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Primary Lateral Sclerosis

PLS

Primary lateral sclerosis is a type of neuromuscular disease affecting the upper motor neuron function, resulting in impaired motor speech production, hyperreflexia, spasticity and paresis of voluntary muscles.


Presentation

The initial presentation of primary lateral sclerosis is usually progressive spasticity and paresis of the voluntary muscles. At an early stage, the lower limbs are affected unilaterally while the later stage is marked by bilateral involvement. Affected patients will subsequently experience difficulty in walking due to stiffness and slowness of their legs. Eventually walking aids may be required. 

Once the disorder progresses to involve the bulbar muscles, patients will present with dysphagia and dysarthria. In certain cases bulbar muscle dysfunction may occur as the initial presentation. Some patients display urine incontinence as a later symptom.

After onset, primary lateral sclerosis typically progresses slowly, but rapid advancement has also been noted. The course of disease may therefore be different from one patient to another.

Vertical Gaze Palsy
  • However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course.[ncbi.nlm.nih.gov]
Muscular Atrophy
  • This locus had not been implicated in ALS or in hereditary spastic parapareses, spinal muscular atrophy, or spinal and bulbar muscular atrophy. [7] A genetically mediated PLS look-alike, progressive familial paraparesis (hereditary spastic paraparesis[emedicine.com]
  • Progressive Muscular Atrophy This form is much less common than ALS or PBP. It can be inherited or sporadic. Progressive muscular atrophy mainly affects your lower motor neurons.[webmd.com]
Hyperreflexia
  • […] y lat·er·al scle·ro·sis considered by many to be a subgroup of motor neuron disease; a slowly progressive degenerative disorder of the motor neurons of the cerebral cortex, resulting in widespread weakness on an upper motor neuron basis; spasticity, hyperreflexia[medical-dictionary.thefreedictionary.com]
  • […] lateral sclerosis Disease definition Primary lateral sclerosis (PLS) is an idiopathic non-familial motor neuron disease characterized by slowly progressive upper motor neuron dysfunction leading to spasticity, mild weakness in voluntary muscle movement, hyperreflexia[orpha.net]
  • Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs.[ncbi.nlm.nih.gov]
  • Spasticity with hyperreflexia, exaggerated jaw jerk and extensor plantar responses were eventually seen in all patients. Anterior horn cell involvement developed in three cases.[ncbi.nlm.nih.gov]
Akinesia
  • In conclusion, these cases represent a subgroup of PLS patients in whom pyramidal slowness may be mistaken for akinesia, and spasticity misconstrued as rigidity, leading to an erroneous diagnosis of atypical parkinsonism.[ncbi.nlm.nih.gov]
Frozen Gait
  • We encountered three patients with primary lateral sclerosis (PLS) showing bradykinesia, frozen gait, and severe postural instability, as well as slowly progressive spinobulbar spasticity.[ncbi.nlm.nih.gov]
Postural Instability
  • We encountered three patients with primary lateral sclerosis (PLS) showing bradykinesia, frozen gait, and severe postural instability, as well as slowly progressive spinobulbar spasticity.[ncbi.nlm.nih.gov]

Workup

The diagnosis of primary lateral sclerosis can be obtained clinically especially if it is first encountered as a late presentation. Diagnostic workup is necessary in ruling out possible differentials since the majority of motor neuron diseases present in a similar way. Laboratory investigations include assessment of cerebrospinal fluid from lumbar punctures to check for infection, genetic studies to rule out familial neuropathies, urine analysis to evaluate heavy metal poisoning and blood work to exclude other infections and metabolic derangement [7].

Imaging workup involves carrying out nerve conduction studies. Slow impulses are characteristic in the late stages of motor neuron diseases. Electromyography is necessary to differentiate between muscle and nerve diseases. Magnetic resonance imaging (MRI) of the brain and spinal cord may also be conducted as adjuncts to rule out possible differential diagnoses [8].

Neurofibrillary Tangle
  • Numerous beta/A4 amyloid positive diffuse plaques (10-15/200x field) were apparent in neocortex, and neurofibrillary tangles immunopositive for paired helical filament were detected in hippocampus.[ncbi.nlm.nih.gov]
  • Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a[ncbi.nlm.nih.gov]

Treatment

Treatment for PLS is mainly supportive; definitive measures are yet to be identified. Spasticity being the major symptom is treated with baclofen and tizanidine. The benzodiazepine group of drugs such as diazepam and clonazepam can also be used to remedy spasticity [9]. Analgesics are prescribed to manage pain arising from spasticity. In certain patients, antidepressants are administered for PLS related depression.

Other supportive measures

  • Physical therapy involves stretch exercises that enhance the range of motion of the joints. This serves to prevent the development of contractures resulting from spasticity. The exercises can be carried out at home by the primary caregiver [10].
  • Non invasive ventilatory support may be required in patients who suffer from respiratory failure which may occur late in the course of the disease.
  • Symptomatic relief can be achieved by use of massage or pool therapy.
  • Occupational therapy may be necessary for patients who develop certain disabilities.

Prognosis

Primary lateral sclerosis has a gradual progression that manifests as insidious development of motor neuron dysfunction and muscle disability. It has no adverse implication on life expectancy but according to statistics from a study on 36 patients with PLS, the disease was linked to an estimated median survival period of 20 years [6].

Etiology

Primary lateral sclerosis results from a degenerative dysfunction of motor cortex neurons leading to clumsiness and slowing down of voluntary muscle movement as well as impaired balance.

Adult form

Adult PLS is considered idiopathic and non-familial.

Juvenile form

Juvenile PLS is an autosomal recessive disorder whose exact etiological mechanism is unknown. However, the characteristic motor neuron dysfunction seen in this condition is attributed to mutations in the ALS2 gene responsible for coding of protein alsin, present in these neurons. Of note is the absence of these gene mutations in adult PLS [3].

Epidemiology

The adult form is more common than the juvenile form. In terms of distribution, PLS shows an age predilection of 40-60 years and a higher male to female ratio.

In a sharp contrast against related conditions like amyotrophic lateral sclerosis, statistics on PLS is not well documented and most of the data available has been inferred from studies on ALS. There is documentation of a PLS incidence rate of 0.01 cases per population of 100,000 [4]. This was generated from reports of 8 patients with PLS, identified from a group of 500 patients with ALS within a 10 year period margin. A PLS prevalence rate of 2 million was then inferred from the ALS patient data that consisted of a population of 4 million [4]. These statistics match data from a conservative estimate which showed that the number of people living with PLS in the United States is below 500. The exactness of these figures is however difficult to prove.

Sex distribution
Age distribution

Pathophysiology

Adult primary lateral sclerosis is considered non-hereditary. An unique autosomal dominant variant of adult PLS was identified in a French-Canadian family, mapping to 4ptel, a gene on chromosome 4p16.1. Similar disorders like ALS, hereditary spastic paraparesis and spinal/bulbar muscular atrophy have also been linked to the locus 4p16.1. [5].

The juvenile form of primary lateral sclerosis occurs rarely and has been mapped to ALS2, a gene on chromosome 2q33.2. This is often the result of a single missense mutation and at least ten deletion mutations of ALS2. ALS2 encodes protein alsin which is important for motor nerve function. Alsin is a guanine nucleotide exchange factor responsible for cell signalling and protein trafficking functions by regulating activity of the Ras superfamily of GTPases [4].

Prevention

Preventive measures for primary lateral sclerosis are yet to be discovered.

Summary

Primary lateral sclerosis (PLS) is a rare condition in the category of motor neuron diseases [1]. It primarily targets facial, upper limb and lower limb corticospinal neurons [2] and its etiological basis is progressive degeneration of neurons in the motor cortex. PLS targets neurons in an ascending manner; beginning with the muscles of the legs, trunk, upper limbs and finally affecting the bulbar muscles which are responsible for the functions of speech, chewing and swallowing. Clinically, it presents with slowly progressive features of paresis, spasticity, slow movement, impaired speech and abnormalities of balance. PLS is more common in men than women and occurs between the ages of 40 and 60 years. In terms of prognosis, PLS is slowly progressive with the disease course encompassing several years and sometimes decades. Commonly, PLS presents in a similar manner as spastic paraplegia or amyotrophic lateral sclerosis (ALS). It therefore requires thorough diagnostic investigations to rule out these differentials.

Patient Information

Definition

Primary lateral sclerosis (PLS) is a disease primarily affecting nerves and muscles. It occurs when upper motor neurons (nerve cells transmitting impulses from the brain) undergo progressive degenerative changes that reduce their functionality. As a result, transmission of impulses to voluntary muscles is slowed down, impairing their strength and function.

Causes

The cause of adult onset PLS remains unknown and such cases tend to occur randomly. However, when the disease occurs in children, it is linked to hereditary causes such as gene mutations that affect the nerve function.

Symptoms

Symptoms vary from one person to another and usually resemble other diseases that affect nerves and muscles. Consultation with a clinician may be necessary. Symptoms may include:

Advanced disease may present with the following:

Diagnosis

A diagnosis of PLS can be achieved from relevant medical history and proper physical examination. It is necessary to carry out investigative tests to rule out other possible disorders which may present in a similar manner.

  • Laboratory assessments include blood tests, urine analysis, cerebrospinal fluid analysis and genetic studies. These are used to rule out infections, heavy metal poisoning and other genetic causes.
  • Imaging studies include magnetic resonance imaging of the brain and spinal cord, nerve conduction studies and electromyography studies. These tests assess the nerve function.

Treatment

Treatment for primary lateral sclerosis is mainly supportive and aims at the alleviation of symptoms. Spasticity of muscles is treated with baclofen and tizanidine. Other drugs such as diazepam and clonazepam may also be administered. Other treatment options include physical and occupational therapy to relieve spasms and prevent the loss of muscle and joint function.

References

Article

  1. Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology. 2006 Mar 14; 66(5):647-53
  2. Younger DS, Chou S, Hays AP, et al. Primary lateral sclerosis. A clinical diagnosis reemerges. Arch Neurol. 1988 Dec; 45(12):1304-7.
  3. Panzeri C, De Palma C, Martinuzzi A, et al. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain. 2006 Ju;. 129:1710-9.
  4. Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain. 1992 Apr; 115 ( Pt 2):495-520.
  5. Valdmanis PN, Dupré N, Rouleau GA. A locus for primary lateral sclerosis on chromosome 4ptel-4p16.1. Arch Neurol. 2008 Mar; 65(3):383-6.
  6. Tartaglia MC, Rowe A, Findlater K, et al. Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up. Arch Neurol. 2007 Feb; 64(2):232-6.
  7. Vinceti M, Solovyev N, Mandrioli J, et al. Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite. Neurotoxicology. 2013 May 31.
  8. Joyce NC, Carter GT. Electrodiagnosis in persons with amyotrophic lateral sclerosis. PM R. 2013 May; 5(5 Suppl):S89-95.
  9. Lee CN. Reviewing evidences on the management of patients with motor neuron disease. Hong Kong Med J. 2012; 18:48-55.
  10. Gibbons C, Thornton E, Ealing J, et al. The impact of fatigue and psychosocial variables on quality of life for patients with motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May 31.

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Last updated: 2019-07-11 20:29