Contributions of the neurological examination to the diagnosis of dementia in Down syndrome




Chapter 13: Contributions of the neurological examination to the diagnosis of dementia in Down syndrome



Ira T. Lotta,*; H. Diana Rosasb,,c; Florence Laib; Shahid Zamand    a Department of Pediatrics, School of Medicine, University of California, Irvine, Orange, CA, United States
b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
c Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
d Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
* Corresponding author itlott@uci.edu, itlott@hs.uci.edu




Keywords


Down syndrome; Alzheimer’s disease; Neurological exam; Seizures; Gait; Mental status; Muscle tone; Reflexes


Acknowledgments


We would like to acknowledge Eric Doran, MS for his assistance in the manuscript preparation. Our research has been supported by AG05142, AG16573, HD065160, and TR001415.


The neurologist has a fundamental role in the evaluation of dementia. Given the strong prevalence of dementia in Down syndrome (DS) [13], the neurologist is often called upon to contribute to the consensus diagnosis. Within the evaluation for dementia in the general population, the neurological evaluation of the elderly requires a thorough history and performance of an age-appropriate examination with special attention to changes that occur with normal aging [4, 5]. The neurologist may utilize standardized questionnaires that record decline from typical functioning in the areas of complex attention, executive functioning, language, learning and memory, perceptual-motor functioning, social cognition, and psychiatric factors [6]. The clinical impression that results from a neurological history and examination is routinely included in the consensus diagnoses for dementia of various etiologies, but especially Alzheimer’s disease (AD) [7, 8].


In people with DS, the clinical diagnosis of dementia based upon experienced judgment has also been shown to be valid and reliable. In a study of 85 adults with DS [9, 10], clinical judgment based upon the neurological evaluation for dementia correctly identified over 84% of patients as compared to the application of ICD-10 criteria (70%) or DSM VDSIM-IV-TR criteria (56%). Yet development of the clinical impression for dementia in DS has unique challenges. Most important among these are the variations in baseline intellectual functioning that are ubiquitous in DS. Most adults with DS will have an intellectual quotient (IQ) in the mild to moderate range of intellectual disability [11] with a cognitive phenotype showing a particular weakness in language [12]. The diagnosis of dementia in DS thus rests on showing a change from a background of variable strengths and weaknesses.


The neurological history


Individuals with DS are always invited to participate in physician discussions about their symptoms but due to the intellectual limitations cited before, may not be able to provide information essential for the diagnosis of dementia. Therefore the role of the informant becomes paramount. Informant interviews have been shown to be useful in the assessment of cognitive decline in the general population with AD [13, 14] particularly when the informant has known the patient for 10 years or more [9]. While standardized neuropsychological tests are detailed elsewhere in this volume (see Chapter 15), the clinician is the one responsible for developing an independent opinion that will contribute to the consensus discussion. Central to this premise is understanding how current symptoms in an adult with DS have changed from preexisting levels of intellectual impairment over time, how these changes interfere with daily functioning, and whether comorbidities are present that can confound the diagnosis [15]. The scope and prevalence of comorbidities in adults with DS have been comprehensively reviewed [1619] (see Chapter 11). This review will focus on selected neurological variables relevant to dementia in DS.


The National Task Group on Intellectual Disabilities has developed an Early Detection Screen for Dementia [20] that can serve as a platform relevant to adults with DS. The informant who provides historical information may be a family member, a paid caregiver in a community residential home, or a member of an authorized agency supported by the State. Informants should have known the patient’s daily activity and health status for at least 6 months, but the longer the better. In assessing dementia, changes over the past year provide a reasonable time frame for comparison, although historical memory by some informants can go back much further and this longer time frame may increase the certainty of a diagnosis.


The following are selected elements in the history that have potential significance for the neurological diagnosis of dementia in DS.


Sensory deficits


Deficits in hearing, vision, and olfaction have been closely associated with dementia in the general population [21]. In a scoping review of older people in the general population who live in care homes, lack of knowledge about hearing and visual screening along with inadequate training regarding assistive aids has created a barrier for effective practice including the diagnosis of dementia [22]. It is common experience that older adults with DS have similar problems.


Hearing loss


Middle ear infections related to malformations in the ear, nose, and throat are common in children with DS [23, 24]. Most of the audiological concerns in children with DS are conductive in part related to congenital malformations in the ear canal and temporal bones. With age, sensorineural hearing abnormalities may be superimposed upon conductive losses making hearing impairment a significant comorbidity in the evaluation of dementia [25]. Up to 73% of adults with DS may have a clinically significant hearing loss [17]. Hearing loss may impact language function and further complicate a diagnosis of dementia [26]. This is of particular concern in people with DS wherein the cognitive phenotype shows relative weaknesses in expressive language, syntactic/morphosyntactic processing, and verbal working memory [12] (see Chapter 15). Therefore review of hearing status becomes imperative in the dementia evaluation with referral for updated audiological testing where necessary.


Visual deficits


Adults with DS have significant visual deficits with reduced sensitivity across spatial frequencies, reduced stereopsis, as well as abnormalities in acuity and color discrimination [27]. These abnormalities are similar to those seen in AD within the general population [28]. Hypoaccommodation appears to be linked to poor visual acuity in people with DS [29]. In a pattern similar to AD in the general population, adults with DS have a specific and substantial deficit in optic flow perception, a finding which may have relevance for getting lost in familiar places as dementia progresses [30]. Since adults with DS have steeper and thinner corneas on examination, they are prone to keratoconus, which can lead to serious visual impairment [31]. If the visual impairment is leading to a functional disability in adults with DS, then keratoplasty may be carefully considered [32]. If an adult with DS is turning the head to look sideways at objects then a cataract should be considered. Cataracts occur at an earlier age in people with DS compared to neurotypical patients. Taken together, visual disabilities may occur in up to 85% of adults with DS [27].


Seizures


Seizures in adults with DS have been associated with increased mortality [3336]. DS and autosomal dominant dementia in the general population share a predilection for early onset seizures [37]. Generalized tonic-clonic and myoclonic seizures are the most common presentation [38] although partial seizures are also frequent. Myoclonus may occur earlier in the course of dementia in both DS and AD in the general population [39]. The presence of seizures in people with DS and dementia is associated with an accelerated cognitive decline [40]. With dementia, impairment of neuronal circuits and overexcitability seem to be associated with the onset of seizures [41]. In the general population, studies of epilepsy indicate an intersection of seizures, dementia, and cerebrovascular disease [42]. Neuronal excitability underlying an epileptic tendency may increase the secretion of amyloid-β and tau [43]. For the neurologist, a history of staring episodes, unresponsiveness, or “spacing out” should raise the possibility of seizures confounding the reports of cognitive decline.


Syncope


For families and caretakers, there is often confusion between syncope and seizures in adults with DS. The differential diagnosis is achieved with a targeted history and witness observations where possible [44]. After age 30 years, hypotension is often experienced by adults with DS [45]. Individuals with DS may have a decreased sympathetic response to stress, less arterial stiffness, as well as a decrease in other atherosclerotic markers consistent with their tendency toward hypotension [46, 47]. However, sinoatrial node dysfunction has also been reported in DS [48] and may require pacemaker placement. In our experience, a syncopal episode is often associated with observable pallor and we encourage caretakers to note this distinction.


Stroke


There is an increased risk of cardioembolic stroke associated with congenital heart disease [49]. In DS, congenital heart disease associated with pulmonary hypertension and cardiac arrhythmias increases the risk of stroke at all ages [50]. In younger patients with DS, moyamoya syndrome is a rare complication that may be associated with hemiparesis and myoclonus. The acute complications of moyamoya seem confined to the pediatric and adolescent age group in DS but MRI evidence of a focal infarct may be found many decades later as an unexpected finding during the evaluation for dementia. While adults with DS have a decreased risk of atherosclerotic stroke, there is an increased prevalence of intracerebral hemorrhage [51]. Microbleeds aligned with cerebral amyloid angiopathy are increased in brain tissue from adults with DS over age 30 years [52, 53] but sequelae from atherosclerosis are noted much less frequently (see Chapter 4).


Psychiatric and behavioral issues


As reviewed by Zis and Strydom [10] and expanded upon in Chapter 14, behavioral and psychological symptoms may precede the development of dementia in DS. These symptoms often take the form of disinhibition, executive dysfunction, and apathy, all reflective of frontal lobe impairment [54, 55]. However, up to 35% of adults with DS may have a background of other comorbid behavioral abnormalities, including bipolar disorder, anxiety symptoms, obsessive-compulsive disorder, attention deficit disorder, and/or autistic symptoms [56]. Thus it becomes imperative to determine whether a psychiatric dysfunction has existed for many years and whether the symptoms are the same, better or worse in comparison to the present evaluation. In the transition to dementia, changes in attention and memory are prominent starting in the 40s [16, 57]. If the individual under evaluation for dementia has been previously treated for psychiatric symptoms, there needs to be awareness that medication response may be less robust than typically expected and/or a lower threshold for behavioral side effects [58]. Medication compliance has been shown to vary by residence type in people with intellectual disabilities (with those living in their own home or in semiindependent arrangement showing less compliance than those living in a community residential setting) [59]. These factors should be taken into account in assessing medications concomitant with the dementia evaluation.


Depression in DS may be manifested by social withdrawal, apathy, weight loss, psychomotor slowing, and even aggression—all symptoms that may confound a diagnosis of dementia. Often these symptoms are related to a situational event such as a change in living arrangement, bereavement, or a sibling moving out of the home. An even more dramatic example of regression is rarely seen in younger adolescents and adults with DS (generally before age 40 years) in which there is an unexplained regression in social skills and cognitive-executive functioning as well as a decline in performance of daily activities [6062] (see Chapter 14). Significant emotional stressors have been found in many cases of this regressive syndrome. In addition to involving a younger age spectrum in DS, this unexplained regression has a more acute pace than that seen in dementia.


Self-talk or “private speech” is quite common in adolescents and adults with DS and is unrelated to psychosis or dementia [63]. However, delusions and hallucinations may occur related to separate psychiatric conditions that may or not be related to dementia [64]. Auditory hallucination and persecution delusions have been seen in up to 31% of individuals with DS and dementia [65]. Other areas of cognition and behavior that may be affected in AD are elicited from the history from caregivers such a decline in judgment (dressing inappropriately for the weather), coarsening of social skills (language or actions that are inappropriate and out of character), emotional lability, temporal disorientation (mixing up night and day), and spatial disorientation (getting lost in familiar surroundings).


Thyroid dysfunction


Clinically significant hypothyroidism or the progression of the subclinical state to symptomatic status may be exaggerated in DS [66, 67]. It is actually subclinical hyperthyroidism that shows a modest association with dementia in the general population and possibly in DS [68]. Current recommendations are to screen for thyroid disease in adults with DS on an annual basis (see Chapter 11). Yet there are many symptoms of frailty in older individuals that have some association to thyroid dysfunction including depressive symptoms, changes in gait, and mobility [69]. Individuals with DS have an increased predisposition to thyroid, gut, and islet autoimmunity [70, 71]. The prevalence of autoimmune disorders has been associated with catatonia in DS [61]. The relationship of autoimmune dysfunction in DS to dementia is unclear but may be related to immunoregulatory genes on chromosome 21. Precocious immunosenescence has been suggested but is not fully endorsed as a mechanism [72]. Children with DS have an increased prevalence of Hashimoto’s thyroiditis which may progress to Grave’s disease over time thereby increasing risk for dementia [73]. An altered immune regulator gene in DS has been implicated in the association with autoimmune disorders [74]. In adults with DS who have cognitive decline, Hashimoto’s thyroiditis must be considered. The encephalopathy associated with Hashimoto’s thyroiditis can mimic dementia as it is characterized by cognitive decline, myoclonus, and behavioral changes [75].


Sleep and dementia


Sleep apnea, its presentation and management has been discussed elsewhere in this volume (see Chapter 12). Sleep disturbance is a common manifestation of AD in the general population. Rapid eye movement sleep patterns and the degree of insomnia appear to predict incident dementia in the general population [76, 77]. Stages of sleep may affect the pathophysiology of AD through abnormalities in the generation and clearance of amyloid-beta (Aβ) [78], Aβ aggregation [79], and glymphatic flow [80]. In DS, little is understood about the mechanisms by which sleep may affect dementia. A cognitive sampling of young adults with DS and obstructive sleep apnea has shown that executive functioning may be disproportionately affected [81]. This is of potential interest because of early deposition of amyloid-beta in the prefrontal cortex in DS but more research is needed in this area.


Menopause


The age at menopause is a risk factor for dementia in women with DS as well as in the general population. Early age at menopause (46 years or younger) is associated with low bioavailability of endogenous estrogen and results in an increased risk for dementia as well as an earlier age of onset [82].


Elements on the general physical examination of neurological interest in DS


A complete physical examination is part of every evaluation for dementia. Some adults with DS who are being evaluated for dementia will not have information regarding their karyotype. In that circumstance, it is helpful for the neurologist to note a few of the basic dysmorphic findings in the disorder that are consistent with DS. Features highly consistent with trisomy 21 are epicanthus, high arched palate, curved 5th finger, and a gap between the first and second toes [83, 84]. There is no evidence that cognitive function and subsequent dementia are related to the number of dysmorphic features. Head circumference which can serve as a proxy for brain size is smaller in DS than in the general population and more marked in males [85]. This discrepancy persists through early childhood and into adult life [86]. Specialized growth curves which include head circumference have been developed for individuals with DS [87]. The smaller scale of the brain in DS is not simply a downscale model of a typically developed brain but is representative of distinct topography [88]. The frontal lobes are foreshortened, the hippocampus smaller, and the occiput steeper than in the typical developing brain. In DS, the brain is characterized by defects in neurogenesis wherein there is disproportionately thicker cortex in the frontal, parietal, occipital-temporal, and posterior cingulate areas [88]. These findings may be related to baseline intellectual disability in DS prior to the onset of dementia.


Neck circumference of greater than 16 in. in women and 17 in. in men has been associated with obstructive sleep apnea [89, 90]. Contributory morphometric facial features include brachycephaly and a decreased maxillary segment [91], which are often present in individuals with DS. The evaluation of suspected sleep apnea in DS is described in Chapter 11.


Manifestations of autoimmune disease and immune activation


Vitiligo and alopecia frequently occur together in DS [92] and may represent the cutaneous extra-thyroidal manifestations of autoimmune disease [93]. In an adult with DS and cognitive decline, these physical findings may rarely relate to Hashimoto’s thyroiditis.


Periodontitis


This source of chronic inflammation and bacterial infections has been increasingly shown to drive a cytokine-based immune response as well as oxidative stress in the brain of individuals with DS. This mechanism can heighten the risk of AD in DS [94]. Thus the clinician should note the state of gum inflammation during the evaluation for dementia and make a dental referral where indicated.


The neurological examination


Mental status


Elements of the mental status examination are listed in Tables 13.



Table 1
























Categories of altered presentation of mental signs and symptoms in people with intellectual disability.

Associated with Examples
Intellectual distortion Impaired abstract thinking (thinking is more concrete or literal)
Poor sense of chronology (unable to faithfully relate timelines of events to psychological states, and thinking tends to be in the “here and now”)
Poor language skills (especially expressive less good than receptive)
Unable to give a rich description of subjective experiences and thoughts, such as emotional distress, delusions, or hallucinations that may be lacking a narrative
Psychosocial masking Lack of wide social experiences Unable to provide an expansive repertoire of thoughts and intentions (such as may express a very limited degree of grandiosity in a presentation of mania, such as believing can drive a car, when never even attempted to even learn to do so)
Cognitive disintegration Reduced resilience or lesser ability to cope with stress that (more readily) leads to decompensation Cognitive resources for the usual means of dealing with distress not readily available and manifesting as difficult, challenging, or strange behaviors (e.g., aggression or shouting inappropriately)
Baseline exaggeration Preexisting maladaptive behavior that may increase in severity or frequency with onset of psychiatric illness Self-injurious or ritualistic behaviors become heightened

Modified from Sovner R, Hurley AD. Four factors affecting the diagnosis of psychiatric disorders in mentally retarded persons. Psychiatr Asp Ment Retard Rev 1986;5:45–49.




Appearance and behavior


Careful observation during the interview can be very informative. An unkempt appearance or poor hygiene may suggest depression, psychosis, or the loss of self-care which can accompany dementia. Gaze avoidance is common in an individual with DS and concomitant autistic features. An unemotional countenance may connote Parkinsonian signs. Restlessness, agitation, and sympathetic overdrive are characteristic of anxiety. Loss of an expected level of congeniality in a person with DS may be one of the signs consistent with psychosis. These observations are particularly important if the history indicates a change from baseline functioning.


Speech and language


One must expect a certain degree of dysphonia in virtually all adults with DS [95]. In part, these abnormalities are due to congenital malformations involving the sinuses and laryngeal structures. For the neurologist, the problem may be complicated by variable degrees of abnormality in visual and auditory processing in adults with DS [96], leading to difficulties in cognitive communication. Overly loud speech may reflect decreased auditory feedback due to hearing loss. Low monotonous speech is seen in depression. Pressured fast speech may reflect anxiety. Repetitive compulsive speech in DS is associated with obsessive-compulsive disorder and autistic state. The complexity of language should be noted (i.e., spontaneous sentences, phrases, single words, or nonverbal) should be documented at baseline and a notation made if this represents a decline from prior ability for later comparison. The neurological characterization of speech at the time of this exam is useful in longitudinal observations for dementia.


Mood and affect


Mood is the state of an emotion whereas affect is the manifestation of the emotional state. Mood changes tend to last longer than changes in affect and are less likely to be altered or caused by specific events. Depression associated with dementia may cause alterations in both mood and affect. On longitudinal exams, there may be a change from an emotionally appropriate manner of reacting to an affect which is less animated, less expressive, and an avoidance of responding to social cues. Hallucinations or delusions may present with a fearful or anxious demeanor. Compulsive behaviors are common in DS and may be precipitated or worsened during stress [97] such as that associated with loss of personal control during dementia. Compulsions take the form of excessive repetition of daily acts such as cleaning, washing, touching, or arranging to name a few. They are different from movement stereotypies which are repetitive, purposeless, and rhythmic [98].


Memory


Short-term memory loss is one of the cardinal features of AD occurring early in the course of dementia. In DS, memory decline may manifest as repeatedly asking the same questions already answered or attempting to repeat an activity that was already completed (such as eating a meal). On exam, a simple short-term memory test generally understandable for adults with DS is to hide a common object such as a coin or paper clip and ask for its retrieval after 5 min.


Cranial nerves (selected for dementia relevance)


Cranial nerve I, olfaction


There is a systematic defect of olfactory circuitry in mouse models of DS [99] suggesting that these pathways may have significance for understanding brain development and aging. In AD, neuropathological changes occur in areas central to olfactory processing including the entorhinal cortex as well as projections to the hippocampus and temporal lobes [100, 101]. Olfactory function is impaired in DS even at younger ages [102] and increases further with age [103]. There is greater olfactory impairment in individuals with DS who carry the apoE4 allele [104]. Thus progressive olfactory impairment may be a marker for dementia. Several tests have been standardized for assessing olfactory impairment in DS including the Sniffin’ Sticks Extended Test [105] and the University of Pennsylvania Smell Identification Test [106]. Given the variability of predementia intellectual functioning in DS, longitudinal performance on these measures may be the most contributory in a consideration of dementia.


Cranial nerve II


The commonly reported concerns are refractive errors, hypoaccommodation, cataract, and keratoconus [107].


Visual acuity


Visual acuity is the most common metric used to monitor ocular health. The use of eye charts to measure acuity is recommended after 3 years mental age [108]. Children and adults with DS characteristically have a mental age well above this cutoff so that visual acuity may be approximated by the office examination. Visual acuity develops slowly in DS and there are refractive errors requiring correction in children, adolescents, and young adults [109]. Despite these ocular challenges, it is possible for most individuals with DS to perform letter acuity testing through matching or naming [110]. The fitting of frames for eye glasses in DS needs to account for the flat nasal bridge or the glasses may be perched on the tip of the nose interfering with corrected vision. Moderate to severe visual loss appears to predict dementia in the general population [111, 112] and is likely to have similar impact for individuals with DS.


Keratoconus


Individuals with DS have thinner and steeper corneas than in the general population, making them prone to keratoconus, a condition which can be increased several hundred-fold [31]. Eye rubbing which is a habitual pattern in some adults with DS may also increase the risk of keratoconus. Keratoconus may be suspected if blurriness of vision continues after corrective refraction. A gene for keratoconus has been linked to chromosome 21 [113]. On neurological exam, a bulging cornea may suggest keratoconus but the diagnosis is usually made by an ophthalmologist or optometrist during an ocular health examination. Several treatments are available for this problem in DS.


Cataracts


Cataracts occur in over 70% of adults with DS and slightly less than half are age related as opposed to congenital [114, 115]. Although slit lamp confirmation by an ophthalmologist is often required, the neurologist can determine whether opacities in the red reflex are present. Untreated cataracts have been associated with falls and disruptive behaviors in the general population with dementia [116].


Other visual findings


The success of intervention for a specific ocular disorder in DS often depends on the improvement in other coexisting ocular dysfunction. In addition to the conditions described before, the following abnormalities may be observed on neurological examination: The optic disc in DS is characterized by various developmental and anatomic abnormalities including hypoplasia and mal-insertion [117], a finding of uncertain clinical significance but one confronting the examiner on funduscopic inspection.


Glaucoma


Glaucomatous degeneration of the optic disc has been observed in adults with DS but not in children [118]. Other ocular abnormalities have been reviewed in DS [119].


Cranial nerves III, IV, and VI


Pupillary function appears to be abnormal in young adults with DS compared to mental age controls, showing a differential dilatation when confronted with a cognitive challenge [120]. However, pupillary abnormalities have not been observed in the general population with early stage AD [121, 122] while more advanced dementia may be associated with less responsive pupils [123].


Strabismus


Ocular mal-alignment in DS is common with strabismus present in 23% and esotropia most frequent [124, 125]. Monocular amblyopia may occur in up to 17% of young adults with DS [126]. Strabismus and resulting amblyopia may impair stereoscopic vision [127] with implications for gait dysfunction in adults at risk for dementia in DS. Although there is no data for adults with DS, disturbance in tracking of saccadic eye movements has been linked to Mild Cognitive Impairment in the general population [128]. The development of eye-tracking technology for use in naturalistic settings is an interesting area for future research as a marker for AD [129].


Nystagmus


The vestibulo-ocular reflex is abnormal in young adults with DS, particularly in men [130]. Nystagmus may be seen throughout the lifespan in DS and may represent defective circuitry within the cerebellum [131]. There is a strong relationship between nystagmus and visual acuity deficits in DS [132]. There is a relationship between nystagmus and tendencies to fall in AD, but it appears to be mediated from vestibular, not central dysfunction [133].


Cranial nerve VIII, hearing


In the neurological evaluation for dementia, any functional change in an individual with DS needs to have an assessment of hearing. The Rinne and Weber tests are often too complex for an individual with DS and yield inconsistent results. We have found that an office substitute comprises whispering a word in each ear and asking the participant to repeat it. This is admittedly not very precise but gives an idea as to whether a serious hearing loss may be present. An inspection of the ear canal may reveal blockage by cerumen and/or a structural problem with the tympanic membrane. The examiner should have a low threshold for referring the individual with DS for a formal audiological assessment as indicated. The prevalence of hearing loss in adults with DS is striking with increases from 43% in the 20–29 year old age group to over 90% at ages 50–59 years [134, 135]. The audiometric profiles in aging adults with DS are similar to that seen in presbycusis within the general population. Adding to the problems of sensorineural hearing loss in DS are dysplastic ear canals stemming from structural abnormalities in middle ear, Eustachian tubes, and midface configurations in DS [136]. In the general population, hearing loss accounts for at least 9% of cases of dementia [137] and audiological treatment has been associated with cognitive improvements [138].


Cranial nerves IX and X


Swallowing dysfunction is a common finding in AD [139]. In DS, dysphagia is increasingly prevalent with aging and especially with dementia [140]. Dysphagia and aspiration pneumonia is a common cause of morbidity and mortality. The gag reflex is an element in the swallowing evaluation of people with DS and its presence, absence, or exaggerated status should be noted.


Motor and cerebellum


These two parts of the neurological examination are considered together because of the overlap in symptom presentation and neurological pathogenesis throughout the lifespan in DS.


Hypotonia


Ligamentous laxity and hypotonia are ubiquitous in people with DS and lead to complications that may impair gait and balance in older adults. These include pes planus, inflammatory arthritis, and scoliosis [141]. The cause of hypotonia in DS has not been identified but studies in the trisomy 21 mouse and neuronal cell cultures suggest that mitochondrial dysfunction plays an important role [142, 143]. Ligamentous laxity over the course of the lifespan in DS may make joints hypermobile. A particular area of concern has been instability of the craniovertebral junction in DS. Abnormally increased movement at the atlantoaxial joint may involve up to 27% of children with DS [144] although a much lower percentage actually become symptomatic. The natural course of this condition is not completely known for adults with DS but the danger is a compressive cervical myelopathy. For the neurologist the following findings are of potential concern in regard to atlantoaxial instability: nuchal rigidity, head tilt, onset of incontinence, change in gait, leg hyperreflexia, and extensor plantar responses [145]. Some of these findings can mimic those of early dementia. Hyperextension of the neck during the induction of anesthesia, contact sports, and the butterfly stroke in swimming may present a particular risk [146].


Gait


Abnormalities are present in individuals with DS across the lifespan and represent an area of concern in the diagnosis of dementia. Safe walking involves intact cognition and executive control. In the general population, there is an increasing prevalence of gait disorders with age, reaching 60% over age 80 years [147]. Adults with DS have difficulties in gait stability as they age along with abnormal kinetics at the hip, knee, and ankle joints [148, 149]. Patellofemoral instability in childhood may presage some of the orthopedic difficulties experienced in adults with DS [150, 151]. Congenital underdevelopment of the cerebellar vermis in DS may be a risk factor for gait instability [152].


In part, due to ligamentous laxity and muscular hypotonia, adults with DS often show dysplasia of the hip and require surgical correction [153]. As a result of these orthopedic concerns, individuals in the age range for evaluating dementia may show an antalgic gait, which is a way to avoid pain while walking. An antalgic gait is characterized by an abnormally shortened stance in comparison to the swing phase of walking. In practice, the patient appears to be limping secondary to pain or to the avoidance of it [154].


However, there are other gait abnormalities that are perhaps more reflective of the motor components of dementia in DS. Gait dyspraxia is characterized by the diminished capacity to correctly use the legs for ambulation when this deficit cannot be accounted for by sensory impairment, motor weakness, poor coordination, or other identifiable causes. In DS, progressive AD pathology characterized by frontal-parietal degeneration and disorders of white matter integrity are linked to gait dyspraxia [155]. Disturbances in executive function would be expected to anticipate gait dyspraxia in DS [155157]. Gait dyspraxia as often seen in individuals with DS and dementia is characterized by a tendency to pause at thresholds whether that be a change from the carpet to a wood floor, a crack in the sidewalk, or the first step in ascending a stair. Getting out of the van from the day program is often painstakingly slow compared to the abilities at a younger age and may represent a manifestation of dyspraxia. In dementia within the general population, falling is a particular risk and is associated with slowed gait velocity, increased gait variability, and decreasing ability to multitask as cognition declines [158]. These same variables apply to adults with DS. Gait and postural control training is effective in DS but more so in children than adults [159, 160]. On exam, gait dyspraxia in DS may be observed as hesitancy to cross a threshold, uncertainty in stair climbing, and difficulty walking over a small obstacle.


Parkinsonian signs may be present in the evaluation of adults with DS. In the general population, 38% of pathologically confirmed cases of Parkinson’s disease (PD) had a concomitant diagnosis of AD [161]. In DS, Parkinsonian symptoms may be seen in 36% of patients with dementia [162]. The cardinal motor symptoms of PD include bradykinesia, resting tremor, rigidity, and postural instability [163]. These signs may also be seen in DS but may overlap in cause with hypotonia, dyspraxia, and other features of developmental instability. It is interesting that it may be that the findings of PD on exam could be associated with the observation of Lewy bodies at autopsy [164] (see Chapter 2).


Pathological reflexes


Pathological or primitive reflexes are typically present early in development of the neurotypical infant and then disappear with maturation. They become potentially relevant to the development of dementia when they reappear during an examination for neurodegenerative disease. The most common pathological reflexes studied have been suck, snout, palmomental, glabellar, and palmar grasp. There is wide disparity of the occurrence of these reflexes among the healthy adult population [165, 166]. But heretofore there has been very little data available concerning the prevalence of pathological reflexes in adults with DS who were being evaluated for dementia. However, a recent investigation at the University of Kentucky (Harp et al., unpublished observations) has found that individual pathological reflexes did not differentiate between demented and nondemented adults with DS. Yet, in aggregate, there were a higher number of these reflexes in demented individuals with DS and they appeared stronger in response to the individual stimulus. Therefore, going forward, it appears reasonable to note how the number and strength of these reflexes correlate with other signs of dementia in DS and change over time.


Conclusions


The neurological contributions to the consensus diagnosis for the presence of dementia in DS rest on characterization of the nature, magnitude, and the course of cognitive decline. Clinical judgment is required to evaluate the influence of factors such as comorbidity, the severity of baseline intellectual disability, and cognitive performance independent of cut-points. The neurological evaluation also focuses on the temporal progression of cognitive decline and the speed of onset. Particularly in people with DS, longitudinal observations are essential. The physical and neurological examinations are directed toward objective evaluation of neurocognitive problems and those features due to DS per se independent of dementia. Taken together the well-formed clinical impression will have a major role in the diagnosis of dementia.



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Sep 12, 2021 | Posted by in NEUROLOGY | Comments Off on Contributions of the neurological examination to the diagnosis of dementia in Down syndrome
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