Neurocognitive and Neurodegenerative Disorders
The term dementia, or, more formally, major neurocognitive disorder, describes a combination of symptoms and clinical findings, collectively called a syndrome, which interferes with people’s cognition or behavior, to the extent that the person requires some additional help compared to the past in pursuing daily activities. It is a term developed to help clinicians communicate a person’s presentation before going into more details; nothing more and nothing less. This means that people with dementia have different levels of disease severity depending on specific symptoms, called a phenotype, and each dementia syndrome is associated with one or more underlying causes, with neurodegenerative brain pathologies and vascular brain disease being the most common. It is also not uncommon for certain dementia syndromes to be accompanied or, even, preceded, by other disorders, such as sleep or seizure disorders. We tend to organize dementia syndromes in the following categories, each having its own historic roots, and explaining the differences in how they are described.
Minor NCD or MCI describes a combination of symptoms and clinical findings, collectively called a syndrome, which affect people’s cognition or behavior, but not severe enough for the person to require help compared to the past in pursuing daily activities. Much like the term dementia, it is a term developed to help clinicians communicate a person’s presentation before going into more details; nothing more and nothing less. This means that people with MCI can present with a set of symptoms, called a phenotype, and each phenotype may be associated with one or more underlying causes, which can range from neurodegenerative brain pathologies, to vascular brain diseases, to metabolic disorders, or even seizure and sleep disorders. In fact, sleep disorders can present several years before cognitive disorders show up, raising the possibility that addressing sleep problems may in fact delay the onset of cognitive symptoms. Symptoms in MCI are organized in the following domains for defining a person’s phenotype: memory, executive function, language, visuospatial-constructional skills and behavior. Depending on the underlying cause of MCI, symptoms may progress, especially in neurodegenerative brain pathologies, remain stable, such as in vascular brain disease, or even improve, if they are caused by treatable sleep problems.
Much like in Minor Neurocognitive Disorder (NCD), people with SCC are concerned that their ability to perform certain cognitive tasks are not as good as they used to be, and out of proportion to getting older. But in contrast to Minor NCD, cognitive performance on standardized neuropsychological tests of people with SCC fall within the normal range. It is possible that these subjective complaints are the first signs of a developing cognitive impairment that will reveal itself over time and should be thoroughly evaluated and followed over time, but in many cases do not persist or lead to any impairments.
Alzheimer’s dementia refers to four main syndromes that have historically been associated with a common brain pathology called Alzheimer’s disease, highlighting that Alzheimer’s dementia (i.e., what phenotype of symptoms that we see on the surface) and Alzheimer’s disease (i.e., what underlying pathology is present in their brain) do not refer to the same thing, although for both the abbreviation is “AD,” making things confusing at times. The common underlying pathology of the four syndromes, Alzheimer’s disease, was originally defined by observations in the early 20th century that certain proteins we all have in our brains, called beta-amyloid and tau, cluster in abnormal ways in certain brain areas, a process called proteinopathy, and interfere with normal brain function. Depending on the distribution of these proteins, especially tau, people develop different syndromic phenotypes. As we come to understand neurodegeneration better, it is becoming clearer that the so-called proteinopathy component of Alzheimer’s disease and other neurodegenerative diseases is only part of the whole picture, and instead several processes, such as immune, vascular, metabolic, and genetic, contribute at various degrees to the gradual functional and structural changes we see in people’s brains that give rise to symptoms. Sleep problems are present in most people with Alzheimer’s dementia, and range from, to and . For many, the brain enters a so-called twilight zone, where people never reach a fully alert state, and also fail to enter adequate deep sleep, invariably interfering with cognitive function during the daytime, but also accelerating proteinopathy.
- Late Age of Onset Alzheimer’s Dementia (LOAD) – Amnestic predominant: This is the most common presentation of Alzheimer’s dementia for the majority of people, affecting primarily people over the age of 65, and with the earliest and predominant symptom being difficulty with memory. It is not uncommon that caregivers will report that their loved ones forget appointments or conversations they recently had, despite being able to recall remote events in detail. Although the majority of people have Alzheimer’s disease in areas of the brain involved in memory consolidation, called the hippocampi, we are becoming aware that, more often than not, people tend to have more than one underlying brain pathology, much like people who have hypertension are more likely to also have high cholesterol or diabetes. As such, a significant number of people also have vascular brain disease or other neurodegenerative diseases when we observe brains under the microscope. This variability of what happens in people’s brains is characteristic in those presenting with Alzheimer’s dementia above the age of 80 where, instead of Alzheimer’s disease, a pathology termed LATE (i.e., Limbic-predominant Age-related TDP-43 Encephalopathy) is the predominant brain pathology. The above highlight the need for expert multidisciplinary approaches in caring for patients with dementia.
- Posterior Cortical Atrophy (PCA) – Visuospatial predominant: First described by Dr. D. Frank Benson, PCA is less common than LOAD and presents in people of a somewhat younger age. Its unique features involve difficulty in visually recognizing complex shapes, such as a face, or exact distances or movement, such as a moving car, despite people having intact elementary visual abilities, such as being able to perceive colors or static shapes. This is because the brain is unable to synchronize its function and combine individual elements of an image into a gestalt percept. PCA takes its name from the fact that areas responsible for these visual functions are in the posterior part of the brain. Many people delay being diagnosed because they assume their problems are caused by poor eyesight, and because other cognitive abilities, such as memory, are intact. Even more, they often suffer from depression that is incorrectly attributed to social causes rather than brain dysfunction. The underlying pathology of PCA is almost exclusively Alzheimer’s disease.
- Logopenic Primary Progressive Aphasia (lvPPA) – Language predominant: The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. The first is one of the Alzheimer’s dementia syndromes, whereas the latter two fall under Frontotemporal Dementia Syndromes. People with lvPPA have a predominant language deficit of word-finding difficulties, which is the result of left posterior temporal lobe dysfunction. People present with marked pauses between words when speaking because they search for the right word, even though they know what words mean, and often use a roundabout way in expressing themselves. It is also common they retain less information when spoken to because it is difficult for them to grasp at once long sentences. This explains why being spoken to with short and direct sentences is a more effective way of communicating with them. For a subset of patients with lvPPA, a history of dyslexia is common, whereas the underlying pathology is almost exclusively Alzheimer’s disease.
- Early Age of Onset Alzheimer’s Dementia (EOAD) – Dysexecutive-Behavioral predominant: A less common phenotype of Alzheimer’s dementia is EOAD, where symptoms start at an age younger than 65 years old. In contrast to its counterpart, LOAD, memory difficulties may not be the predominant deficit, and instead difficulty in organizing and planning (key features of executive function), or marked apathy, are often driving daily difficulties. Furthermore, and in contrast to the other three Alzheimer’s dementia syndromes, brain atrophy is less pronounced, often requiring specific biomarkers of Alzheimer’s disease neurodegeneration to verify the diagnosis. Patients with EOAD are often misdiagnosed as having other types of neurodegenerative diseases, such as , highlighting the importance of expert team protocols in their diagnosis.
FT-NCD, better known by the term Frontotemporal Dementia (FTD), refers to three dementia syndromes that share in common neurodegeneration of frontal or anterior temporal lobes. This pattern of neurodegeneration is called Frontotemporal Lobar Degeneration (FTLD) and symptoms of abnormal social behavior (proteinopathies involved in FTD are much more diverse than in Alzheimer’s disease, with certain syndromes being more frequently associated with certain proteinopathies, and in which genetic causes are not uncommon for a subset of patients. Parkinsonism defined as a variable combination of slowness in movement (bradykinesia), muscle stiffness, tremor, or imbalance, is very common in certain FTD syndromes, especially if the underlying pathology is a tauopathy. Sleep problems are also common and present in at least three out of four people, especially and .) or language difficulties ( and ) define their clinical presentation. Furthermore, the
- Behavioral Variant Frontotemporal Dementia (bvFTD): In the characteristic syndrome of bvFTD, patients often have their first symptoms in their 50s where they may become socially disinhibited, lose empathy, perseverate, develop unique eating habits or binge eat, become apathetic, or have trouble in organizing and planning complex tasks. Their socially inappropriate behaviors can range from unprovoked swearing to pronounced flirtatious behavior, whereas the lack of empathy and self-centered behavior is especially hurtful to their loved ones who believe that patients no longer care for them. Many patients even divorce and find a new partner, before symptoms interfere with daily independence, which explains why their behaviors are often misinterpreted as a midlife crisis and diagnosis is delayed. The executive-behavioral deficits of bvFTD are also a common reason for families becoming bankrupt and enter debt. A subset of people is also affected by in the form of Amyotrophic Lateral Sclerosis (ALS), where people lose control of voluntary movement and become weak. This gives rise to the combined syndrome of bvFTD-ALS, highlighting the need for early comprehensive evaluation by a multidisciplinary team of experts. The common proteinopathies of bvFTD involve abnormal clustering of the proteins tau and TDP-43 (TAR DNA binding protein 43), whereas Alzheimer’s disease is only present in few patients.
- Non-fluent/Agrammatic Primary Progressive Aphasia (nfvPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. is one of the Alzheimer’s dementia syndromes, whereas the other two are Frontotemporal Dementia Syndromes. People with nfvPPA have a predominant deficit in speech or language planning and organization, which is the result of impaired left frontal lobe function. This is perceived as either a difficulty (a) in precisely organizing the motor sequences of effective speech, or (b) in properly applying grammar when speaking. As a result, symptoms may include stuttering speech, poor articulation, or omission of words in a sentence. Some people may become mute even if other cognitive functions, such as memory, are relatively intact. It is also not uncommon for people with nfvPPA to overlap with other neurodegenerative diseases, such as (Progressive Supranuclear Palsy Syndrome) or , depending on the underlying proteinopathy that caused the symptoms in the first place. As in most FTD, the most common proteinopathies relate to abnormal clustering of tau or TDP-43 proteins.
- Semantic Variant Primary Progressive Aphasia (svPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic.
In PSPS people tend to have difficulties in moving their eyes vertically or maintain their balance. As a result, they often have unexpected falls and report a difficulty reading through lines in a book. Cognitive-behavioral symptoms are practically always present, especially with difficulties in speech fluency, motivation, and planning. parkinsonism with muscle stiffness and slowness in movement, explaining people often being misdiagnosed having Parkinson disease. In contrast, however, to Parkinson disease where the underlying pathology is due to abnormal synuclein protein deposition, PSPS almost always have an abnormal underlying tau proteinopathy., with insomnia interfering significantly with people’s lives. The most typical characteristic of PSPS is
CBS is one of the most variable dementia syndromes, where people have difficulties in perceiving the position of their limbs in space or in controlling their movements accurately. In some people, the so-called alien limb phenomenon is present, where limbs seem to move as if they have a mind of their own. For example, hands may compete with each other when buttoning shirts. In other instances, people may not realize being touched if they don’t look at that part of the body, a phenomenon called neglect. Symptoms of parkinsonism are present in most people, becoming stiff and having difficulty in moving, further delaying accurate diagnosis. CBS takes its name from the cortical and basal ganglia of the brain being affected in the disease process, but the cause of the syndrome ranges from a tauopathy in more than half of people, to Alzheimer’s disease in a third of people.
SA-NCD refers to three syndromes with overlapping clinical symptoms, namely Lewy Body Dementia (LBD), Parkinson Disease Dementia (PDD), and Multiple System Atrophy (MSA), that usually affect people over age 50 and share α-synuclein proteinopathy as the common underlying pathology. This pathology is distributed differently across the brain and body between the three syndromes, leading to the three overlapping, but different, phenotypes. Even though people with any of the three have some level of parkinsonism symptoms, the predominant symptoms early in the disease process are different between them. Specifically, people with LBD mostly have cognitive-behavioral symptoms, people with MSA have pronounced autonomic deficits, whereas people with PDD predominantly have parkinsonism motor symptoms upon which other symptoms may follow. That said, all of the above symptoms tend to be present at different frequencies between the three as α-synuclein pathology spreads across the nervous system, explaining why physicians give a diagnosis of synucleinopathy rather than of an individual syndrome. Sleep disorders are very common and pronounced in synucleinopathies, with people being sleepy or going in and out of sleep frequently within the day, having sleep apnea, and almost four out of five having the telling symptom of REM-behavior disorder (RBD), which may present several years before parkinsonism occurs. For older people with SA-NCD, it is not uncommon for additional brain pathologies to be present, such as Alzheimer’s disease or vascular brain disease, contributing to symptom severity.
- Lewy Body Dementia (LBD): The cognitive-behavioral symptoms of LBD are usually affecting executive functions of planning, organizing, multitasking, and thinking fast, as well as visuospatial functions of constructing complex objects or perceiving things. It is not uncommon for people to mention visual hallucinations, often misperceiving things in poorly lit environments and in settings where they get sleepy. Similarly, they may report a sense of shadows at the edge of their vision as if someone is following them, which disappear when they turn to look. A fluctuating level of alertness within several minutes makes all the above symptoms even more pronounced and can help in making a diagnosis. Autonomic symptoms of constipation, dizziness upon standing suddenly, and erectile dysfunction are also common, but may not be troubling to many patients. Similarly, parkinsonism invariably presents in all people as symptoms progress, but may not be pronounced from the very beginning.
- Multiple System Atrophy (MSA): In MSA, autonomic symptoms are often severe and have patients seek medical help. People tend to faint frequently due to orthostatic hypotension or slow heart rate, and erectile dysfunction is commonly present even years before other symptoms. Motor symptoms are invariably present and distinguish two MSA phenotypes depending if they are predominantly parkinsonian (MSA-P), with stiff slow movements, or cerebellar (MSA-C), with poor coordination of goal-directed movements and imbalance. Fluctuating levels of alertness and cognitive symptoms of slow processing speed are also present but not often the ones that trigger the first visit to the physician’s office. When noticed, cognitive difficulties affect executive function of planning and organization of thinking, whereas memory is relatively spared. A concerning symptom to caregivers is the loud noise during sleep called stridor, highlighting sleep disordered breathing and the need for sleep study testing and treatment.
- Parkinson’s Disease Dementia (PDD): In PDD, people are mainly affected by motor symptoms of bradykinesia (slowness in movement), rigidity (muscle stiffness), imbalance and resting tremor that are usually worse on one side of the body. Not all symptoms need to be present, although bradykinesia and stiffness are almost always present. Most people have a decreased facial expression, termed masked facies, that is often interpreted as depression when combined with bradykinesia, even though patients may not complain of depression. The accompanying symptoms of REM-behavior disorder (RBD), constipation, erectile dysfunction and decreased ability to smell are usually present, with RBD presenting several years before motor symptoms. As in other synucleinopathies, cognitive features affect executive function of organizing and planning with decreased processing speed, but are milder than in other synucleinopathies, and the fluctuations in level of alertness are not as pronounced.
VaD refers to cognitive impairment whose cause is an underlying vascular injury such as an ischemic stroke or intracerebral hemorrhage. Symptoms are highly variable depending on the location and extent of the vascular injury, with executive, language, and visuospatial symptoms presenting more frequently, but also learning and memory, as well as behavioral symptoms interfering with daily life. People may become unable to attend or process information fast, plan or make effective decisions and prevent mistakes, speak or understand what they are told, perceive visual or other stimuli, recall information effectively, or remain motivated or even empathize. Motor symptoms are also present and usually recognized by others before cognitive symptoms. Symptoms may present suddenly right after a large stroke or a stroke affecting a critical brain area, or gradually as a result of extensive vascular injury to the small brain vessels. The specific cause of the stroke can range from clots forming in atherosclerotic large vessels feeding the brain or in the heart of people with atrial fibrillation, which in turn travel to the brain and cause ischemia, to direct injury of brain vessels leading to local ischemia or bleeding. Vascular risk factors that can be modified and prevent future strokes are hypertension, hyperlipidemia, diabetes, smoking and , whereas regular moderate exercise and a Mediterranean diet further help vascular integrity.
Sleep and Circadian Rhythm Disorders
Chronic Insomnia Disorder is present in about one in seven to one in ten adults with symptoms of difficulty initiating sleep, maintaining sleep or waking up earlier than desired despite adequate opportunity for sleep. International criteria require that these symptoms interfere with daily life and must be present for more than three times a week for more than three months. This way, brief episodes of insomnia most people naturally experience across the lifespan are not misdiagnosed as chronic insomnia. In children, symptoms can also relate to either resistance to sleeping or needing rituals to sleep. In adults, it is associated with other medical conditions, including cognitive impairment, cardiovascular and metabolic disorders, chronic pain and depression. In such conditions, detailed evaluation with neuropsychological and laboratory tests may clarify an underlying cause to the insomnia and direct a combined treatment that improves quality of life. First line treatment for almost all people is Cognitive Behavioral Therapy for Insomnia (CBTi), whereas medications are considered for a period of time for certain people.
ISS refers to inadequate sleep amount for a period of 3 months and is often misinterpreted as insomnia by patients due to the common feature of not falling asleep when desired. However, in contrast to insomnia syndromes where people have the opportunity to sleep, people with ISS are usually not given the opportunity to sleep or do not pursue sleep and, if sleep is pursued, they tend to fall asleep within minutes. ISS is usually accompanied by excessive daytime somnolence, a sense of fatigue, and inability to focus and perform tasks effectively in the daytime, which are the main symptoms people visit their clinician for. People with ISS are at increased risk of neurological (e.g., dementia, stroke), cardiovascular (e.g., heart attack, hypertension), and metabolic-endocrine (hypothyroidism, diabetes, hyperlipidemia) problems. ISS is driven by social causes that lead to sleep deprivation, such as extended work hours or being a caregiver to others. The detrimental effects of ISS worsen as sleep deprivation accumulates over time, whereas weekend catch-up sleep, although helpful, is not sufficient to fully replenish the body’s lost rest. As a syndrome caused by social factors, treatment is achieved by changes in social habits, which also avoids unnecessary use of medications or coffee that people tend to take to remain awake.
Sleep apnea is the most commonly diagnosed syndrome of sleep disordered breathing (SDB) and refers to shallower breathing or breathing arrests during sleep that lead to either a decrease in the body’s oxygen or awakenings from sleep. About a third of adult men and post-menopausal women, and 9% of pre-menopausal women have sleep apnea. It is classified generally into Obstructive Sleep Apnea (OSA) and Central Sleep Apnea (CSA), depending on whether the disordered breathing is caused by narrowing or collapsing of the upper airway (OSA), or by a decreased or non-existent respiratory effort (CSA). The main risk factors for OSA are male sex, narrow upper airway anatomy, and age. CSA is observed in people with certain neurological or cardiac diseases (e.g., heart failure), although brief central apnea events are normally observed in people the first seconds of entering sleep and in pre-kindergarten children during REM sleep. The vast majority of people with sleep apnea have or are at risk of cardiac (e.g., arrhythmias), metabolic (e.g., hyperlipidemia, diabetes), neurological (e.g., stroke, dementia) and psychiatric (e.g., depression and anxiety) disorders. Of the cognitive deficits associated with sleep apnea, vigilance is the most affected, but improves with treatment of sleep apnea as deep sleep is achieved.
SDB also explains why many people use the bathroom in the middle of the night (nocturia) even though they don’t have prostate or cardiac problems, because certain hormones that regulate urine production are poorly regulated due to decreased oxygen. It is not uncommon for men to receive surgical prostate procedures for nocturia, even though the cause to their symptoms is sleep apnea. In children that remain asleep throughout the night, SDB can present as enuresis into later childhood. Children with sleep apnea may also not seem sleepy in the daytime, and are often given a diagnosis of Attention Deficit Hyperactivity Disorder that is treated with stimulants, which could otherwise improve by treating the underlying sleep apnea.
The view that only obese older men who are sleepy in the daytime and snore loudly have SDB is incorrect, and instead even young thin women and children have SDB. Very thin younger people with SDB may not have the typical sleep apnea described above, and instead have the, often undiagnosed, syndrome Upper Airway Resistance Syndrome (UARS). People with UARS take progressively more effortful breaths during sleep because their body tries to push air through the bottleneck caused by a long and thin upper airway, which in turn leads to brief arousals. Sleep becomes fragmented and unrefreshing, leading to trouble focusing in the daytime, but not necessarily causing daytime somnolence.
The first line treatment for sleep apnea is Positive Airway Pressure (PAP) therapy during sleep where ambient air is pushed into the airway through the nose (or nose and mouth in some cases). This air works like a wedge that stabilizes the airway and prevents its collapse. For people who also have problems exhaling enough CO2 during sleep or have CSA (e.g., morbid obesity, neuromuscular disorders, cardiac disease), non-invasive ventilation (NIV) machines are more effective.
Hypersomnia syndromes refer to excessive sleepiness in the daytime even though people have had adequate and fair quality sleep the previous nights. Distinct from hypersomnia is hypersomnolence, a symptom referring to sleepiness in the daytime that does not necessarily lead to sleep. There are three main hypersomnia syndromes: narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).
NT1 is the best described hypersomnia and it is caused by decreased levels of a chemical produced at the hypothalamus of the brain called hypocretin or orexin (Hcrt/Orx). Hcrt/Orx helps people consolidate sleep periods, preventing the brain from going in and out of sleep randomly. As a result, people with NT1 report excessive daytime somnolence with sudden sleep attacks and fragmented unrefreshing sleep at night. Because sleep and wake are poorly dissociated, people have experiences as if being simultaneously in both states, such as having dream-like hallucinations around sleep periods, and sleep paralysis with inability to move for several seconds upon awakening. Almost unique to NT1 is the symptom of cataplexy, where people report sudden loss of muscle tone where their jaw drops or their knees buckle with strong emotional reactions, such as laughter. Diagnosis of NT1 is based on sleep studies both at night (overnight polysomnography [PSG]) and in the daytime (multiple sleep latency test [MSLT]) that reveal fast onset of sleep and especially REM sleep. To the extent available, Hcrt/Orx levels in the cerebrospinal fluid that is obtained through a lumbar puncture are also helpful in making a diagnosis.
NT2 is similar to NT1 with excessive sleepiness in the daytime and rapid onset of REM sleep on PSG and MSLT, but it is not accompanied by low Hcrt/Orx levels or by cataplexy symptoms. People with IH, instead, do not have rapid onset of REM sleep on PSG or MSLT even though they fall asleep within minutes during testing. They also don’t have cataplexy symptoms or low orexin levels, and their main complaint is long sleep duration throughout a 24-hour period that usually lasts 12-14 hours.
For a group of people with excessive daytime sleepiness, especially when this first presents over age 55, there is frequently co-existing cognitive impairment, which justifies a clinician’s decision to pursue multidisciplinary evaluation with neuropsychological testing and brain imaging to examine if the hypersomnolence symptoms hint to a comorbid neurocognitive disorder such asor .
Overall, people with hypersomnia syndromes usually benefit by pharmacological therapies that consolidate sleep and wake periods, and by establishing daily habits, such as scheduling naps in the daytime and being exposed to sunlight in the morning, that decrease the chance of a sudden urge to sleep.
CRSD are syndromes where the timing of sleep throughout the day, the so-called circadian rhythm, is out of synchrony to the established societal norms. People whose natural sleep-wake cycle is much later than most, falling asleep in the early morning hours and waking up very late in the day, are typical “night owls” and have a Delayed Sleep Phase Chronotype, whereas people who are “morning larks,” going to bed early in the evening and waking up very early in the morning have an Advanced Sleep Phase Chronotype. These chronotypes have a strong genetic background, are regulated by the body’s response to sunlight and a hormone secreted in the evening called melatonin, but are only considered disorders if they interfere with people’s lives. People with Delayed Sleep Phase Disorder (DSPD) often misinterpret their delayed sleep-wake cycle as insomnia and may pursue inappropriate pharmacological or other treatments, because the symptom recognized is an inability to fall asleep at a socially expected time. It is not uncommon for people with DSPD to become sleep deprived during workdays and have catch-up sleep on weekends. Delayed Sleep Phase Chronotypes are extremely common in teenagers as their body changes, justifying later school start times and their association to better student academic performance. In contrast, Advanced Sleep Phase Chronotypes are more common in older people, possibly an indication of less sunlight passing through the eyes due to cataracts or, even, early neurodegenerative changes in sleep-wake regulating brain centers.
In older people with neurocognitive disorders due to advanced neurodegeneration it is common to observe Irregular Sleep-Wake Rhythm Disorder, during which circadian rhythms become fragmented even though total sleep time remains normal. As a result, people go in and out of sleep throughout the 24-hour cycle.
A rare but well-described CRSD is the non-24-hour CRSD, where some people who are blind or lack specific light receptors in the eye have a gradual delay of their circadian rhythm, progressing their sleep-wake times over the 24-hour cycle. Not all people who are blind will have non-24-hour CRSD, because the specific light receptors can be intact, even though visual stimuli are not perceived in the brain.
In addition to intrinsic causes leading to CRSD, there are two extrinsic mechanisms that can lead to difficulties in daily life. The first, called Shift Work Rhythm Disorder, presents in people who are forced to have a work schedule that interferes with their natural sleep times. Similar to people with DSPD, they may become sleep deprived and, because their circadian rhythms are poorly consolidated, also exhibit features of insomnia or excessive daytime somnolence depending on the time of day. The second extrinsic mechanism of CRSD is jet lag, observed in people traveling across multiple time zones by plane, where their internal circadian rhythm is misaligned to their new environment.
Therapies for CRSD include pharmacological and non-pharmacological approaches that an expert can recommend.
NREM parasomnias are complex behaviors during deep NREM sleep (slow-wave sleep) and are divided into confusional arousals, sleep related sex behaviors (sexsomnia), sleep walking, and sleep eating. Because they occur at a stage of sleep that the cortex is inactive, people waking up from NREM parasomnias are confused and have no recollection of their actions. Being a variation to an underlying sleep stage where NREM sleep and wakefulness are not fully dissociated, people with one NREM parasomnia may exhibit other NREM parasomnias at different times. They are usually associated with sleep deprivation, alcohol consumption or certain medications. A NREM parasomnia specific to children is night terrors, where children wake up frightened and crying inconsolably during sleep with no recollection of a bad dream. If the diagnosis of a NREM parasomnia is not clear from the history or videos provided, an overnight sleep study is required to distinguish it from other neurological disorders that can occur during sleep (e.g., seizures), or from other parasomnias that may have a different underlying cause and prognosis (e.g., RBD vs. NREM parasomnias).
REM parasomnias are complex behaviors that occur during REM sleep (dream sleep) with the main culprit being REM Behavior Disorder (RBD). RBD refers to acting out of dreams, where people move violently as if fighting off someone in 80% of cases, or perform complex movements as if playing a musical instrument or a sport. People are able to recall elements of a dream in most cases upon awakening, because RBD reflects an overlapping state between REM sleep and wakefulness. This dissociated state is caused by dysfunction of a part of the brain called the brainstem. In contrast to NREM parasomnias, however, RBD is almost always associated with an underlying brain disease, which in most cases is a, such as Parkinson’s disease or Lewy Body Dementia. RBD is often the first symptom of a synucleinopathy, preceding other symptoms by an average of eight years, with some people having had RBD symptoms for up to 50 years before motor symptoms. RBD is also observed in other conditions that affect the brainstem where REM sleep and wakefulness are poorly dissociated, that affect the brainstem, such as , spinocerebellar ataxia type 3, and certain rare immune-mediated encephalopathies (e.g., IgLON5). A sleep study with video monitoring is almost always indicated for its diagnosis, because of its clinical association to an underlying brain disease that can be managed with pharmacological or non-pharmacological therapies.
Sleep talking without any other abnormal sleep behaviors is not considered a parasomnia and can present at any stage of normal sleep in healthy people.
People with RLS report an irresistible urge to move their legs, or other limbs, while awake and not moving, especially at night. This is very uncomfortable and often noted when entering the bed to sleep or taking a long ride in a vehicle. The experience improves by massaging the limbs or getting up and walking, but will get worse again when getting into a resting position. It is often present in people who have iron deficiency and is even present in children. It is not uncommon for people to become sleep deprived or to report insomnia symptoms. Iron supplementation or medications that reduce the uncomfortable feeling are helpful, depending on the cause of RLS. Although older studies suggested an association of RLS to leg movements during sleep, this is not supported by the recent literature.
Neuromuscular and Motor Neuron Disorders
MND are a family of diseases defined by the degeneration of motor neurons that control voluntary muscle movements. There are three main MND: Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), and Progressive Muscular Atrophy (PMA). The most common MND is ALS where both upper motor neurons and lower motor neurons are affected. Degeneration of upper motor neurons alone defines PLS, whereas degeneration of lower motor neurons defines PMA. Another specific type of MND is Progressive Bulbar Palsy (PBP) where the degeneration preferentially affects motor neurons of the brainstem that control throat and facial muscles. Depending on the type and distribution of motor neurons affected in MND, there are differences in how symptoms present and progress. Almost invariably, however, motor neuron degeneration leads to people losing control of voluntary movement, becoming weak, and gradually being unable to speak clearly, even though they retain their ability to feel and think. Additional problems with disease progression include swallowing difficulties and excessive salivation, to which a parenteral feeding tube and medications improve quality of life. Furthermore, people eventually tend to suffer from respiratory failure due to weak breathing, and non-invasive ventilation has been proven to increase survival in MND. For those people where upper motor neurons are affected, such as in ALS, are not uncommon.
Epilepsy and Seizure Disorders
The term Epilepsy refers to a syndrome during which people have recurrent unprovoked seizures that arise from abnormal, hypersynchronous, and sustained brain hyperactivity. Depending on the affected hyperactive part of the brain, a person’s seizures present in different ways, such as an abnormal sensation (e.g., taste, smell, vision, or sound), movement (e.g., uncontrollable shaking or posturing), or behavior (e.g., loss of consciousness).
Autoimmune Neurological Disorders
Multiple Sclerosis (MS) is a disease of the brain and spinal cord defined primarily by inflammatory damage to the sheath (myelin) of neuronal cells that is often accompanied by neurodegeneration of the neurons themselves. A key pathological process leading to MS is the mistargeted action towards myelin of the body’s immune cells that normally serve as a defense mechanism to external agents, such as viruses. Symptoms vary depending on the area of the brain and spinal cord that is affected, and can range from imbalance to double vision and numbness. Most symptoms last a few days and improve as the inflammation resolves, but recurrent attacks, called relapses, can eventually lead to permanent deficits. For this reason, pursuing early and effective disease modifying treatment protocols is often recommended to prevent long-term permanent deficits. It not uncommon for people with MS to experience relapse-like events of previously resolved symptoms if their body is under stress, such as during a fever or having a hot shower. These do not reflect a relapse of the disease and resolve when the stressful factor resolves as well.