AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Primary lateral sclerosis (PLS) is a progressive, degenerative disease of upper motor neurons characterized by progressive spasticity (ie, stiffness). It affects the lower extremities, trunk, upper extremities, and bulbar muscles (usually in that order).

Classification of motor neurons

The cell bodies (soma) of lower motor neurons reside in the spinal cord or the brain stem, and the axons ("fibers") are connected directly to muscles at the neuromuscular junctions. These are considered first-order motor neurons because they are connected directly to the muscles.

The soma of upper motor neurons reside in the brain, where they control the activity of lower motor neurons. Second-order motor neurons can be distinguished from higher-order motor neurons. Second-order motor neurons are upper motor neurons whose cell bodies reside primarily in the precentral gyrus or the primary motor cortex of the frontal lobe. They send fibers that directly connect to lower motor neurons in the brain stem that innervate the muscles of the face, pharynx, and larynx or to lower motor neurons in the spinal cord that innervate the limb, trunk, and respiratory muscles.

Third- and higher-order motor neurons are located in the frontal lobes of the brain anterior to the precentral gyrus (ie, the "prefrontal cortex"). These neurons are involved in planning and organizing motor activity and direct the second-order motor neurons. The soma of these third- and higher-order motor neurons reside in the brain, and their axons form associative or commissural projections within the brain.

Classification and terminology of motor neuron diseases

Motor neuron diseases (MNDs) are progressive degenerative diseases in which death of the cell bodies of motor neurons is the primary process. These should be distinguished from diseases in which primarily the axons of motor neurons are affected. The traditional classification of MNDs is according to the affected cell types, as follows:

• Upper motor neurons alone - PLS
• Lower motor neurons alone - Progressive muscular atrophy (PMA) and the spinal muscular atrophies (SMAs)
• Upper and lower motor neurons - Amyotrophic lateral sclerosis (ALS)

ALS is the most common of the MNDs. In British-English–speaking areas, ALS is often called "motor neurone disease" (singular), but this chapter will reserve the term MNDs (usually in plural form) as an umbrella term. Therefore, not every MND is ALS.

Clinical presentation

ALS may present initially with signs of only upper or lower motor neuron involvement. Thus, a process that initially is considered PMA or PLS has the potential to be reclassified as ALS if sufficient signs of both upper and lower motor neuron involvement develop over time. In some cases, such reclassification may occur only at autopsy (eg, pyramidal tract involvement is found in patients who did not have signs of upper motor neuron involvement during life and whose disease was therefore classified on clinical grounds as PMA).

Recent reports have described patients with one of the genes for familial ALS in whom only lower motor neuron involvement was seen during life and at autopsy. Most investigators would classify this disease pattern as ALS, on the basis of the gene's presence (even though its clinical expression was incomplete). This position is supported by the recently revised World Federation of Neurology diagnostic criteria for ALS.

Patients with PLS occasionally have mild, nonspecific, and nonprogressive findings of denervation on electrodiagnostic testing. The severity of the denervation and re-innervation does not resemble that seen in ALS and does not justify these patients' being classified as having ALS. These patients may be concerned that their PLS eventually could evolve into ALS. Although absolute guarantees cannot be given, deriving some measure of reassurance from the overall slow progression in these patients is reasonable.

Pathophysiology

The cause of PLS is unknown. The terms pathophysiology and pathogenesis refer at this time to histological consequences of unknown etiologic factors, which result, in turn, in the clinical manifestation of PLS.

Five reports that include autopsy findings in 6 patients with PLS differ in the pathological changes they describe. Two major factors may account for the different pathological findings. First, uncertainties exist regarding the diagnosis in some of the series. This is discussed below in regard to one of the patients in the series described by Pringle et al in 1992. Second, since the diagnosis of PLS is based on clinical presentation and the exclusion of known look-alikes, the identification of more than a single pathologic process once the histology becomes available is not surprising.

Younger et al described 3 patients who had demyelination of the corticospinal tracts without gliosis or discernible loss of Betz cells in the precentral gyrus. The pathology in these patients appeared to affect the myelin sheath of the axon of the upper motor neuron or the axon itself rather than that of the upper motor neuron cell body. The clinical course in these patients was faster than that of the typical patient with PLS; one died within 13 months of onset, and another was bedridden within 2 years of onset.

In contrast, histologic findings in the 3 other patients were of involvement of the precentral gyrus and loss of Betz cells. Brain MRIs of 7 patients reported by Pringle et al showed cerebral atrophy that was most pronounced in the region of the precentral gyrus in 5 patients, was present only in the precentral region in 1 patient, and was most prominent in the frontoparietal region in another patient. These imaging findings are consistent with the findings at autopsy.

Single photon emission computed tomography (SPECT) studies in 2 patients showed reduced uptake in the motor cortex, as did positron emission tomography (PET) studies in 2 of 3 patients (Pringle et al, 1992). Magnetic resonance spectroscopy (MRS) showed abnormal N-acetylaspartate/creatine ratios in 12 of 18 patients with PLS.

Clinical neurophysiologic studies confirm upper motor neuron dysfunction in PLS: motor evoked potentials (MEPs) are absent or delayed, and peripheral conduction is normal. Minimal denervation activity (ie, fibrillation potentials) may be found in distal muscles.

In summary, PLS is a clinical diagnosis, and most reports (combining imaging and autopsy series) indicate neuronal loss in the precentral gyrus. However, more than one pathologic process may be responsible for the clinical presentation. For example, diffuse Lewy body disease was the underlying pathology in 1 patient who presented with PLS by clinical criteria.

Frequency

United States

Data on the incidence of PLS are uncertain. In contrast, data on ALS are well documented: ALS affects 2-3 individuals per 100,000 population each year. The 8 patients with PLS reported by Pringle et al in 1992 were identified over a period of 10 years among a population of 500 patients with ALS. Inferring a population base of approximately 4 million people from the ALS patient data (assuming these are mixed prevalence and incidence data) would result in a prevalence of 2 per million for PLS, assuming all cases were identified.

Further assuming an average disease duration of 20 years (close to the reported median of 19 y), this prevalence would translate into an annual PLS incidence rate of 1 per 10 million (0.01 case per 100,000 population per year), which is approximately 0.5% of that of ALS. The tentative nature of these estimates should be emphasized. They are consistent with a conservative estimate that not more than 500 people with PLS currently are living in the United States. Independent validation of this estimate would be difficult. Recent case reviews by Pringle et al suggest that half may not have had PLS; this would reduce the estimates above accordingly.

Adult-onset PLS is a sporadic disease. An autosomal-recessive, childhood-onset form has been described. A genetically mediated look-alike, progressive familial paraparesis, is a separate condition with a more limited clinical extent and a more benign course.

Mortality/Morbidity

In general, PLS is not considered to shorten life expectancy. It may affect the quality of life gradually and adversely as progressive disability and dysfunction accrue. This may not be true for patients who are young at onset, whose lives may be shortened by PLS.

Sex

The female-to-male ratio in a report of 8 patients was 1:1. However, only 1 of 9 patients reported by Younger et al in 1988 was female. The small numbers preclude a definitive statement regarding predilection to PLS.

Age

The reported age of onset ranges from 35-66 years with a median of 50.5 years in one series. Onset in a patient as young as 20 years was reported by Younger et al in 1988.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• PLS usually presents with gradual-onset, progressive, lower-extremity stiffness and pain due to spasticity. Onset is often asymmetrical.
• Pringle et al in 1992 reported ages of onset that ranged from 35-66 years (median 50.5 y), while Younger et al in 1988 reported onset in a patient as young as 20 years in another series. The median duration of PLS is approximately 20 years.
• As PLS progresses, patients may develop balance problems with a tendency to fall. Axial muscle involvement may result in lower back and neck pain, which may aggravate back or neck pain from other causes (eg, degenerative disc disease, osteoporosis).
• As the upper extremities become involved, patients may have difficulties with activities of daily living (ADLs). Involvement of the organs of speech may result in spastic dysarthria (which initially may be mild).
• Swallowing and breathing may be compromised late in the disease.
• The slow rate of progression provides most patients and families with time to adapt to the changes and identify resources for support. Conversely, the overall duration and magnitude of the burden placed on the family and caregivers is commensurately greater than it would be in a more rapidly progressing disease.
• General considerations
• • The most common causes of myelopathy in this age group are cervical spondylosis and chronic progressive multiple sclerosis (MS). Both are more common than PLS.
  • Some conditions may present initially with pure upper motor neuron dysfunction, such as progressive multifocal leukoencephalopathy (rarely without the characteristic MRI findings) or spongiform encephalopathy, but have a rapid course that would preclude consideration of PLS.
  • If appropriate, also consider and exclude HIV-associated myelopathy.
  • Whether serial electromyography (EMG) has a role in diagnosis of PLS is uncertain; EMG would be used to look for evolution of lower motor neuron findings in the absence of clinical evidence to suggest a change into ALS.

Physical

• Signs of upper motor neuron dysfunction may include limb and trunk spasticity, pathological spread of deep tendon reflexes, clonus, pathological reflexes (such as Babinski sign), and spastic dysarthria.
• Signs of involvement of other systems should not be present. In particular, no cerebellar findings, involuntary movements, sensory findings, findings suggesting lower motor neuron dysfunction (such as fasciculations), visual findings, or bladder dysfunction should be observed.
• Diagnostic criteria
• • The diagnostic criteria for PLS proposed by Pringle et al in 1992 include insidious onset of spastic paresis in adults, which usually begins in the lower extremities. Affected individuals typically have no family history of similar disorders.
  • Spastic pareses should be symmetric and progress gradually in a manner consistent with corticobulbar and corticospinal tract dysfunction. Duration should be at least 3 years, and other diagnoses should be excluded by imaging and laboratory tests.
  • The suggestion by Pringle et al that the diagnosis may be made within 3 years of symptom onset contradicts the 5 years' duration that was required by the criteria proposed by Stark and Moersch in 1945. The criteria of Pringle et al also permit bulbar or upper extremity onset for PLS.
  • One patient in the series of Pringle et al, who was diagnosed as having PLS by their criteria but not according to the criteria of Stark and Moersch, had bulbar onset and progressed to "essentially anarthria" within 2 years.
    • This patient showed occasional fibrillation potentials in the pronator quadratus, thenar, and interosseus muscles 4 years after onset of disease.
    • The reported follow-up ( <5 y) was the shortest in that series.
    • This patient's course resembles that of ALS (albeit with a slower than average rate of progression) more than PLS.

    Thirteen out of 29 patients with UMN symptom onset reported by Gordon et al, initially diagnosed as PLS, evolved to UMN-dominant ALS over within 3.7 years of symptom onset. They advise a period of 4 years of observation, before a patient is considered to have PLS.

  • Thirteen of 29 patients with upper motor neuron symptom onset reported by Gordon et al, initially diagnosed as having PLS, evolved to having upper motor neuron–dominant ALS within 3.7 years of symptom onset. Gordone et al advised a period of 4 years of observation before a patient is considered to have PLS. However, in patients with bulbar onset, requiring a 5-year period of observation and greater diligence to exclude lower motor neuron involvement may be prudent before diagnosing PLS (rather than ALS).
• In summary, concern for future evolution into ALS cannot be allayed by a workup shortly after symptom onset.
• • Lower extremity onset and slow progression (at least 3-5 y) would increase confidence in the diagnosis of PLS and decrease the likelihood of a later evolution into ALS.
  • From the standpoint of disease impact on patient survival and disability, rate of progression rather than diagnostic classification is the determining factor. Nevertheless, acceleration of the course may be expected if lower motor neuron signs develop in a patient who was thought to have PLS.

Causes

The cause of PLS is not known.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hereditary spastic paraparesis (HSP)
Konzo
Neurolathyrism
Spinocerebellar ataxias
Tumors of the spinal cord

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies should include hemogram, erythrocyte sedimentation rate, vitamin B-12 level, and, as indicated, Venereal Disease Research Laboratory (VDRL) (or rapid plasma reagent [RPR]), Lyme, and HIV serology tests.
• Cerebrospinal fluid (CSF) analysis should include protein and glucose concentrations, cell count, and an MS panel.

Imaging Studies

• MRI studies are obtained to exclude alternative diagnoses. MRI, MRS, SPECT, and PET changes have been described in some patients, but the usefulness of these studies in making the diagnosis early in the presentation of PLS is not known.
• Similarly, diffusion tensor imaging and magnetization transfer imaging may provide insight into the pathophysiological process of ALS and PLS, by providing objective imaging evidence to support the clinical findings of upper motor neuron dysfunction. Further investigation is needed to determine and to compare the utility of various neuroimaging markers in making the diagnosis of PLS, in comparison to the clinical examination findings.
• At this time, therefore, these advanced imaging techniques cannot be used alone to confirm or exclude the diagnosis of PLS.

Other Tests

• Motor and sensory nerve conduction studies should be normal.
• Needle EMG helps distinguish PLS from ALS by identifying electrophysiologic evidence of widespread lower motor neuron involvement.
• Repeat electrodiagnostic testing occasionally is needed to determine whether lower motor neurons are involved.
• As overall activity diminishes, muscle atrophy may suggest lower motor neuron involvement. Such changes may be distinguished from muscle atrophy due to disuse secondary to upper motor neuron impairment on clinical grounds (eg, no fasciculations) and, more definitively, by electrophysiological testing. Occasionally, sparse, scattered, nonprogressive changes of denervation (ie, fibrillation potentials) may be seen in distal muscles.
• Motor evoked potentials may show abnormalities of the upper motor neurons, but this test is not readily available in many centers.
• Lower extremity somatosensory evoked potentials occasionally show prolonged latencies in patients with PLS, in the absence of sensory symptoms. This subclinical involvement of central sensory axons suggests that in those patients, the disease pathophysiology is not restricted to upper motor neurons, but rather affects them preferentially.
• Genetic testing for HSP may be considered if the presentation and family history suggest the condition, and the results of the testing can be used to impact the management of the patient. Appropriate genetic counseling should be offered patients with HSP, and patients should be referred for genetic testing.

Procedures

• A lumbar puncture should be considered to rule out other causes of spasticity (eg, MS) after appropriate imaging studies have been obtained.

Histologic Findings

See Pathophysiology.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Mechanism-specific treatments directed at the pathological process that underlies PLS have not been identified. Consequently, treatments are directed at alleviating symptoms and may be classified as follows:

• Pharmacologic: Treatments for spasticity include baclofen (Lioresal), tizanidine (Zanaflex), and the benzodiazepines, such as diazepam (Valium) or clonazepam (Klonopin). Patients in whom oral treatment does not provide adequate relief may wish to consider intrathecal baclofen (ie, infusion of medication directly into the CSF via a surgically placed continuous infusion pump). However, patients must be selected appropriately to ensure that those who receive this treatment are likely to benefit. Patients who experience pain due to spasticity may benefit from analgesics. Those who become depressed may require antidepressants.
• Physical therapy: Stretching exercises, usually used in combination with pharmacologic treatment, may help alleviate spasticity. A program of stretching/strengthening exercises, which may be done at home, may promote full range of joint motion and reduce the risk of contractures. Patients who are weak may require passive range of motion exercises to be administered by their caregivers. Attempting to overcome severe spasticity with physical therapy alone may result in torn or strained muscles or tendons. Hence, physical therapy that causes pain should be avoided or modified. Other modalities, such as massage or pool therapy, may provide symptomatic relief.
• Assistive devices: These may be needed to compensate for specific disabilities. Periodic evaluation for these by physical and occupational therapists may be beneficial.
• Support groups: Due to the rarity of PLS, support groups exclusive to patients with PLS are not likely to be available. Subscription to the national PLS newsletter may enable patients to identify others within a community with whom they might form an informal support group (see Patient Education).
• Multidisciplinary clinic: Armon reported in 1999 that patients in the later stages of PLS may benefit from evaluation and follow-up at multidisciplinary clinics such as those available for the more common ALS. These multidisciplinary clinics may provide, in a single location, physical and occupational therapy, speech and swallowing evaluation and therapy, nutritional assessment and counseling, and respiratory assessment.
• Other: Patients late in the course of PLS may develop ventilatory failure and may require noninvasive ventilatory support.

Surgical Care

Some patients with spasticity that is not controlled with oral medications may be candidates for intrathecal baclofen. A continuous infusion pump is implanted surgically under the skin with the tip of the infusion catheter in the thecal sac.

Consultations

Depending on the type and degree of dysfunction, the following consultations may be considered:

• Physical medicine specialist
• Occupational therapist
• Psychologist/psychiatrist: Many patients with PLS present with neurocognitive impairments reflecting an executive dysfunction. Formal assessment may help in educating patients and families and set the stage for using ameliorative and coping strategies.
• Nutritionist
• Genetic counselor: Appropriate genetic counseling should be offered to patients with HSP and patients with unexplained upper motor neuron symptoms who are referred for genetic testing.

Diet

A balanced diet based on the patient's physical activity and other needs is recommended to avoid excessive weight gain or inanition.

Activity

Activity should be maintained as tolerated to maximize existing function and to preclude accelerated dysfunction due to disuse and development of contractures.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications to alleviate spasticity are discussed here. Patients in whom oral medications do not provide adequate relief may wish to consider intrathecal baclofen (ie, via continuous infusion pump).

Drug Category: Skeletal muscle relaxants

These agents are used to treat reversible spasticity associated with MS or spinal cord lesions.

Drug Name	Tizanidine (Zanaflex)
Description	Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces.
Adult Dose	4-32 mg/d PO in divided doses; titrate dose until beneficial effects observed or adverse effects preclude further increases
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, cognitive impairment, liver dysfunction
Interactions	Tizanidine-induced somnolence, stupor may be increased by alcohol; clearance decreased by oral contraceptives; can increase hypotensive effects when administered with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal impairment; may result in elevation of liver enzymes; may result in cognitive changes or fatigue; avoid driving or other activities requiring alertness until cognitive functions no longer affected

Drug Category: Benzodiazepines

These agents may act in the spinal cord to induce muscle relaxation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Frequency of outpatient follow-up depends on the patient's need for symptom control. It may range from monthly initially to every 4-6 months once optimal treatment is established (provided that no new symptoms appear).

Complications

• Dysfunction and disability accrue as PLS progresses. These are dealt with by the treating physician as they arise.

Prognosis

• Dysfunction and disability accrue as PLS progresses. In most cases, because of its slow course over approximately 20 years, PLS does not clearly shorten patients' lives. This may not be true for patients who are very young at PLS onset, because their premorbid life expectancy would have been more than 20 years.
• PLS progresses at a much slower rate than ALS. Therefore, patients with PLS may expect to live longer.
• Issues of progressive disability are shared by all patients with all forms of MNDs, regardless of type.
• Disability is usually commensurate with clinical progression and develops at a slower rate in patients with PLS than in those with ALS. The specific disabilities of the 2 diseases may differ.

Patient Education

• Physician's role
• • Distinction between PLS and other MND (particularly ALS) and the uncertainty of PLS evolving into ALS
  • Availability of fairly effective symptomatic treatment using a multidisciplinary approach
  • The possible (current or future) impairment or medication effects that would make driving, operating some types of machinery, and certain work environments (such as working on roofs or ledges) unsafe
• Information resources for patients: These resources are listed for informational purposes. Listing these resources does not imply endorsement. Patients should obtain specific treatment recommendations from their physicians.
• • PLS Web site - Primary Lateral Sclerosis Web Site
  • Newsletter - SYNAPSE: A PLS Newsletter, 95 Campion Road, North Andover, MA 01845 or email markw732@yahoo.com
  • Discussion groups
    • Yahoo Health Groups PLS-FRIENDS
    • National Organization for Rare Disorders, 55 Kenosia Avenue, PO Box 1968, Danbury, CT 06813-1968.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• PLS and its treatment may interfere with the ability to operate a motor vehicle (or other mechanical machinery) safely. The work environment should be reviewed for potential risks (eg, working on a roof or a narrow ledge). Patients with early PLS may not be limited in these respects, but they should be reassessed as the disease progresses.
• • Patients and physicians should follow the specific laws of their jurisdictions regarding notification of licensing authorities and automobile insurers.
  • Patients should be informed of these risks and counseled in accordance with the laws of their jurisdiction, taking their present and future condition into consideration. Such communications should be documented carefully.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families, and friends. Third ("Year 2000") Edition. 18pp. Loma Linda, California. 1999. [Full Text].
• Arruda WO, Coelho Neto M. Primary lateral sclerosis. A case report with SPECT study. Arq Neuropsiquiatr. Sep 1998;56(3A):465-71. [Medline].
• Beal MF, Richardson EP. Primary lateral sclerosis: a case report. Arch Neurol. Oct 1981;38(10):630-3. [Medline].
• Brown WF, Ebers GC, Hudson AJ, et al. Motor-evoked responses in primary lateral sclerosis. Muscle Nerve. May 1992;15(5):626-9. [Medline].
• Brugman F, Wokke JH, Vianney de Jong JM, et al. Primary lateral sclerosis as a phenotypic manifestation of familial ALS. Neurology. May 24 2005;64(10):1778-9. [Medline].
• Caliandro P, Pazzaglia C, Tonali P, Padua L. Diagnosis of multifocal motor neuropathy. Lancet Neurol. Jul 2005;4(7):393; author reply 393. [Medline].
• Chan S, Shungu DC, Douglas-Akinwande A, et al. Motor neuron diseases: comparison of single-voxel proton MR spectroscopy of the motor cortex with MR imaging of the brain. Radiology. Sep 1999;212(3):763-9. [Medline].
• Cruz Martinez A, Trejo JM. Transcranial magnetic stimulation in amyotrophic and primary lateral sclerosis. Electromyogr Clin Neurophysiol. Jul-Aug 1999;39(5):285-8. [Medline].
• Donaghy M. Classification and clinical features of motor neurone diseases and motor neuropathies in adults. J Neurol. May 1999;246(5):331-3. [Medline].
• Fisher CM. Pure spastic paralysis of corticospinal origin. Can J Neurol Sci. Nov 1977;4(4):251-8. [Medline].
• Gascon GG, Chavis P, Yaghmour A, et al. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuropediatrics. Dec 1995;26(6):313-9. [Medline].
• Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology. Mar 14 2006;66(5):647-53. [Medline].
• Hudson AJ, Kiernan JA, Munoz DG, et al. Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res Bull. 1993;30(3-4):359-64. [Medline].
• Hudson AJ, Kiernan JA, Munoz DG. Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res Bull. 1993;30(3-4):359-64. [Medline].
• Lerman-Sagie T, Filiano J, Smith DW, Korson M. Infantile onset of hereditary ascending spastic paralysis with bulbar involvement. J Child Neurol. Jan 1996;11(1):54-7. [Medline].
• Milano JB, Neto MC, Hunhevicz SC, et al. Intrathecal baclofen for spasticity in primary lateral sclerosis. J Neurol. Jun 2005;252(6):740-1. [Medline].
• Park RM, Schulte PA, Bowman JD, et al. Potential occupational risks for neurodegenerative diseases. Am J Ind Med. Jul 2005;48(1):63-77. [Medline].
• Piquard A, Le Forestier N, Baudoin-Madec V, et al. Neuropsychological changes in patients with primary lateral sclerosis. Amyotroph Lateral Scler. Sep 2006;7(3):150-60. [Medline].
• Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain. Apr 1992;115 ( Pt 2):495-520. [Medline].
• Rowland LP. Primary lateral sclerosis, hereditary spastic paraplegia, and mutations in the alsin gene: historical background for the first International Conference. Amyotroph Lateral Scler Other Motor Neuron Disord. Jun 2005;6(2):67-76. [Medline].
• Stark FM, Moersch FP. Primary lateral sclerosis: a distinct clinical entity. J Nervous Mental Disease. 1945;102:332-337.
• Strong MJ, Gordon PH. Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?. Amyotroph Lateral Scler Other Motor Neuron Disord. Mar 2005;6(1):8-16. [Medline].
• Wang S, Melhem ER. Amyotrophic lateral sclerosis and primary lateral sclerosis: The role of diffusion tensor imaging and other advanced MR-based techniques as objective upper motor neuron markers. Ann N Y Acad Sci. Dec 2005;1064:61-77. [Medline].
• Younger DS, Chou S, Hays AP, et al. Primary lateral sclerosis. A clinical diagnosis reemerges. Arch Neurol. Dec 1988;45(12):1304-7. [Medline].

Article Last Updated: Mar 8, 2007