There are four classic types of motor neuron disease: amyotrophic lateral sclerosis (ALS); progressive spinal muscular atrophy; progressive medullary paralysis; and primary lateral sclerosis. Among them, ALS is the common clinical type, and its pathology is based on progressive degeneration of brainstem motor nuclei and anterior horn nerve cells of the spinal cord, corticospinal tracts or corticobulbar tracts, with symptoms of upper and lower motor neuron damage, such as progressive worsening muscle atrophy, weakness, spasticity, positive pathological signs, without sensory disturbances and urinary and bowel disorders. Currently, the diagnostic criteria for ALS established at the 1994 Spanish conference are still used: (1) signs of lower motor neuron involvement, including muscle weakness, atrophy and tremor of the muscle bundles in at least three sites in the medulla oblongata, cervical medulla, thoracic medulla and lumbar medulla, including clinically asymptomatic sites with EMG abnormalities; (2) signs and symptoms of upper motor neuron involvement – active or hyperactive tendon reflexes or clonus (2) signs and symptoms of upper motor neuron involvement – active or hyperactive tendon reflexes or clonus, pseudobulbar palsy, Hoffmann’s sign and Babinski’s sign; (3) progressive course of the disease; (4) excluding other progressive diseases of the nervous system.
ALS is now classified as a degenerative disease of the central nervous system along with Alzheimer’s disease (AD) and Parkinson’s disease (PD), but the development and nature of ALS is usually more rapid and severe, with death due to dyspnea and dysphagia 3 to 5 years after the onset of symptoms. Unfortunately, there is still a lack of effective treatment for ALS.
Traditionally, it was believed that cognitive function remained normal in ALS patients, but this concept was changed by a report published by Hudson in 1981, which was a review that focused on the pathological changes of neuronal loss and spongiform degeneration in the frontal and frontotemporal cortex in both sporadic and familial ALS, most prominently in layers 1 to 3 of the cortex. These pathological changes can also be seen in AD and frontotemporal dementia (FTD), especially in the latter, but are not characteristic of AD, which is characterized by memory impairment, language impairment, visual-spatial impairment, computational impairment, and dyscalculia.
In FTD, behavioral and personality changes are most prominent and continue throughout the course of the disease. Since the publication of Hudson’s article, more and more attention has been paid to the cognitive function of ALS. In recent years, with the development of neuroimaging, neuropsychology and neuropathology, it has been found that frontotemporal dysfunction or frontotemporal syndrome is present in a minority of ALS patients, accounting for more than 50%, but only about 5% of them actually meet the diagnostic criteria for FTD. Frontotemporal dysfunction is divided into 3 clinical syndromes: (i) frontal variant FTD (fvFTD); (ii) progressive non-fluent aphasia (pNFA); and (iii) semantic dementia (SD).
Clinical subtypes of frontotemporal functional impairment in ALS.
a. ALS alone.
b. ALS with cognitive impairment (ALSci, meaning impairment in at least one area of cognitive function that does not meet the diagnostic criteria of Neary et al).
c. ALS with behavioral impairment (ALSbi).
d. ALS with FTD (meeting the diagnostic criteria of Neary et al).
e. FTD with ALS-like pathology (clinical presentation of FTD with ALS-like changes in pathology but no corresponding symptoms during life).
f. ALS with dementia (refers to ALS with AD or vascular dementia).
ALS cognitive impairment presentation.
Cognitive impairment in ALS is usually very insidious and requires detailed neuropsychological testing to determine. The most common impairments are impaired executive planning, impaired attention, and impaired verbal and nonverbal fluency. Verbal fluency impairments, whether in writing or speech, are prominent and are the earliest impairments to appear.
Verbal fluency tests are recognized as early and sensitive indicators of impaired executive function in patients divided into (i) phonological fluency; and (ii) semantic fluency tests.
Characteristics of behavioral impairment in ALS.
Disinhibition is the most common phenomenon. There are many pathological behaviors, clinically presenting as emotional retardation, emotional indifference, indifference to one’s disease status, disinhibition in social activities, overreaction to sensory stimuli, overeating, and stereotyped behavior.
Diagnosis of cognitive and behavioral impairment in ALS.
The Simple Mental State Examination of Intelligence (MMSE) has relatively low sensitivity and little significance in screening for abnormal frontotemporal function. Frontal Assessment Battery (FAB) – more sensitive to frontal dysfunction, significantly correlates with the degree of frontal metabolism, and the FAB is simple and rapid to operate, but there is no clear cut-off value for clinical diagnosis. Speech fluency test – one of the most sensitive indicators, which can be divided into speech fluency and semantic fluency test, among which speech fluency test is more sensitive to frontal lobe damage, especially for those with left frontal lobe damage. The Wisconsin Card Sorting Test measures concept formation, flexibility of thought, and sustained response (sensitive but not specific to frontal lobe damage), and the Stroop Color Word Test measures inhibitory control. In conclusion, patients with early cognitive impairment in ALS should try to select tests that are sensitive to the orbitofrontal lobe, and the Frontal Behavior Inventory (FBI), Neuropsychiatric Inventory (NPI), and Frontal System Behavior Score (FrSBe) are commonly used to assess behavioral impairment in ALS.
Differential diagnosis of ALS cognitive and behavioral impairment.
ALS cognitive-behavioral impairment should be differentiated from pseudo-dementia caused by medications, depression, and CO2 retention due to various hypoventilation syndromes.
Appendix.
I. Clinical manifestations of frontal lobe variant FTD.
The onset of the disease is insidious, with early social behavior and personality changes, emotional dullness and lack of insight, but memory and visuospatial functions are relatively preserved; behavioral changes are the most significant features of FTD, including stereotypy – rigid work and rest schedule, single thought process, and no interruption of speech. Abnormal movements – repeatedly touching the corners of clothes, quilt, smacking the mouth, restless legs, repetitive convergence, tailing, etc. Personality changes – irritable, aggressive, selfish. Hyperphagia- Gluttony, sweet tooth, soap swallowing. Disinhibition-singing, urinating and defecating, talking about privacy at will, etc. Exploitation behavior – repeatedly opening and closing TV, doors and windows, cutting things with scissors on the table, etc.
II. Progressive nonfluent aphasia.
It is a group of syndromes characterized by progressive loss of language function. It is a group of syndromes characterized by a progressive loss of language function. It has an insidious onset, mostly in elderly males, with naming aphasia and difficulty understanding language (grammar/words).
Mesulam diagnostic criteria
(1) Difficulty in finding words in natural conversation or through a formal psycholinguistic examination, with occult and progressive impairment in object naming or word comprehension.
(ii) All limitations in the patient’s daily life within 2 years of the discovery of the condition are limited to the language impairment.
(iii) The pre-morbid language function was intact.
④No apathy, disinhibition, near-event amnesia, visuospatial impairment, visual recognition deficits, or abnormal sensorimotor function within 2 years of disease onset.
⑤Conceptual-motor disuse and computational inability can occur within 2 years of disease onset.
(6) Impairment of other neurological functions can occur 2 years after disease onset, but progression of language impairment remains the most significant and continues throughout the course of the disease
(7) Lack of specific etiology of stroke and tumor.
III. Semantic dementia
Semantic memory and comprehension impairment with progressive aggravation is the characteristic manifestation. Memory: relative retention of near memory and impairment of distant memory. Language: inability to name, impaired word comprehension. Facial recognition: greatest difficulty in recognizing public faces. Object recognition: not obvious in early stages, gradually appearing. Behavioral changes: self-centered and stereotyped.
Diagnostic criteria for semantic dementia (1998).
1. Description of clinical features: Semantic (understanding of word meanings and object recognition) impairment is the earliest and most prominent symptom and is present throughout the course of the disease. Other cognitive functions include no impairment or relative preservation of memory.
2. Core diagnostic features: (1) insidious onset and gradual progression (2) language impairment with the following features: spontaneous speech as fluency, speech voids, and continuous progression; memory loss for word meanings, manifested as naming and comprehension impairment; semantic mispronunciation. or/and (3) Perceptual impairment: facial loss of recognition Recognition and discrimination impairment of familiar faces; joint loss of recognition Discrimination impairment of objects. (4) Preservation of perceptual matching and picture regeneration (5) Preservation of individual word repetition (6) Relative preservation of reading aloud and dictation of commonly used words
3. Supporting diagnostic symptoms: (1) Speech and language: compulsive language; use of idiosyncratic vocabulary; no phonological mispronunciation; can read aloud but does not understand what is being read aloud; normal computation. (2) Behavioral disorders: lack of empathy; narrow interests, prejudice; stingy. (3) Somatic symptoms: no or primitive reflexes, motor inability, tonicity and tremor in the late course of the disease.
(4) Laboratory tests (1) Neuropsychological: significant semantic deficits, inability to understand the meaning of words, to name or recognize objects and faces; normal phonology and grammar, normal perceptual processing. (2) EEG: normal (3) Brain imaging (structural or functional): significant anterior temporal lobe abnormalities (symmetric or asymmetric).