Primary Lateral Sclerosis

Etiology

The etiology of PLS remains unclear and is thought to occur sporadically.[1] Some study results suggest a genetic component, with reported genes associated with pathogenic variants of PLS, including juvenile onset (ALS2 and ERLIN2) and adult-onset (C9orf72).[2][7] Other genes of interest include PARK2, SYNE2, genes associated with HSP (eg, SPAST, SPG7, and SPG11), and genes associated with ALS and frontotemporal dementia (eg, FIG4, OPTN, UBQLN2, DCTN1, and TBK1).[2][8] Further studies are warranted to define the genetic contribution and pathophysiology of PLS.

Epidemiology

PLS is predominantly a disorder in men with a man-to-woman ratio between 2:1 and 4:1, which represents about 2% to 3% of patients with motor neuron disease.[9] The incidence is estimated at 0.1 per 100,00 per year.[2][10] No differences in ethnicity have been reported.[2][11] Symptoms typically start around the 5th to 6th decade of life, with the mean age of symptoms around 50 years, although heterogeneity exists.[1] Age of onset can help clinicians diagnose PLS as this is nearly a decade earlier than nonfamilial ALS and almost a decade earlier than HSP.[1][4] 

Pathophysiology

PLS is caused by dysfunction of the descending corticospinal tracts, although the precise molecular and cellular mechanisms remain unclear. PLS is a sporadic disease; only a small percentage of patients with clinically definite criteria for PLS will have identifiable pathological mutations.[1] One mechanism of upper motor neuron dysfunction is intracellular trafficking problems due to the lack of expression of Alsin, a protein encoded by ALS2.[12] In mouse models, depletion of Alsin led to the disintegration of corticospinal tract neurons in the pons, pyramidal decussation, and cervical spinal cord.[13] Recessive loss-of-function mutations in ALS2 have been seen in atypical forms of PLS, although these have also been seen in HSP.[2] Genetic knowledge regarding ALS, HSP, and PLS is still incomplete, and research is ongoing.

Histopathology

No pathognomonic histopathological changes are seen in PLS, but several changes are consistent with the diagnosis. These changes include chronic degeneration or loss of the white matter associated with the descending corticospinal tracts, absence of Betz cells, and degeneration of the primary motor cortex, with relative preservation of lower motor neurons.[14] Immunohistochemistry can show ubiquitin-immunoreactive neuronal cytoplasmic inclusion bodies in the motor cortex with mild or absent lower motor neuron involvement.[15] 

Ubiquitin-immunoreactive neuronal cytoplasmic inclusion bodies have also been detected in the hippocampus and prefrontal areas.[15] Transactive response deoxyribonucleic acid-binding protein of 43 kDa (TDP-43) inclusions can be seen in the primary motor cortex, corticospinal tract, hippocampus, and frontotemporal region of patients with PLS.[14][15] Although rare, TDP-43 immunoreactive pathology was found in lower motor neurons but averaged less than 1 inclusion per tissue section.[14] 

History and Physical

Clinical Features

PLS is predominantly found in men, with clinical onset usually in the 5th to 6th decade of life.[1] Symptom onset is insidious with slow progression, frequently involving the lower limbs first. A minority of patients can have bulbar onset with symptoms of dysarthria, dysphagia, nasal speech, and pseudobulbar affect.[1][2] Symptoms of PLS include stiffness, poor coordination, balance difficulties, urinary frequency or urgency, and bulbar symptoms.[1] Early involvement of the lower limbs is often described as gait disturbances, mild weakness, or a loss of balance. The progression of symptoms is generally slow, spreading from side to side and from region to region, with the average symptom duration ranging from 7.2 to 14.5 years.[5] Progression is variable and seems to stop after several years. PLS differs from ALS in that the need for a feeding tube or permanent assisted ventilation is low at 7% and less than 1%, respectively.[16] 

Involvement of the lower limbs in PLS is most frequently symmetric, although rare phenotypes have been described. A rare phenotype known as the “hemiplegic variant” is characterized by slow progressive ascending weakness that begins in a distal lower limb and progresses to a proximal ipsilateral lower limb or upper limb, with associated pyramidal signs.[17] Bladder involvement described as increased frequency and possible retention is common in PLS and is seen in around 33% to 50% of patients.[4][11] Cognitive impairment can also be observed within the spectrum of frontotemporal dementia and frontal lobe dysfunction (executive function), although not as commonly as in ALS.[1][2][18] Neuropsychiatric manifestations in PLS include deficits in social cognition, motivation, verbal fluency, and executive dysfunction.[3][19]

Physical examination reveals selective upper motor neuron (UMN) dysfunction, including hyperreflexia (eg, Hoffman sign and extensor toe responses), spasticity, or clonus. A UMN  pattern of weakness may also be seen, for example, in extensors in the upper extremities and flexors in the lower extremities. No sensory symptoms or lower motor neuron (LMN) signs (eg, fasciculations and muscle atrophy) should be present unless explained by another comorbid condition. Stiffness is seen more frequently as a presenting symptom in PLS compared to ALS (47% versus 4%).[14] Weakness described by the patient is often due to a combination of stiffness, increased tone, and reduced coordination rather than true muscle weakness. Abnormalities in ocular movements may also be seen, including the loss of smooth pursuit, issues with fixation, and supranuclear palsy.[20]

Diagnostic Criteria 

The 2020 consensus diagnostic criteria for PLS include age older than 25, symptoms of progressive UMN dysfunction for at least 2 years involving at least 2 of 3 regions (ie, lower extremity, upper extremity, or bulbar), and the absence of sensory symptoms unexplained by a comorbid condition, active LMN degeneration, or an alternative diagnosis that better explains symptoms.[4] Diagnostic certainty was introduced with the new diagnostic criteria and can be further characterized as probable PLS or definite PLS. Probable PLS is defined by the absence of significant active LMN degeneration at 2 to 4 years, and definite PLS is defined as more than 4 years from symptom onset. The probable PLS category aims to enroll patients with PLS earlier in clinical trials for possible disease-modifying treatment before disability becomes advanced. Clinical disability can be evaluated using the revised ALS Functional Rating Scale, Penn Upper Motor Neuron Score, the Modified Ashworth Scale, or the PLS functional rating scale.[21]

Evaluation

No diagnostic test can definitively diagnose PLS, as this condition is a clinical diagnosis that requires obtaining a thorough clinical history and family history and performing a comprehensive physical examination. Laboratory and diagnostic studies are used to rule out alternative causes of UMN dysfunction in the brain or spinal cord. 

Laboratory Studies 

Laboratory studies that exclude alternative differential diagnoses include vitamin B12, copper, human immunodeficiency virus, human T lymphotropic virus I/II, Lyme disease (in certain cases), cerebrospinal fluid (CSF) evaluation, and paraneoplastic panels.[1] Neurofilaments are an emerging biomarker that reflects and quantifies neuronal loss. These levels tend to be much lower in PLS than in ALS, but differences between UMN-predominant ALS and PLS warrant further studies.[22] CSF chitinases are another potential biomarker lower in PLS than in ALS. However, additional studies in larger cohorts and PLS versus UMN-predominant ALS are needed.[4][23] 

Electromyography

A diagnostic challenge in PLS is differentiating it from UMN-predominant ALS, especially in patients that present in the early phase of the disease. Further complicating diagnosis, the EMG in patients with PLS can sometimes show minor LMN changes, including sparse fibrillations usually limited to 1 or 2 muscles, fasciculations, and enlarged motor unit potentials.[5][24] Minimally increased insertional activity and positive sharp waves or fibrillation potentials in extremity muscles are permitted in the diagnostic criteria for PLS.[4] Electromyogram (EMG) findings that show mild and nonprogressive LMN involvement are tolerated in the probable PLS category.[4] A normal EMG with minimal denervation not fulfilling the El Escorial criteria for ALS is also needed to diagnose PLS. After 4 years, the probability of developing new LMN changes on EMG is low, around 20%.[15] Because of this, after 4 years from symptoms onset, probable PLS is defined as definite PLS.[4]

Imaging Studies

MRI of the brain and spinal cord must be negative for alternative causes of UMN symptoms, although atrophy of the precentral gyrus is allowed.[7] Brain MRI can sometimes be helpful and show focal “knife edge” atrophy of the precentral gyrus and T2 hyperintensities in the corticospinal tracts thought to be secondary from Wallerian degeneration; these changes are not specific to PLS.[1][6] Corpus callosum, brainstem, and cerebellar abnormalities can also be seen.[3][25][26] Significant diffusivity alterations in the superior cerebellar peduncle have been noted in PLS, which suggests cerebro-cerebellar pathway disruption likely contributing to the motor and coordination disability seen in PLS.[4] The presence of a “stripe sign” or focal fluorodeoxyglucose hypometabolism in the precentral gyrus has also been associated with PLS but is not a differentiating feature from ALS.[4][27]

Additional Diagnostic Studies

Transcranial magnetic stimulation (TMS) is a neurophysiological test that can quantify UMN dysfunction and may be helpful in the diagnosis of PLS. In patients with PLS, TMS shows longer central motor conduction times, higher cortical threshold, and absence of reproducible cortical responses in PLS compared to ALS.[24][28] Cortical excitability is also preserved in HSP, helping differentiate HSP from PLS using TMS.[29] TMS has the potential to aid in the diagnosis of PLS, but this technology is not widely available. 

Genetic testing can be helpful in complex cases and is usually performed in patients with symmetric progressive UMN involvement restricted to the lower limbs to differentiate PLS from HSP. HSP has over 50 different genes described, with the most common dominant and recessive forms secondary to mutations in SPG4 (spastin) and SPG11 (spatacsin), respectively. Additional testing for the C9orf72 mutation can also be done if there is a high suspicion of UMN-predominant ALS, although this mutation can sometimes occur in PLS.[13]

Treatment / Management

Currently, no cure or disease-modifying treatment for PLS has been identified.[1] Treatment is centered on symptom management and improving the quality of life in patients with PLS. Given the numerous symptoms seen in PLS, an interprofessional approach should be taken to improve mobility, reduce spasticity, and facilitate activities of daily living. Physical and occupational therapy are vital in improving gait and balance and can help determine the need for additional durable medical equipment. Speech therapy can be helpful in those with bulbar symptoms who have dysphagia or speech difficulties. Spasticity is often the most disabling symptom, and first-line oral agents include baclofen, benzodiazepines, and tizanidine. Patients who have sedating adverse events from these agents but have benefits may trial intrathecal baclofen and subsequent baclofen pump placement. Botulinum toxin type A can also be used to treat spasticity.[30]

Anticholinergics are used to manage excessive secretions similar to ALS. Examples include glycopyrrolate, scopolamine, or atropine drops. In select patients who do not respond to oral medications, botulinum toxin injection into the submandibular gland can be helpful. Cognitive and neuropsychological features can be seen in PLS, and cognitive screening tests should be implemented in patients with PLS to assess for possible frontotemporal dysfunction, language deficits, and problems with executive function.[3] Formal neuropsychological testing should be done in patients who perform poorly on these cognitive screening tests. 

Pseudobulbar affect is commonly seen in PLS, and recognition with screening and early treatment with medications can reduce social withdrawal and positively impact patients' quality of life. Treatment with dextromethorphan/quinidine is commonly used. In patients who cannot tolerate dextromethorphan/quinidine or do not benefit from treatment, amitriptyline or fluvoxamine can be trialed. However, neither has been studied in controlled trials for the pseudobulbar effect.[1] Screening for mood symptoms, especially depression, is essential, and early referral to a psychiatrist or therapist is recommended when appropriate. Riluzole, a Food and Drug Administration-approved drug for ALS that provides a modest survival benefit of a few months, has not shown survival benefits in patients with PLS and is currently not recommended in the treatment of PLS.[1]

Differential Diagnosis

The differential diagnosis of PLS includes neurodegenerative, neuroinflammatory, metabolic, infectious, structural, and vascular etiologies. Neurodegenerative conditions to consider include UMN-predominant ALS, HSP, and Alexander disease. Upper motor neuron-predominant ALS can be difficult to distinguish between PLS given similar initial clinical symptoms. The development of clinically progressive lower motor neuron involvement helps distinguish UMN-predominant ALS from PLS, although this may develop years after initial presentation. Features that are more common in UMN-predominant ALS compared to PLS include a bulbar onset of symptoms, weight loss, medical research council grade less than 4 on the initial visit, and reduced forced vital capacity.[4][31]

HSP and PLS have considerable clinical overlap, making distinguishing these diagnoses difficult. Both can have early onset lower limb involvement with marked UMN dysfunction. However, HSP usually has symmetrical weakness limited to the lower extremities rather than PLS, which can involve both the upper and lower extremities. A family history or relevant genetic variants is also seen in HSP, with up to 70 genetic variants recognized so far.[8] More common autosomal dominant forms of HSP will present in the second to third decade of life, while PLS mainly occurs in the fifth to sixth decade. The presence of a family history is more suggestive of HSP, as PLS is considered a sporadic disease. Other features that favor HSP include diminished vibratory sensation on physical exam, slower disease progression, absence of bulbar involvement, and earlier and symmetric onset of the disease.[4][32] Given the significant heterogeneity in PLS, genetic testing remains essential for diagnosing PLS and ruling out HSP. 

Neuroinflammatory conditions that can present similarly to PLS include primary progressive multiple sclerosis (PPMS) and stiff person spectrum disorder. PPMS is easily differentiated from PLS, with MRI showing inflammatory brain and spinal cord lesions. Stiff person spectrum disorder can present similarly but is distinguished through antibodies (eg, glutamic acid decarboxylase 65-kilodalton isoform, amphiphysin, glycine receptor, and dipeptidyl-peptidase-like protein 6) found in the serum or CSF. In seronegative cases with high suspicion for stiff person spectrum disorder, EMG can be helpful, showing co-contraction of agonist and antagonist muscles with continuous motor unit activity on insertion. Progressive solitary sclerosis is a rare disorder that can present with symmetrical and unilateral UMN dysfunction with progressive motor impairment that is considered a localized variant of multiple sclerosis. A single demyelinating lesion with oligoclonal bands in the cerebrospinal fluid is present in the central nervous system.[33]

Metabolic conditions that can present similarly to PLS include adrenomyeloneuropathy and deficiencies of copper and of vitamins such as B12 and E.[34] In its most severe form, vitamin B12 deficiency presents with subacute combined degeneration affecting the corticospinal tracts and the dorsal columns. Copper and vitamin E deficiencies can present similarly to myelopathies with or without sensory involvement. Copper deficiency is often seen in patients taking zinc supplementation or those with a history of bariatric surgery. Vitamin E is fat-soluble, and fat malabsorption conditions can lead to deficiencies. Examples of these conditions include Crohn disease, cystic fibrosis, cholestatic hepatobiliary disease, and exocrine pancreatic insufficiency.

Nutrition labs should be checked since these conditions have significant clinical heterogeneity. Adrenomyeloneuropathy is an uncommon, inherited, slowly progressive disorder that affects the spinal cord. Diagnostics can show elevated blood levels of adrenocorticotropic hormone, elevated serum very long chain fatty acids, brain MRI white matter abnormalities, and mutations in the ABCD1 gene.

A few infectious etiologies can present similarly to PLS. Syphilis can present with myelopathy and UMN signs, although classically, it presents as tabes dorsalis with dorsal column involvement. Serologic and CSF testing for venereal disease can help distinguish neurosyphilis from PLS. Human T-lymphotropic viruses (HTLV) I/II can present with myelopathy and a normal neuroaxis MRI mimicking PLS. Clinical history can help diagnose HTLV as it is endemic to southwestern Japan, the Caribbean, South America, and sub-Saharan Africa. Serologic and CSF testing for HTLV antibodies confirms the diagnosis of HTLV-associated myelopathy.[34]

Structural lesions that present similarly to PLS include foramen magnum lesions, syringomyelia, parafalcine meningioma, spinal cord tumors, or spinal cord compression, which are seen on MRI and easily separated from PLS. Vascular abnormalities, including ischemic lesions or spinal arteriovenous malformations, can also lead to myelopathies and are usually seen on MRI if large enough. Magnetic resonance angiography or a digital subtraction angiography is sometimes needed if gadolinium-enhanced MRI cannot visualize the vascular malformation.[34] 

Prognosis

Patients with PLS often have a benign clinical course with a more prolonged survival compared to patients with ALS. Patients with PLS are frequently concerned about possible progression to ALS. Most patients with UMN-predominant ALS will develop LMN signs or EMG changes within 4 years of symptoms onset.[35][36] Patients with selective UMN involvement who do not develop LMN involvement after 4 years typically remain with pure UMN involvement and have a normal lifespan.[15][35][37] 

The progression of symptoms is variable but generally slow, with the average symptom duration ranging from 7.2 to 14.5 years.[5] PLS differs from ALS in that the need for a feeding tube or permanent assisted ventilation is low at 7% and less than 1%, respectively.[16] Although PLS is usually not life-shortening, it carries a significant disease burden, often from refractory spasticity.

Complications

PLS can have various clinical manifestations but often leads to similar complications. The most frequent complications seen in PLS include movement issues and falls secondary to gait impairment, balance difficulties, and weakness. Other complications include swallowing difficulties, speech changes, bladder problems (eg, frequency or retention), and pseudobulbar affect. Given the progressive and irreversible nature of the disease, mood symptoms like depression are frequently seen in patients with PLS.