeling and usually little uncompensated active denervation
5) With disease progression: changes of active denervation (fibrillation potentials) become more prominent, while there is ongoing, active (and uncompensated) reinnervation, latter evidenced by abundance of varying, polyphasic motor unit potentials
6) Greater occurrence of variability of motor unit potentials in rapidly progressive disease
7) Low-amplitude (sometimes short-duration) polyphasic motor unit potentials may be seen in inadequate collateral reinnervation: usually associated with rapidly progressive course; may indicate a worse prognosis when abundant
8) In most severely affected muscles, changes could be limited to severely reduced recruitment of short-duration, small-amplitude motor unit potentials: “nascent unit” potentials, indicative of early distal-to-proximal reinnervation after severe denervation axonopathy
11. Other ancillary testing a. Mild to moderate elevation in creatine kinase level b. Neuroimaging of brain and spinal cord to exclude mim-
icking disorders of neuraxis c. Anti-ganglioside autoantibodies, acetylcholine receptor
antibodies, genetic testing for Kennedy’s syndrome may need to be done in select situations
d. Muscle biopsy may be needed to exclude underlying muscle disease
H. Inherited Amyotrophic Lateral Sclerosis 1. Most familial variants exhibit autosomal dominant
inheritance 2. Most common of these (up to 20% of familial cases) is
due to mutation of superoxide dismutase 1 (SOD1) gene (ALS1)
3. Often presents with weakness, atrophy, and absence of reflexes in a single limb
4. Autosomal dominant familial ALS a. Clinically indistinguishable from sporadic ALS b. More severe phenotype in homozygotes than heterozygotes c. ALS1: due to mutation of the SOD1 gene on chromo-
some 21q22.1 1) Most common form of familial ALS (up to 20% of
familial cases) 2) More than 100 different mutations have been identi-
fied (most are autosomal dominant inheritance, rare cases of autosomal recessive inheritance)
3) Most common mutations: A4V (exon 1) and D90A (exon 4)
4) Up to 3% of cases of sporadic ALS have mutations in SOD1 gene
5) SOD1 protein: cytoplasmic protein acts to detoxify oxygen radicals and prevent oxidative damage
6) SOD1 mutation: reduced dismutase activity and toxic gain-of-function (enhanced free radical formation, abnormal copper metabolism, and catalysis of tyrosine residue nitration by peroxynitrite)
7) Mean age at onset: 46 years 8) Clinical presentation and progression closely resemble
sporadic ALS 5. Autosomal recessive familial ALS: three main
phenotypes a. Type I (designated ALS5)
1) Linked to chromosome 15q15-q22 2) Found in North African and European populations 3) Age at onset: usually in second decade 4) Predominant lower motor neuron signs 5) Early hand involvement (sometimes for years) 6) Pattern of weakness: distal more than proximal, arms
more than legs 7) Late bulbar involvement, absence of pseudobulbar
affect as with ALS2 (discussed below) b. Type II
1) Age at onset: first or second decade 2) Involvement confined to lower limbs: usually pre-
sents with footdrop 3) Spastic paraplegia and lower extremity amyotrophy 4) Bulbar sparing
c. Type III (designated ALS2) 1) Mean age at onset: 6.5 years (up to third decade) 2) Linked to chromosome 2q33 3) Early onset of spastic paraplegia (presentation of juve-
nile primary lateral sclerosis) 4) Mild, very slowly progressive, then amyotrophy devel-
ops: predominantly distal (legs > arms) 5) Pseudobulbar affect
6. X-linked familial ALS a. Linked to chromosome Xp11-q12 b. Rare
I. Spinal Muscular Atrophy (SMA) 1. Overview
a. Clinically heterogenous group of disorders characterized by muscle weakness and atrophy without sensory loss or upper motor neuron findings (pure lower motor neuron syndrome) (Fig. 20-3)
b. Pathologically due to degeneration of motor neurons (anterior horn cells) in spinal cord and brainstem
c. Most common forms of SMA present in childhood with
symmetric proximal (more than distal) limb weakness and atrophy; show autosomal recessive inheritance
2. Genetics a. Autosomal recessive inheritance in most cases of SMA
types I to III, linked to chromosome 5 (autosomal dominant or X-linked transmission is exceedingly rare exception)
b. Autosomal recessive inheritance in 70% of adult-onset SMA (type IV), linked to chromosome 5
c. Autosomal dominant inheritance in 30% of adult-onset SMA (type IV), not linked to chromosome 5 (genetically heterogeneous)
d. Homozygous deletions of SMN1 (telomeric survival motor neuron 1) gene are responsible for 95% to 98% of childhood SMA (rarely found in adult-onset SMA): small mutations in SMN1 gene have been identified in other 5% of SMA patients
e. Homozygous mutations of SMN2 (centromeric survival motor neuron 2) gene more commonly identified in adult-onset SMA 1) SMN protein is involved in messanger (m)RNA
splicing 2) Motor neurons have high rate of RNA metabolism 3) Dramatic difference in phenotypic severity between
SMA type I to III suggests involvement of additional genes: candidate genes include SMN2 and NAIP (neuronal apoptosis inhibitory protein gene) a) SMN2 is homologous to SMN1 and is an ineffi-
cient producer of SMN protein b) Up to four copies of SMN2 on each chromosome c) SMN protein levels determine phenotypic severity d) Higher number of SMN2 copies would yield high-
er load of SMN protein and less severe phenotype: SMN2 gene is modifier of disease severity in SMA
e) Loss of SMN2 gene occurs in 5% of normal, asymptomatic population
f) NAIP is deleted in approximately 80% of patients with SMA type I, but in very few patients with SMA type II or III (more common in patients with SMA type I)
3. Electrodiagnosis a. Reduced amplitude CMAP; normal sensory nerve action
potentials b. Needle EMG
1) Spontaneous activity: fibrillation potentials and positive waves in all subtypes
2) Voluntary activity: long-duration, large-amplitude motor unit potentials (especially with SMA types III and IV)
4. SMA type I (Werdnig-Hoffmann disease)
a. Autosomal recessive inheritance b. Presents at birth or shortly thereafter (up to 6 months of
age) with hypotonia 1) In utero: mothers may experience decreased fetal
movement c. Bulbar involvement: weak cry, poor feeding, tongue
atrophy and fasciculations (extraocular movements are spared)
d. Loss of cough reflex and inaudible cry with progression e. Absence of head control (“floppy infant”) f. Severe diffuse, symmetric weakness (worse proximally);
patients often in “frog-leg” position (externally rotated and abducted legs and flexed knees); patient never sits independently
g. Diffusely areflexic h. Contractures are rare in early stages, but usually develop
with advanced disease (often at knees, rarely at elbows) i. Reduced anteroposterior diameter of thorax, pectus
excavatum j. Respiratory insufficiency due to weakness of intercostal
muscles (preserved diaphragmatic function until late in disease course), causing paradoxical respirations
k. Normal intellect l. Rapid progression; death usually before age 2 years
m. Serum creatine kinase: typically, normal levels 5. SMA type II (arrested Werdnig-Hoffmann disease,
juvenile SMA) a. Autosomal recessive inheritance b. Most common pattern, accounting for approximately
45% of SMA cases c. Age at onset, speed of progression, and prognosis are
intermediate between SMA types I and III d. Age at onset: before 18 months, with gradual progressive
weakness and delayed motor milestone; patients never stand
e. Patients able to sit with support if positioned and eventually sit unsupported, but never stand
f. “Tremor” of hands: minipolymyoclonus (and fasciculations)
g. With progression, often contractures of knees and hips, scoliosis, and other orthopedic complications
h. Death usually after age 2 (7 months-7 years, some as late as the third or fourth decade)
i. Serum creatine kinase: typically, normal levels 6. SMA type III (Wohlfart-Kugelberg-Welander
syndrome) a. Autosomal recessive inheritance (most cases) b. Patients normal at birth c. Presents after 18 months of age (usually 5-15 years), usu-
ally in late childhood or adolescence d. Many patients are able initially to achieve normal motor
milestones, able to stand and walk unassisted, but later deteriorate and are usually wheelchair-bound
e. Symptoms at presentation: progressive proximal weakness and atrophy; waddling gait and exaggerated lumbar lordosis
f. With progression, patients often use Gower’s maneuver to arise from supine position
g. Fasciculations and tremors are more common than in SMA type I or II
h. Deep tendon reflexes may be uniformly absent or reduced
i. If onset before age 2: stop walking by age 15, greater predisposition for orthopedic complications such as scoliosis, worse prognosis
j. If onset after age 2: better prognosis, likely ambulate into fifth decade, fewer orthopedic complications
k. Serum creatine kinase: elevated levels, up to 10 times normal (normal in SMA types I and II)
l. Normal or slightly reduced life expectancy 7. Adult-onset SMA (SMA type IV)
a. Mostly autosomal dominant or autosomal recessive inheritance
b. Adult onset: age at onset is older than 20 c. Very slow progression over decades d. Normal life expectancy e. Usually does not involve respiratory or bulbar muscles
(unlike Kennedy’s syndrome) 8. Distal hereditary motor neuronopathy
a. Group (types 1-7) of rare disorders with distal lower and upper limb weakness
b. Not formally part of SMA classification but clearly related to these disorders because of pure involvement of lower motor neurons
c. Age at onset and mode of inheritance vary
d. Previously known as the spinal form of Charcot-MarieTooth disease because of very similar clinical picture of slowly progressive distal atrophy and weakness: distinguishable from Charcot-Marie-Tooth disease by 1) Normal sensory examination 2) Normal sensory action potential amplitudes on nerve
conduction studies 3) Axonal motor conduction studies (conduction veloci-
ty normal or reduced in proportion to amplitude loss) 9. Fazio-Londe disease
a. May be sporadic; otherwise, autosomal dominant or autosomal recessive inheritance
b. Normal at birth c. Age at onset: 1 to 12 years d. Motor neuron disease predominantly limited to lower
cranial nerves (progressive bulbar palsy), may also include ptosis and facial weakness
e. Progression variable 10. Brown-Vialetto-van Laere syndrome
a. Progressive bulbar palsy with deafness b. Normal early development c. Age at onset: usually in second decade d. Weakness is primarily bulbar (tongue atrophy and fascic-
ulations, dysphagia) and facial e. Bilateral sensorineural hearing loss
11. Juvenile monomelic amyotrophy a. Also called Hirayama’s disease b. Age at onset: late teens or early twenties c. Predilection for Asian men d. Presenation: gradual onset and progression of painless
weakness and atrophy e. Predominantly affects muscles innervated by C7-T1
nerve roots: proximal more than distal, typically unilateral (may be bilateral)
f. Deep tendon reflexes: reduced or absent g. Progression of weakness continues for 2 to 3 years, may
stabilize within 5 years after onset h. Progression may continue for decades (referred to as
O’Sullivan-McLeod syndrome) i. Pathophysiology may be related to mechanical distortion
of cervical spinal cord and focal compression of dura mater and spinal cord against vertebrae during neck flexion
12. Hexosaminidase A deficiency a. Autosomal recessive inheritance: mutation of HEXA
gene on chromosome 15q23-q24, encoding protein hexosaminidase A, responsible for degrading ganglioside GM2
b. Clinical phenotypes 1) Infantile hexosaminidase A deficiency (Tay-Sachs dis-
ease [TSD])
a) Complete deficiency of enzyme activity b) Infants normal at birth c) By 3 to 6 months of age: mild motor weakness,
exaggerated startle response, myoclonus d) By 6 to 8 months of age: developmental arrest and
regression, no new motor skill is learned and the child begins to lose some acquired motor skills i) Reduced visual attentiveness ii) Cherry-red spot
e) By 8 to 10 months of age: rapid deterioration, diminution in myoclonus and spontaneous movements, deterioration in vision (cherry-red spot)
2) Juvenile hexosaminidase A deficiency a) Heterozygotes with varying degrees of residual
enzymatic activity b) Normal early motor milestones c) By 2 to 10 years of age: incoordination and ataxia
become apparent d) Developmental regression: cognitive decline e) Spasticity and seizures by end of first decade f) By 15 years of age: decerebrate rigidity, persistent
vegetative state g) Deterioration in vision: much later than the infan-
tile form (TSD); optic atrophy and retinitis pigmentosa may be observed late in disease course
3) Chronic, adult-onset hexosaminidase A deficiency a) Late-onset GM2 gangliosidosis b) Slowly progressive symmetric proximal weakness,
atrophy, fasciculations, dysarthria c) Cerebellar ataxia d) Some have extrapyramidal signs of dystonia,
choreoathetosis e) Some have psychiatric manifestations (without
dementia), including recurrent depression, manic depression, depression with psychotic features, acute psychosis
f) Sensory neuropathy with abnormal sensory-nerve action potentials
c. Diagnosis: absent to near-absent serum hexosaminidase A enzymatic activity (or in white blood cells) in symptomatic person, in presence of normal or elevated activity of the β-hexosaminidase B isoenzyme
13. Kennedy’s syndrome or X-linked spinobulbar muscular atrophy
a. Genetics 1) X-linked recessive 2) CAG trinucleotide repeat expansion in the androgen
receptor gene (AR) on chromosome Xq11-q12 3) Longer lengths of CAG repeats: correlate with earlier
age at onset
4) Genetic anticipation: larger expansion in CAG repeat number, especially with paternal transmission
b. Clinical features 1) Insidious, slowly progressive atrophy and weakness of
limb and bulbar muscles beginning in the 3rd to 5th decades
2) Proximal hip and shoulder-girdle weakness: most individuals have difficulty walking up the stairs after 1 to 2 decades of symptoms
3) 1/3 of patients require a wheelchair 20 years after the onset of symptoms
4) Muscle cramps and fasciculations may precede the onset of definite weakness and wasting: characteristic facial (especially perioral) fasciculations
5) Other features: muscle atrophy, absence of reflexes 6) Tongue muscle atrophy and fasciculations 7) Dysarthria and dysphagia may occur 8) Unlike the other inherited motor neuronopathies, a
mild sensory neuronopathy may also be present, related to degeneration of dorsal root ganglia: abnormal sensory potential amplitudes on nerve conduction studies do not exclude this diagnosis
9) Signs of mild androgen insensitivity 10) Gynecomastia 11) Testicular atrophy 12) Reduced fertility 13) Unlike some of the other androgen receptor muta-
tions, sexual differentiation and development of secondary sexual characteristics are normal
c. Treatment 1) Androgen therapy is not beneficial and may be harm-
ful: exogenous androgen therapy causes translocation of the mutant receptor-ligand complex from the cytoplasm to the nucleus where the CAG encoded polyglutamine expanded protein is more toxic
2) The role of antiandrogen treatments in Kennedy’s syndrome is being evaluated
A. Neoplasms (see Chapter 16)
B. Multiple Sclerosis (see Chapter 14)
C. Syringomyelia 1. Fluid-filled cavity in spinal cord 2. May be primary, spontaneous, or secondary (latter usu-
ally posttraumatic or associated with spinal cord
intramedullary or extramedullary tumors) 3. Associated with Chiari I or II malformation 4. There may or may not be associated foramen magnum
obstruction 5. Two subgroups
a. Communicating syringomyelia 1) Caused by primary dilatation of central canal 2) Often associated with abnormalities of foramen mag-
num such as Chiari I malformations 3) Also called hydromyelia 4) Pure central localization
b. Noncommunicating syringomyelia 1) Intramedullary cyst not communicating with central
canal or subarachnoid space 2) Often due to trauma, tumor, or arachnoiditis 3) Pure paracentral localization
6. Localization of syrinx is variable a. Pure central b. Pure paracentral c. Central and paracentral
7. Clinical presentation a. Variable depending on location and level of lesion in
spinal cord b. Typical presentation of expanding central syrinx often
starts with capelike distribution of dissociated sensory loss (preferential involvement of pain and temperature rather than vibratory or joint position sensation because of early, segmental involvement of crossing spinothalamic tracts)
c. With further expansion of syrinx, anterior horn cells tend to be involved (causing axial and appendicular weakness and atrophy)
d. With further expansion of syrinx, intermediolateral columns containing sympathetic pathways are involved and produce Horner’s syndrome
e. With further expansion of syrinx, corticospinal tracts and posterior columns are involved
f. Various brainstem symptoms when associated with Chiari II malformation
g. Asymmetric hand weakness or gait disturbance are common symptoms when associated with Chiari I malformation
h. Extension of syrinx into brainstem is called syringobulbia 8. Diagnosis: requires neuroimaging (Fig. 20-4)
a. MRI: most sensitive imaging b. Identify the syrinx, localization, and extent c. Provide means for radiographic follow-up d. Identify cause and underlying condition, particularly
associated neoplasm (gadolinium must be administered) e. Identify associated conditions (e.g., Chiari
malformations)
9. Treatment a. Percutaneous aspiration of syrinx, terminal ventriculosto-
my, shunting b. Posterior fossa decompression for treatment of posterior
fossa abnormalities c. Resection of underlying causative tumor
A. Cause 1. May be due to combination of spondylosis, spondylo-
listhesis, facet joint arthropathy, ligamentum flava hypertrophy, congenital narrowing of spinal canal, degenerative osteophytosis, and vertebral disk bulging and disk herniation (extrusion)
B. Area Involved: usually lower cervical or lower lumbar segments
C. Cervical Spinal Stenosis and Myelopathy 1. Spasticity, hyperreflexia distal to level of myelopathy 2. Reduced or absent deep tendon reflexes, atrophy, and
lower motor neuron pattern of weakness at level of stenosis
3. Variable degrees of sensory symptoms and possibly poorly localizing pain (central origin), but neck pain usually not prominent
4. Lhermitte’s sign may be present 5. Sphincter dysfunction may occur, usually after onset of
any sensory or motor (or both) symptoms 6. Clinical course may remain stable or may progress in
variable fashion
D. Lumbar Spinal Stenosis: may have variable presentation
1. Asymptomatic 2. Insidious onset of neurogenic claudication: intermittent
leg discomfort (pain with or without paresthesias) produced by walking or standing straight for prolonged period
3. Slow relief with rest (almost immediate relief with vascular claudication): leaning forward or sitting is required, symptoms are not relieved with rest in standing position
4. Symptoms often relieved by leaning forward (as in riding a bicycle or leaning against a grocery cart, unlike vascular claudication)
5. Variable degrees of exercise or walking distance produces
symptoms (as opposed to vascular claudication in which fixed degree of exercise or walking distance induces symptoms)
6. Persistent, progressive back and leg pain and chronic cauda equina syndrome, often asymmetric distribution
7. May be associated with radicular symptoms
E. Epidural Lipomatosis 1. Due to nonneoplastic hypertrophy of extramedullary
adipose tissue in spinal epidural space (Fig. 20-5) 2. Usually occurs at thoracic or lumbosacral segments 3. Causes
a. Most cases associated with chronic corticosteroid use b. Others: Cushing’s disease, Cushing’s syndrome, pituitary
prolactinoma, hypothyroidism, and (rarely) obesity c. May be idiopathic
4. Most frequently reported symptom is back pain, followed by lower limb weakness, and (rarely) sphinter dysfunction
5. Regression of compressive tissue when corticosteroids are withdrawn
6. Treatment: symptomatic measures, withdrawal of corticosteroids if possible, decompressive laminectomy with resection of epidural adipose tissue
F. Epidural Abscess 1. May develop rapidly (evolving over several days) or
gradually (over several weeks) 2. Fever, back pain, local spine tenderness, and radicular
pain are usually first manifestations 3. Patients may present with shock, sepsis, encephalopa-
thy: focal spine tenderness and back pain may not be apparent
4. Weakness may evolve rapidly into paraparesis or quadriparesis
5. More than half of acute abscesses are Staphylococcus aureus
6. Infection in epidural space may be result of a. Direct extension of infection in contiguous structures
(e.g., vertebral osteomyelitis, soft tissue infection, decubitus ulcer): brittle diabetes mellitus, intravenous drug abuse, and chronic alcoholism are risk factors for osteomyelitis and diskitis that may extend to epidural space
b. Hematogenous spread from distant source (intravenous drug abuse is risk factor)
c. Direct penetrating trauma to the back 7. Cerebrospinal fluid (CSF) examination is contraindicat-
ed: sudden shifts in CSF pressure may cause herniation of spinal cord, and passing the needle through the abscess may spread the infection to subarachnoid space
8. Diagnosis usually made with MRI 9. Treatment relies on immediate initiation of antibiotics,
with or without surgical debridement or spinal decompression (or both)
G. Epidural Hematoma 1. Abrupt onset of extramedullary spinal cord
compression 2. May present with sharp pain in chest or upper back 3. Should be suspected in patients receiving
anticoagulation
A. Radiation-Induced Myelopathy: transient radiation myelopathy
1. Self-limiting 2. Occurs within first year after radiation 3. Usually presents with paresthesias and Lhermitte’s sign 4. May be caused by transient demyelination or drop out
of oligodendrocytes (or both)
B. Vascular Disease of Spinal Cord: spinal cord ischemic syndromes and vascular malformations are discussed in Chapter 11
C. Infectious Disorders of Spinal Cord 1. Tropical spastic paraparesis: human T-cell leukemia
virus type 1 (HTLV-I)–associated myelopathy a. Transmission: vertical (mother to child), sexual,
parenteral b. Most infected persons are asymptomatic and never
develop myelopathy; only 1 in 250 develop myelopathy c. Age at onset: usually after 30 years (depends on mode of
transmission) d. Chronic, slowly progressive myelopathy, primarily at
thoracic segments: spastic paraparesis of lower limbs and spastic bladder
e. Cerebellar ataxia may complicate the gait disorder f. May be associated with demyelinating polyneuropathy g. Slower progression in younger patients h. Intravenous drug abusers at a greater risk for acquiring
infection with HTLV-I i. Pathology
1) Predominantly involves middle and lower thoracic cord, extending to involve entire spinal cord
2) Neuronal cell loss and gliosis, with microvacuolization 3) Demyelination often accompanies long tract axonal
degeneration: involves corticospinal, spinocerebellar, and spinothalamic tracts
4) Hyalinoid thickening of media and adventitia of microvasculature, with mononuclear perivascular infiltrates
j. HTLV-I is also associated with T-cell lymphoma and leukemia
k. HTLV-II has also been associated with a progressive myelopathy (much less common than HTLV-I)
2. HIV-1-associated vacuolar myelopathy a. Often occurs in the late stages of human immunodefi-
ciency virus (HIV) infection b. Often associated with acquired immunodeficiency syn-
drome (AIDS) dementia complex and peripheral neuropathy
c. Clinical features 1) Slowly progressive spastic paraparesis (weakness
exceeding the spasticity) 2) Gait ataxia 3) Sphincter dysfunction (bowel and bladder
dysfunction) 4) Paresthesias and pain in lower limbs 5) Large-fiber (posterior column) sensory loss (major
small-fiber sensory loss indicates underlying concurrent peripheral neuropathy)
d. Pathology 1) Multifocal microvacuolation, spongiform
degeneration 2) Loss of myelin 3) Lipid-laden macrophages 4) Pathologic changes predominantly involve dorsal and
lateral tracts 5) Pathologic features resemble subacute combined
degeneration 3. Herpesvirus-related myelopathy
a. Most commonly occurs in immunocompromised persons (e.g., AIDS patients or those receiving immunosuppressants after transplantation)
b. May be seen with varicella-zoster virus infection, herpes simplex virus type 2, Epstein-Barr virus, and cytomegalovirus (only rarely with herpes simplex virus type 1)
c. Varicella-zoster virus 1) Remains dormant in dorsal root ganglia 2) When reactivated, virus spreads to involve the roots
and causes herpes zoster radiculitis, with severe radicular pain, sensory loss, and weakness; accompanied by vesicular rash
3) May also spread centripetally to cause necrotizing myelopathy
4) Myelopathy may be recurrent 5) CSF: varicella-zoster DNA detected with polymerase
chain reaction (PCR) 6) MRI: abnormal T2 signal, contrast enhancement,
and enlargement of spinal cord at affected segments d. Herpes simplex type 2
1) Genital herpes 2) Inflammatory myelitis and radiculitis (usually lum-
bosacral): may be recurrent 4. Syphilis of spinal cord
a. Tabes dorsalis 1) Predominantly syndrome of dorsal columns: progres-
sive ataxia (predominantly sensory ataxia), proprioceptive loss, rombergism, incoordination, lancinating or lightning-like pains, Lhermitte’s sign
2) Genitourinary dysfunction, including atonic bladder and sexual dysfunction (impotence)
3) Loss of deep tendon reflexes 4) Pupils: irregular or unequal in most patients 5) Argyll Robertson pupils: impaired light reaction, pre-
served pupillary constriction to accommodation 6) Natural history and clinical progression (in sequence)
a) Tabetic pain phase: gradual onset and progression of lancinating “tabetic” pain and sphincter dysfunction
b) Ataxic phase: development of severe ataxia and trophic changes, including Charcot joints; worsening tabetic pain
c) Paralytic phase: cachexia, paralysis, and atrophy with stiffness; worsening sphincter dysfunction and other autonomic features
7) Pathology a) Demyelination and rarefaction of posterior
columns (especially fasciculus gracilis) and dorsal roots, with neuronal loss and gliosis
b) Chronic inflammatory disease of dorsal root ganglia: sparse leptomeningeal mononuclear infiltration, neuronal loss, and nodules of Nageotte (ganglion cells have degenerated)
b. Syphilitic spinal cord meningoencephalitis 1) Transverse myelitis: gradual onset and progression of
limb weakness (legs > arms) with spasticity, hyperreflexia, and extensor plantar responses (mimicking cervical myelopathy), and sensory loss
2) Pathology: leptomeningeal inflammation and thickening with granulomatous arteritis of spinal cord parenchyma, predominantly involving lateral columns
c. Gummatous neurosyphilis of spinal cord: avascular gummas may be intramedullary (resembling
intramedullary gliomas) or extramedullary (causing cord compression), localized form of meningeal syphilis
d. Spinal vascular syphilis: responsible for spinal cord infarction
e. Other extramedullary (compressive) syphilitic syndromes that could affect spinal cord 1) Aortitis and aortic aneurysms: cause erosion of adja-
cent vertebrae and compression of underlying spinal cord
2) Lesions of vertebrae: osteitis or trophic changes (Charcot vertebrae)
5. Acute poliomyelitis a. Poliovirus infection of the nervous system, with viral
affinity for anterior horn cells in brainstem and spinal cord
b. Afflicts less than 1% of patients infected with poliovirus c. Present day: rare cases of acute poliomyelitis in U.S.
