Differential Diagnosis in Neurology

4.5. Spastic Paraparesis

Anatomical Feature of Transverse Myelitis

• Spinothalamic tract (STT)
  • Lissauer's tract distributes afferent information two levels above and below the entry level (important in thoracic cord)
  • Sacral fibers distributed most laterally in STT; cervical fibers most medially
• Dorsal column system:
  • Leg fibers medially (fasciculus gracilis); arm fibers more laterally (fasciculus cuneatus)
  • Sacral fibers outermost most dorsally
  • Visceral pain ventrally in both fasciculi
• Cervical cord involvement frequently causes dropped sensory level to T4–T6 or the abdomen; rarely a discrete far lateral lesion may cause leg or sacral sensory symptoms
• Associated spinocerebellar or cuneocerebellar (C1–C4) compromised with the sensory abnormalities

Clinical Features of Transverse (Longitudinal Myelopathy Myelitis)

• Heralded by band like pressure or pain at the segmental level
• Paresis below the level
• Bladder affected if both sides of the cord are involved:
  • Epidural involvement-earlier and more severe urinary dysfunction than intramedullary lesions
  • Cervical Intramedullary lesion:
    • Sudden loss of urine with Valsalva maneuver
  • Transverse lesion:
    • Urgency with difficulty in initiation of micturition (lesion between the pontine or cervical bladder micturition centers and the parasympathetic supply to the detrusor muscle (Onuf's nucleus) Incoordination of ignition of micturition and release of the external sphincter.
• Conus medullaris level:
  • Loss of initiation of micturition and a paralyzed bladder that is insensate to filling pressures

Hereditary Spastic Paraparesis (Strümpell–Lorrain Syndrome)

• General considerations: Hereditary spastic paraparesis is a clinically and genetically heterogenous disorder with inter and intra familial variation. It is divided into AD, AR, X-linked and syndromic forms. In addition, spastic paraparesis complicates many acquired forms of spinal cord pathologies and is a major component of both demyelinating and dysmyelinating conditions. At present, 18 genetic loci have been reported of which ten are AD, three X-linked and five are autosomal recessive. The pure form is an insidiously progressive spastic paraparesis with a neurogenic bladder and distal vibratory loss in the legs. Uncomplicated HSP refers to the pure form in which both the corticospinal and dorsal column systems are involved. Complicated HSP has additional neurological deficits that include optic neuritis, macular and cerebellar degeneration, ichthyosis, seizures, cataracts, cognitive dysfunction, and extrapyramidal signs.
• Genetic features: The average age of onset of symptoms is due to which genetic locus may be involved in uncomplicated HSP; otherwise they present similarly.
  • HSP linked to 2p (SPG4 and SPG13) overlap in time of onset with other early symptomatic forms (SPG10, SPG3 and SGP 12).
  • The average age of onset after age 20 is most typical of SGP8 and SGP 6
  • Approximately 50% of AD uncomplicated HSP are linked to SPG4
  • Approximately 50% of AR HSP is SPG 11 on chromosome 15q13–q15.
  • A rare AR HSP has been mapped to chromosome 16q; the protein product is known as paraplegin. Some kindreds have other neurological deficits such that this mutation leads to a complicated form.
  • Two genes have been identified for an X-linked form of complicated HSP
• Clinical features of uncomplicated HSP:
  • Bilateral lower extremity weakness; anterior tibialis, hamstrings and iliopsoas muscles are most involved
  • Deep tendon reflexes are increased; Babinski signs are prominent (often at rest and by midfoot) the legs are spastic
  • Upper extremity strength, bulk, facility of movement and tone are normal
  • Pes cavus is frequent (if not there other diagnosis should be sought)
  • Gait is abnormal due to limited thigh flexion and dorsiflexion of the feet; circumduction maybe prominent as is increased adductor tone. Hyperlordosis and a short swing phase during gait is prominent.
  • Decreased muscle bulk of the lower extremities
  • Progressive mild loss of proprioception and vibratory sense in the distal lower extremities

Autosomal dominant HSP chromosomes

AD Hereditary Spastic Paraparesis

• General considerations:
  • Two forms based on age at presentation
    • Type 1 < age 35
    • Type II > age 35
  • Sib-Sib correlation in age of onset is high; onset occurs in the same decade in 2/3 of families
  • Mean age of onset in males and affected offspring is earlier than females
  • Penetrance is variable; inter and intra familial phenotypic variation is normal

Clinical features of AD HSP type 1

• Onset occurs in the first to fourth decade
• Initial presentation:
  • Motor delay
  • Abnormal gait
  • Leg weakness
  • Asymptomatic
• Upper extremity:
  • Weakness < 26%
  • Hyperreflexia 45%
  • Mild ataxia 15%

Lower Extremity Signs and Symptoms of Type 1

• Spasticity – 90%
• Weakness – 55%
• Distal sensory loss – 20%
• Urinary symptoms – 15%
• Pes cavus – 30%
• Disease duration 20–35 years
• Wheelchair bound by age 60

Clinical Presentation AD Type II

• Onset third to seventh decade
• Initial presentation:
  • Abnormal gait
• Upper extremity signs and symptoms:
  • Weakness – 47%
  • Hyperreflexia – 50%
  • Ataxia – 20%

Lower Extremity Signs and Symptoms

• Spasticity – 100%
• Weakness – 90%
• Distal sensory loss – 80%
• Urinary symptoms – 50%
• Pes caves – 20%
• Disease duration – 15 to 25 years
• Loss or depression of ankle reflexes 15%
• Sexual dysfunction rare and a late occurrence
• Increased abdominal reflexes early
• No bowel dysfunction
• Type II more severe symptoms than Type 1 in general
• Babinski signs are present
• Decreased strength of iliopsoas, hamstrings an anterior tibialis muscles

Specific Autosomal Dominant Diseases

SPG3

• General considerations:
  • Chromosome 14q; 10–15% of all AD patients with AD HSP
  • Anticipation occurs
• Clinical features:
  • Pure form
  • Anticipation has been noted

SPG 3A

• General considerations:
  • AD
    • Atlastin 1 mutation
  • Early onset
  • Disease of African Americans
• Clinical features:
  • Age of onset, 4–14 years
  • Primarily pure spastic gait disorder
  • No spasticity in upper limbs
  • Rare tongue fibrillation, decreased visual acuity
  • Decreased visual acuity

• Differential point from SPG4:
  • Delayed auditory and visual evoked potentials

SPG4

• General considerations:
  • Chromosome 2p22
    • Spastin gene
  • Most common form of AD spastic paraparesis
• Clinical features:
  • Pure form
  • Decreased vibration
  • Urinary symptoms

SPG6

• General considerations:
  • Chromosome 15q
• Clinical features:
  • Pure form
  • Pes cavus

SPG8

• General considerations:
  • Chromosome 8q
• Clinical features:
  • Pure form

SPG9

• General considerations:
  • Chromosome 10q 23.3–q24.2
• Clinical features:
  • Cataracts
  • Gastrointestinal reflux
  • Motor neuropathy

SPG10

• General considerations:
  • Chromosome 12q13
  • Kindred described coding for kinesin
    • Possible microtubule binding activity
• Clinical features:
  • Pure form

SGP12

• General considerations:
  • Chromosome 19q13
• Clinical features:
  • Pure form

SGP13

• General considerations:
  • Chromosome 2q24–34
• Clinical features:
  • Pure form

Autosomal Recessive HSP

SPG5

• General considerations:
  • Chromosome 8q
• Clinical features:
  • Pure form
  • Onset first decade; disease duration of 10–30 years
  • Initial sign is a spastic gait
  • Upper extremity weakness (30%) and hyperreflexia – 50%
  • Lower extremity signs and symptoms:
    • Spasticity 100%
    • Weakness of legs 90%
    • Distal sensory loss < 20%
    • Urinary symptoms 30%
    • Pes cavus 50%
    • Sib-sib correlation of time of onset less than AD form of HSP

SPG7

• General considerations:
  • Chromosome 16q; paraplegin gene
    • Associated with mitochondrial abnormalities of skeletal muscle
    • Nuclear encoded
    • Proteolytic and chaperone activities
    • Many but not all patients have ragged red fibers and cytochrome oxidase negative fibers
• Clinical features:
  • Pure form
  • Complicated form associated with:
    • Dysphagia and dysarthria
    • Optic atrophy
    • Axonal neuropathy
    • Cerebellar and cerebral atrophy
    • Evidence of vascular lesions
    • Mitochondrial defects on muscle biopsy

SPG14

• General considerations:
  • Chromosome 3q 28
• Clinical features:
  • Complicated form associated with:
    • Mental retardation
    • Distal motor neuropathy

Autosomal Recessive Spastic Paraparesis with a Thin Corpus Callosum

• General considerations:
  • AR; primarily in Japanese patients; linked primarily to chromosome 15q13–15
• Clinical features:
  • Mental retardation
  • Spastic paraparesis
  • Symptoms start in second decade
  • Associated sensory loss and urinary incontinence develop with age
• MRI evaluation:
  • Thinned corpus callosum
• Magnetic stimulation demonstrate abnormalities in central motor pathways

Differential Diagnosis of AR HSP with Thin Corpus Callosum

• Corpus callosum agenesis with peripheral neuropathy (Andermann syndrome)
  • Mental and physical retardation
  • Seizures
  • Sensorimotor polyneuropathy
  • Optic atrophy
• CRASH Syndrome

X-Linked Recessive HSP

SPG1

• General considerations:
  • LICAM gene (neural cell adhesion molecule)
    • Variably expressed in females
    • Allelic to MASA cell adhesion syndrome whose clinical features are:
      • Mental retardation
      • Aphasia
      • Spastic paraplegia
      • Adducted thumbs
    • Other LICAM gene mutation syndromes
• Clinical features:
  • Thin corpus callosum
  • Mental retardation
  • Adducted thumbs
  • Spastic paraparesis
  • Hydrocephalus
• Complicated form associated with:
  • Hydrocephalus
  • Aphasia
  • Adducted thumb

SGP2

• General considerations:
  • Chromosome Xq11.2
  • Proteolipid protein gene (PLP)
    • Encodes an intrinsic myelin protein
    • Allelic to Pelizaeus–Merzbacher disease
• Clinical features:
  • Early onset severe and slowly progressive phenotypes have been noted in the same families
  • Associated CNS white matter lesions
  • Pure form:
    • Onset up to the second decade
    • Disease duration 10–25 years
    • Initial presentation
      • Spastic gait
    • Upper extremity signs and symptoms:
      • Weakness-none
      • Hyperreflexia < 10%
    • Lower extremity signs and symptoms
      • Spasticity – 80%
      • Weakness – none
      • Rare distal sensory loss
      • No urinary symptoms
      • No pes cavus

X-Linked Recessive HSP Allelic to Pelizaeus–Merzbacher Disease (PMD)

• Clinical features:
  • Progressive dementia
  • Nystagmus noted in infancy
  • Choreoathetosis
  • Spasticity
  • Diffuse cerebral hypomyelination by MRI

Differential Diagnosis

• Complicated hereditary Spastic Paraparesis
  • Spectrum of genetically distinct diseases
  • Spastic paraparesis is associated with other neurological deficits that may be predominant

AR Complicated HSP

• Associated neurological signs
  • Cerebellar degeneration
  • Sensory neuropathy
  • Optic atrophy and dysarthria
  • Amyotrophy resembling ALS
  • Deranged skin pigmentation

Associated neurologic syndromes associated with AR HSP

• Charlevoix–Saquennay
  • Dysarthria
  • Ataxia
  • Distal amyotrophy
  • Spastic paraparesis
  • French Canada
• Mast's Syndrome:
  • Dysarthria
  • Dementia
  • Athetosis
  • Spastic paraparesis
• Troyer's Syndrome
  • Short stature
  • Mental retardation
  • Ataxia
  • Amyotrophy
  • Spastic paraparesis
• Sjögren–Larsson Syndrome
  • Ichthyosis
  • Mental retardation
  • Spastic paraparesis
• Hellin's Syndrome
  • Mental retardation
  • Macular degeneration

AD Complicated Hereditary Spastic Paraparesis

• Signs associated with spastic paraparesis
  • Cerebellar degeneration
  • Amyotrophy of the hands
  • Peroneal muscular atrophy
  • Sensory neuropathy
  • Intention tremor
  • Extrapyramidal signs
  • Muscular dystrophy
  • Abnormal skin pigmentation
• Symptom complexes associated with hereditary spastic paraparesis
  • Dystonia, athetosis, dementia, amyotrophy
  • Retinal degeneration, dementia, dysarthria, amyotrophy
  • Optic atrophy

Associated Neurologic Signs and Symptoms with X-Linked Recessive Complicated Hereditary Spastic Paraplegia

• Mental retardation and optic atrophy
• Deafness
• Dysarthria, athetosis, amyotrophy

Differential Diagnosis of Hereditary Forms of Spastic Paraplegia

Machado–Joseph Disease (SCA3)

• General considerations:
  • Chromosome 14
    • AD
  • CAG repeat disease
• Clinical features:
  • Ataxia
  • External ophthalmoplegia
  • Spastic paraparesis
  • Bulging eyes
  • Amotrophy

X-Linked ALD

• General considerations:
  • Disease of CNS white matter and the adrenal cortex:
    • ABCD1gene
  • Incidence of 1 in 50,000 people
  • Four major subgroups in affected males:
    • Childhood form (severe)
    • Adolescent form
      • Onset between 10–21 years
    • Adrenomyeloneuropathy (AMN)
      • Onset in the late twenties
      • Sphincter disturbances
      • Distal sensory loss
      • Progressive paraparesis
    • Primary adrenal insufficiency
      • Slowly progressive over decades
      • No neurologic abnormalities
    • ALD has X-linked inheritance
      • Carrier females have neurological signs and symptoms (usually AMN phenotype)
      • Mean age of onset 38 years; later onset than males
      • Reduced penetrance; milder phenotype in females
• Clinical features:
  • No real distinction clinically between HSP and AMN
• Laboratory features of ALD:
  • Plasma concentrations of very long chain fatty acids are increased in 99% of males; greater than 85% in females
• EMG evaluation:
  • AMN, a subtype of ALD frequently demonstrates decreased nerve conduction velocities

Adrenomyeloneuropathy (AMN)

• General considerations:
  • Subtype as noted above of X-linked ALD
• Clinical features:
  • Onset after the second decade
  • Progressive spastic paraparesis
  • Prominent sensory loss in the legs
  • Sphincter disturbances
  • Female carries have spastic paraparesis
  • Hypoadrenalism
  • Hypogonadism
• Laboratory evaluation:
  • Very long chain fatty acids
  • Choreoathetosis Spasticity Syndrome
  • Planto–Palmar Keratoderma (PPK)

Werner's Syndrome

• General considerations:
  • Chromosome
    • AR
• Clinical features:
  • Premature balding
  • Severe atherosclerosis
  • Osteoporosis
  • Hypogonadism
  • Juvenile cataracts
  • Diabetes mellitus
  • Spastic paraparesis
  • Peripheral neuropathy

Mitochondrial defects

• General considerations:
  • AD
• Clinical features:
  • Spastic paraparesis

Familial Paroxysmal Dystonia I

Paroxysmal Non-Kinesigenic Dyskinesia (Paroxysmal Dystonic Choreoathetosis)

• General characteristics:
  • AD; chromosome 2 q 26–31; calcium channelopathy
• Clinical features:
  • Attacks last minutes to hours
  • Occur spontaneously at rest
  • Dystonia, chorea, athetosis, ballism and speech arrest; combinations of these movements may occur
  • Preceded by paresthesias, stiffness and occasionally formications
  • Triggered by stress, fatigue, caffeine, alcohol
  • Frequency is less than PKC
• Pathology:
  • Familial
  • Some patients linked to chromosome 2 q:
    • Migraine prevalent in these patients
    • Diazepam drug of choice
  • Hypoparathyroidism
  • Perinatal encephalopathy
  • Basal ganglia calcification
  • Infantile hemiplegia
  • Head trauma
  • Thyrotoxicosis
  • HIV infection
  • Anoxia
  • Brain tumor

Variants of Kinesigenic Dyskinesia

• General characteristics:
  • Paroxysmal exertion induced dyskinesia
• Clinical features:
  • Induced by prolonged exercise
  • Legs affected greater than arms

Paroxysmal Hypnogenic Dyskinesia

• Clinical features:
  • Involuntary movements only occur during sleep

Globoid Cell Leukodystrophy (Krabbe's Disease)

• General considerations:
  • AR
  • Deficiency of galactosylceramidase
• Clinical features:
  • Adult onset variant
  • Optic atrophy
  • Seizures
  • Spastic paraparesis
• Laboratory evaluation:
  • Marked slowing of NCV by EMG
  • High CSF protein
  • Multinucleated macrophages or globoid cells in CNS white matter

Metachromatic Leukodystrophy

• General considerations:
  • ARSA gene
  • Lysosomal enzyme arylsulfatase A deficiency
• Clinical features:
  • Late infantile, onset 6 months to 2 years
  • Juvenile, onset 3 to 16 years
  • Adult MLD presentation:
    • Behavioral abnormalities (psychosis)
    • Spastic paraparesis
    • Pathology:
      • Metachromatic inclusions within Schwann cells and macrophages
      • Segmental peripheral nerve demyelination abnormality thin myelin sheaths
  • AB Variant
    • Activator protein deficiency
    • Normal in vitro activity of arylsulfatase A

Dentato-Rubral-Pallido-Luysian Atrophy (DRPLA)

• General considerations:
  • Chromosome 12p; usually 49–88 repeat CAGA nucleotides
  • Homozygosity for an allele carrying intermediate CAG repeat number
• Clinical features:
  • Adult onset > 40 years of age
    • Ataxia
    • Choreoathetosis
    • Dementia
  • Specific patient with paraparesis and:
    • Truncal ataxia
    • Dysarthria
    • 41 CAG repeats
    • No dementia, seizure, myoclonus or other involuntary movements

Familial Hyperlysinemia

• General considerations:
  • AR; AASS gene
  • Deficiency of alpha-amino adipic semialdehyde synthases essential for lysine degradation
• Clinical features:
  • Intellectual impairment
  • Epilepsy
  • Progressive spastic paraparesis
• Laboratory evaluation:
  • Hyperlysinemia
  • Hyperlipinuria

Adult Onset Alexander's Disease

• General considerations:
  • AR; mutation affects GFAP
  • Intermediate filament glial fibrillary acidic protein (GIAP)
  • Astrocytic cytoplasmic inclusions called Rosenthal fibers
• Clinical features:
  • Onset third to fifth decade
  • Early exacerbations
  • Palatal myoclonus
  • Cerebellar dysfunction
  • Hyperreflexia
  • Spastic paraparesis