D



D



Degenerative diseases of childhood



Keywords


Degenerative Diseases of Childhood, white matter, gray matter, genetic testing, mitochondria, metabolism


Degenerative diseases of childhood may be classified in a number of ways, as they represent a heterogeneous set of disorders. Widespread availability of genetic testing has shed light both on multiple genes causing similar phenotypes, but also milder late-onset and adult forms of many of these disorders.



  1. I. Diseases that predominantly affect white matter (present with long tract signs [spasticity and hyperreflexia], optic atrophy, cortical blindness, or deafness)

    1. A. Metachromatic leukodystrophy: autosomal recessive (AR); arylsulfatase A deficiency or saposin B deficiency; diffuse demyelination and accumulation of metachromatic granules; age of onset 2 to 5 years; with peripheral neuropathy; magnetic resonance imaging (MRI) characteristically shows sparing of arcuate fibers.
    2. B. Krabbe disease: AR; beta-galactosidase deficiency; globoid cells; age of onset 4 to 6 months; restlessness, irritability and progressive stiffness; optic atrophy; hyperacusis; peripheral neuropathy; MRI—arcuate fibers spared and parieto-occipital lobes involved early, high-density basal ganglia.
    3. C. Adrenoleukodystrophy (ALD): X-linked recessive; acyl coenzyme A (Acyl-CoA) synthetase deficiency resulting in accumulation of very long-chain fatty acids; ABCD1 gene mutation; single peroxisomal enzyme deficiency; childhood ALD—neurologic symptoms before adrenal insufficiency; adrenoleukomyeloneuropathy—spinal cord and nerves involved, age of onset in 20s to 30s, paraparesis and adrenal dysfunction almost at the same time; MRI—occipital lobes and splenium of the corpus callosum affected, marked contrast enhancement; pathologically, three distinct zones are identified: innermost zone with necrosis, intermediate zone of active demyelination and inflammatory changes, and peripheral zone consisting of demyelination without inflammation.
    4. D. Pelizaeus-Merzbacher disease: X-linked recessive; deficient proteolipid protein 1 (PLP1) expression; newborn—nystagmus and opsoclonus; axial hypotonia; tongue fasciculations; ataxia. Childhood onset—dementia, tremor and choreoathetosis; MRI—hypomyelination, perivascular white matter spared producing a “tigroid pattern”; involves arcuate fibers. A similar disorder is found with GJA12 mutations- called Pelizaeus-Merzbacher like disease.
    5. E. Alexander disease: sporadic; GFAP mutations. Neuropathology shows Rosenthal fibers; macrocephaly; MRI—frontal lobe hyperintensities, basal ganglia or brainstem involvement (+) contrast enhancement.
    6. F. Canavan disease: AR; aspartoacylase deficiency; normal for first 1 to 2 months, then by 6 months develop macrocephaly, hypotonia, seizures, and loss of early milestones; widespread vacuolation; MRI—near or total lack of myelin, involves arcuate fibers.
    7. G. Cockayne syndrome: AR; defective DNA repair; microcephaly, large ears, sunken eyes, joint contractures, delayed psychomotor development; age of onset 2 years; retinitis pigmentosa, progeria; MRI—hypomyelination, perivascular calcification in basal ganglia and cerebellum.
    8. H. Chédiak-Higashi syndrome: AR; mutations in CHS1 gene; lysosomal disorder resulting in neutrophil dysfunction with impaired phagocytosis leading to defective bactericidal abilities; intracytoplasmic inclusions in neutrophils and neurons, most prominent in pons and cerebellum; albinism, pancytopenia, susceptibility to infection, nystagmus, hepatosplenomegaly; mental retardation, cerebellar and long tract signs, cranial and peripheral neuropathy.

  2. II. Neuroaxonal dystrophy: mutations of PLA2G6 gene, neuroaxonal spheroids along axons, especially neuromuscular junction; onset between 1 and 2 years, upper and lower motor neuron signs. Cognitive and motor regression, seizures, progressive motor sensory neuropathy, and hypotonia.

    1. J. Phenylketonuria: AR; phenylalanine hydroxylase deficiency; developmental delay, hyperactive deep tendon reflexes, lighter pigmentation, musty odor. MRI—arcuate fibers spared, optic radiations most affected. Often detected in newborn screening surveillance monitoring; mental retardation results if not treated early. Treatment with low phenylalanine diet—must avoid aspartame, an artificial sweetener that contains phenylalanine; evidence is accumulating that a low phenylalanine diet must be maintained lifelong to avoid precipitating cognitive decline.

  3. III. Diseases that predominantly affect gray matter (present with myoclonus, seizures, and cognitive impairment)

    1. A. Lipidoses

      1. 1. Tay-Sachs disease (GM2 gangliosidosis): AR; hexosaminidase A deficiency; mainly found in Ashkenazi Jews; onset 3 to 6 months, excessive startle, macrocephaly, macular cherry-red spot; MRI—hyperintense signal in caudate, thalamus, and putamen on T2-weighted images. A late-onset variant presenting as an ataxic syndrome is also present.
      2. 2. Gaucher disease: AR; glucocerebrosidase deficiency; type III—early to mid-childhood, seizures, ataxia, dementia, subacute neuronopathy; hepatosplenomegaly. Enzyme therapy has been developed. Parkinson disease is also associated with glucocerebrosidase mutations.
      3. 3. Niemann-Pick disease: AR; sphingomyelinase deficiency. Type A—infantile, hypotonia, pulmonary interstitial disease, organomegaly, macular cherry-red spot. Type B—neurologically normal. Type C—mutation in gene NPC1 and NPC2. Between 3 and 8 years of age, presents with spasticity, seizure, vertical gaze paresis, ataxia, and dementia.

    2. B. Neuronal ceroid-lipofuscinosis: “fingerprint” inclusions of lipofuscin within cytosomes on electron microscopy of leukocytes; presents with dementia, vision loss, ataxia, myoclonus, seizures; infantile, late infantile (photoconvulsive response at 3 Hz on EEG), juvenile (Batten disease), adult (Kufs disease).
    3. C. Mucopolysaccharidoses

      1. 1. Hurler syndrome: AR; α-L-iduronidase deficiency; mucopolysaccharides accumulate in neurons (meganeurites) and in histiocytes (gargoyle cells) in perivascular spaces; gargoyle-like facies, dwarfism, kyphosis, corneal clouding, mental retardation, hepatosplenomegaly, severe psychomotor deterioration, death within 5 to 10 years of onset; MRI—macrocrania, thick dura, perivascular “pits”; concave or “hooked” thoracolumbar vertebrae.
      2. 2. Hunter syndrome: X-linked recessive; iduronate 2-sulfatase deficiency; spinal cord compression, hydrocephalus, optic nerve compression, cervical myelopathy, hearing impairment, thick dura, perivascular “pits.”
      3. 3. Sanfilippo syndrome: AR; heparin-N-sulfatase deficiency; normal until age 2 to 6 years, then progressive dementia; hyperactive, aggressive, insomnia; spastic and movement disorder; death in second to third decade of life.

  4. IV. Diseases that primarily affect gray and white matter

    1. A. Leigh disease (subacute necrotizing encephalopathy): mitochondrial disorder with no male-male transmission; spongiosis, demyelination, astrogliosis and capillary proliferation in basal ganglia, brainstem, and spinal cord; infantile—onset at age 2 years of hypotonia, vomiting, and seizures; childhood; adult—fifth to sixth decades; MRI—hyperintense foci in globus pallidus (GP), putamen, and caudate.
    2. B. Myoclonic epilepsy with ragged-red fibers: mitochondrial; muscle biopsy—ragged red fibers; myoclonic epilepsy, myopathy, progressive external ophthalmoplegia, multiple infarcts in cortex and white matter.
    3. C. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: mitochondrial; myopathy, encephalopathy, lactic acidosis, stroke-like episodes, migrainous headaches, large and multifocal infarcts mainly in parietal and occipital lobes.
    4. D. Kearns-Sayre syndrome: mitochondrial; elevated pyruvate; progressive external ophthalmoplegia, cerebellar ataxia, heart block, and pigmentary retinopathy. Treatment is supportive with pacemaker and coenzyme Q10; progressive disease; death is common in third and fourth decade from central nervous system or cardiac complications.
    5. E. Alpers disease: etiology uncertain: hypoxic injury versus AR inheritance. Onset before age 6 years; myoclonic seizures appear early, then mental retardation and spasticity or opisthotonus.
    6. F. Menkes disease: X-linked recessive; ATP7A gene mutation; defective transmembrane copper transport; seizures, hypotonia develops into spastic quadriparesis; light-colored and brittle hair, hyperextensible joints, skeletal anomalies; susceptible to sepsis, heat-intolerant. Decreased serum copper and ceruloplasmin. Supportive and replacement therapy with copper histidine.
    7. G. Zellweger syndrome: AR; multiple peroxisomal enzymes; craniofacial abnormalities, hypotonia, severe weakness, seizures, and apnea. MRI—heterotropia, pachygyria, or polymicrogyria. Supportive treatment.

  5. V. Diseases that predominantly affect basal ganglia (present with movement disorders)

    1. A. Huntington disease: autosomal dominant (AD); CAG repeat with age of onset inversely proportional to age of onset; chorea, dystonia, myoclonus, ataxia, dementia, and personality changes; atrophy of caudate and enlarged frontal horns of lateral ventricle. The Westphal variant may present in teenage years with an akinetic-rigid syndrome. Poor prognosis with 10 to 15 years survival from time of diagnosis. Chorea may be treated with tetrabenazine or deutetrabenazine.
    2. B. Neurodegeneration with brain iron accumulation: AR and due to multiple genes. Iron deposits in GP and substantia nigra (SN); dystonia, mental retardation, stiff gait, equinovarus, dementia, retinitis pigmentosa, optic atrophy; low signals in GP and SN on T2-weighted images MRI, low signal surrounds region of high signal “eye of tiger” sign. Iron chelation has been studied, but clinical effects minimal or absent.
    3. C. Fahr disease: AD; first 2 years mental retardation and movement disorder; microcephaly, hypertonia. MRI—prominent calcification in basal ganglia, dentate nuclei, centrum semiovale, and subcortical white matter. Calcifications can be seen in multiple conditions, including TORCH syndrome.
    4. D. Wilson disease: chromosome 13, AR; P-type ATPase deficiency, ATP7B gene mutation. Defect in copper metabolism with decrease in ceruloplasmin and serum copper. Copper deposits in liver and basal ganglia; onset 8 to 16 years. Parkinsonism, seizures, ataxia, dementia, hemolytic anemia, liver dysfunction, and Kayser-Fleischer rings. Treatment is zinc, penicillamine, and tetrathiomolybdate.
    5. E. Dystonia musculorum deformans: AD; most common genetic cause of childhood dystonia. Age of onset before 20 years. Focal dystonia in limb progressing to generalized. Treatment with anticholinergic medication (see Dystonia).
    6. F. Aminoacidurias

      1. 1. Glutaric aciduria type 1: AR; glutaryl-CoA dehydrogenase deficiency (lysine to tryptophan); macrocephaly, dystonia, and dyskinesia; MRI—high-signal changes in basal ganglia and caudate; affects mitochondrial activity and preferentially involves basal ganglia leading to “bat wing” dilatation of sylvian fissures. Treatment includes protein and lysine restriction, and carnitine and riboflavin supplementation.
      2. 2. Methylmalonic acidemia: AR; secondary to blockage of conversion of methylmalonic acid (MMA) to succinyl-CoA leading to MMA accumulation; poor feeding and hypotonia, hyperammonemia, and ketoacidosis; MRI—hyperdensities in GP. Protein restriction.


References


Daroff R.B., Jankovic J., Mazziotta J.C., Pomeroy S.L., eds. Bradley’s neurology in clinical practice. ed 7 Elsevier; 2015.


Dulac O., Lassonde M., Sarnat H.B., eds. Pediatric neurology, Part I/II/III. ed 1 Elsevier; . Handbook of Clinical Neurology. 2013;vol. 111/112/113.



Dementia (See also AAN Guideline Summaries Appendix)



Keywords


Dementia, Major Cognitive Impairment, Minor Cognitive Impairment, Alzheimer Disease, Frontotemporal Dementia, Dementia with Lewy Bodies, AβPP, PSEN, APOE, Hachinski Ischemic Scale


Dementia is a clinical syndrome characterized by loss of multiple cognitive functions and emotional abilities in an individual with previously normal intellect and clear consciousness (i.e., in the absence of delirium). Though there is evidence of declining age-specific incidence of dementia in the Western world, the worldwide prevalence is expected to continue to increase due to increased life expectancy.


In its latest iteration, the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) changed the previous diagnosis of dementia and cognitive disorder categories to neurocognitive disorders (NCDs), separating cognitive impairments into major and mild categories (see Tables 42 and 43). Major cognitive impairment (dementia) is characterized by significant cognitive decline in at least one cognitive domain that interferes with daily function (Table 44). It is classified by etiology and presentation into Alzheimer dementia, frontotemporal lobar dementia, Lewy body disease, and other conditions (Table 45). It excludes patients with isolated deficits, such as aphasia or apraxia, and symptoms that occur during delirium.



Table 42







DSM-5 Diagnostic criteria for major neurocognitive disorder (Previously dementia)

A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (learning and memory, language, executive function, complex attention, perceptual-motor, or social cognition)


B. The cognitive deficits interfere with independence in everyday activities. At a minimum, assistance should be required with complex instrumental activities of daily living, such as paying bills or managing medications


C. The cognitive deficits do not occur exclusively in the context of delirium


D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia)



Table 42



Table 43







DSM-5 Diagnostic criteria for mild neurocognitive disorder (Previously cognitive disorders—NOS)

A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual motor, or social cognition) based on:


a. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and


b. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.


B. The cognitive deficits do not interfere with capacity for independence in everyday activities (i.e., complex instrumental activities of daily living such as paying bills or managing medications are preserved), but greater effort, compensatory strategies, or accommodation may be required.



Table 43



Table 44







Diagnosis of dementia
Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) symptoms that:

1. Interfere with the ability to function at work or at usual activities; and


2. Represent a decline from previous levels of functioning and performing; and


3. Are not explained by delirium or major psychiatric disorder;


4. Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from the patient and a knowledgeable informant and (2) an objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing. Neuropsychological testing should be performed when the routine history and bedside mental status examination cannot provide a confident diagnosis.


5. The cognitive or behavioral impairment involves a minimum of two of the following domains:


a. Impaired ability to acquire and remember new information—symptoms include: repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route.


b. Impaired reasoning and handling of complex tasks, poor judgment—symptoms include: poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities.


c. Impaired visuospatial abilities—symptoms include: inability to recognize faces or common objects or to find objects in direct view despite good acuity, inability to operate simple implements, or orient clothing to the body.


d. Impaired language functions (speaking, reading, and writing)—symptoms include: difficulty thinking of common words while speaking, hesitations; speech, spelling, and writing errors.


e. Changes in personality, behavior, or comportment—symptoms include: uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, and socially unacceptable behaviors.



Table 44



Table 45







Conditions causing dementia

1. Potentially reversible causes of dementia


a. Neoplasms (gliomas and meningiomas)


b. Metabolic disorders (hypo/hyperthyroidism, renal failure, hepatic failure, Cushing disease, Addison disease, Wilson disease, and hypopituitarism)


c. Trauma (subdural hematoma)


d. Toxins (alcohol, heavy metals, and organic poisons)


e. Infections (bacterial/fungal/viral/parasitic meningoencephalitis, neurosyphilis, HIV, and brain abscess)


f. Autoimmune disorders (systemic lupus erythematosus, multiple sclerosis, and vasculitis)


g. Drugs (antidepressants, anxiolytics, sedatives, anticonvulsants, anticholinergics, and antiarrhythmics)


h. Nutritional deficiencies (thiamine, folate, vitamin B12 and vitamin B6)


i. Psychiatric disorders (depression, schizophrenia, and mania)


j. Other disorders (normal pressure hydrocephalus, Whipple’s diseases, sleep apnea, and sarcoidosis)


2. Irreversible causes of dementia


a. Degenerative diseases (Alzheimer disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, Parkinson’s disease, diffuse Lewy body disease, olivopontocerebellar atrophy, ALS-parkinsonism-dementia complex, Hallervorden-Spatz disease, Kufs disease, adrenoleukodystrophy, and metachromatic leukodystrophy)


b. Vascular dementia (multiple small/large infarcts, Binswanger’s disease, CADASIL; see later discussion)


c. Traumatic (dementia pugilistica and TBI)


d. Infectious (CJD, postencephalitic dementia, and progressive multifocal leukoencephalopathy)



Table 45


CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CJD, Creutzfeldt-Jakob disease.


Examination for dementia should include assessment of multiple areas of cognitive performance, including memory, language, perception, praxis, attention, judgment, calculation, and visuospatial functions. The presence of psychiatric features (affective disorder, hallucinations, delusions, and anxiety) must also be sought. Questions about the patient’s activities and self-care capabilities should be obtained from collateral sources of information (caregiver). Acquiring family history is essential. Short, standardized mental status tests such as the Mini-Mental State Examination are widely used. Mild cognitive deficits may require more extensive neuropsychologic testing. Depression is common and treatable. It should be screened for in all patients being evaluated for dementia.


According to the latest guidelines from the American Academy of Neurology (see Appendix), laboratory workup should include a vitamin B12 level and thyroid function test, as B12 deficiency and hypothyroidism are common in the elderly. A complete blood count (CBC) and chemistry panel are often performed. Screening for syphilis is not recommended unless the patient has a clear risk factor or history of a prior syphilitic infection, or lives in one of the few areas in the United States where syphilis is frequently seen. Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is used to rule out structural lesions. Other tests (EEG, lumbar puncture, HIV titer, serologic testing for vasculitis, heavy metal screening, angiography, brain biopsy) are indicated only if suggested by the history or examination. In younger adults, dementia may be caused by late-onset childhood metabolic diseases, and special studies may be required.


Alzheimer disease


Alzheimer disease (AD) is the most common etiology for dementia in adults, accounting for 50% to 60% of cases. AD is characterized by progressive cognitive and functional deficits. In the United States, its prevalence is 11% by age 65, and 32% by age 85. Incidence can double every 4.4 years after age 60. The biggest risk factors are advanced age and female sex (which may be explained by the fact that women typically live longer than men), though family history, hypertension, diabetes, smoking, low socioeconomic status, stress, endocrine dysfunction, low education level, and head injury also increase risk. Lower risk has been suggested in those taking nonsteroidal anti-inflammatory drugs (NSAIDS), postmenopausal women on estrogen replacement therapy, individuals with a higher education level or socioeconomic status, individuals engaging in mentally demanding tasks, and those with apolipoprotein E (APOE) ɛ2 genotype.


Clinical Presentation


Early symptoms of AD include difficulty remembering recent conversations, names, or events, and apathy and depression. Subtle decreases in the ability to focus attention and recall remote events become more prominent with disease progression. Later, there is disorientation, confusion, poor judgment, and personality changes. Delusions and hallucinations may occur. Language decline (particularly word finding in spontaneous speech) and anomia (especially for parts of objects) impair communication. Ultimately, impairments in visuospatial dysfunction, apraxia, and complications from difficulty speaking, walking, and aspiration lead to mounting morbidities and mortality.


Pathology


AD is associated with progressive extracellular accumulation of β-amyloid peptide (Aβ) plaques in the brain, and twisted strands of intracellular tau protein tangles. While the exact mechanism is unknown, this accumulation is associated with decline in choline acetyltransferase activity, as well as neurodegeneration throughout the brain, particularly in the hippocampus and posterior cingulate, lateral parietal, and medial frontal cortices.


Genetics


AD develops at an earlier age in patients with various genetic mutations, particularly those coding for amyloid-β precursor protein (AβPP) on chromosome 21, presenilin 1 (PSEN1) on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1. Additionally, APOE handles lipid metabolism and trafficking, and serves as the primary modulator of cholesterol in the brain. It has multiple isoforms associated with both early- and late-onset familial AD (see Table 45), with the APOE ɛ4 being the largest known genetic risk factor (Table 46). To date, over 20 additional genes have been associated with late-onset AD.



Table 46





























Genetic factors linked to alzheimer disease risk
Genetic Factor Chromosome Involved Age at Onset (years)
Down syndrome 21 > 35
Amyloid precursor protein mutation 21 45–66
Presenilin 1 mutation 14 28–62
Presenilin 2 mutation 1 40–85
Apolipoprotein ɛ4 19 > 60

From Martin, J. B. (1999). Molecular basis of the neurodegenerative disorders. N Engl J Med, 340(25), 1970–1980.


Diagnosis


Diagnostic criteria for dementia are outlined in Table 44. In AD, the onset of dementia is insidious and worsens over time. Patients meeting these criteria may be diagnosed with AD with reasonably high sensitivity (81%), and specificity (70%). Clinical diagnostic criteria have been revised into probable and possible AD (Table 47). While autopsy remains the only definitive diagnostic tool, biomarkers such as reduced Aβ and elevated tau levels in the cerebrospinal fluid, the advent of high-resolution molecular MRI, and positron emission tomography (PET) demonstrating Aβ deposits and reduced fluorodeoxyglucose (FDG)-uptake in the medial, basal, and lateral temporal lobes, and medial parietal cortex, suggest a high likelihood of AD.



Table 47













Diagnosis of alzheimer disease
Probable AD dementia:

1. Patient meets criteria for dementia described earlier in the text, and in addition, has the following characteristics:


a. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;


b. Clear-cut history of worsening of cognition by report or observation; and


c. The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories.


i. Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least one other cognitive domain, as defined earlier in the text.


ii. Nonamnestic presentations:


1. Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present.


2. Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present.


3. Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.


d. The diagnosis of probable AD dementia should not be applied when there is evidence of (a) substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) core features of Dementia with Lewy bodies other than dementia itself; or (c) prominent features of behavioral variant frontotemporal dementia; or (d) prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or (e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.


2. Probable AD dementia with increased level of certainty


a. Probable AD dementia with documented decline:


i. In persons who meet the core clinical criteria for probable AD dementia, documented cognitive decline increases the certainty that the condition represents an active, evolving pathologic process, but it does not specifically increase the certainty that the process is that of AD pathophysiology.


ii. Probable AD dementia with documented decline is defined as follows: evidence of progressive cognitive decline on subsequent evaluations based on information from informants and cognitive testing in the context of either formal neuropsychological evaluation or standardized mental status examinations.



3. Probable AD dementia in a carrier of a causative AD genetic mutation


a. In persons who meet the core clinical criteria for probable AD dementia, evidence of a causative genetic mutation (in Amyloid precursor protein [APP], Presenellin-1 [PSEN1], or Presenellin-2 [PSEN2]), increases the certainty that the condition is caused by AD pathology. The workgroup noted that carriage of the ɛ4 allele of the apolipoprotein E gene was not sufficiently specific to be considered in this category.

Possible AD dementia:

1. Atypical course: Atypical course meets the core clinical criteria in terms of the nature of the cognitive deficits for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates insufficient historical detail or objective cognitive documentation of progressive decline, OR


2. Etiologically mixed presentation: Etiologically mixed presentation meets all core clinical criteria for AD dementia but has evidence of (a) concomitant cerebrovascular disease, defined by a history of stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) features of Dementia with Lewy bodies other than the dementia itself; or (c) evidence for another neurological disease or a non-neurological medical comorbidity or medication use that could have a substantial effect on cognition



Table 47


AD, Alzheimer disease.


From McKhann, G. M., Knopman, D. S., Chertkow, H., et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 7(3), 263–269.


Differential Diagnosis


It is important to note other features that may indicate atypical dementia. Vascular dementia, the second most common cause of dementia, can be distinguished from AD based on evidence of strokes on neuroimaging, abrupt onset, stepwise deterioration, focal neurologic signs and symptoms, and risk factors for stroke. Pick disease, or frontotemporal dementia (FTD), features early disinhibited behavior and frontal lobe dysfunction, with asymmetrical frontal or temporal lobe atrophy on neuroimaging. Lewy body dementia may present with psychosis, or with extrapyramidal signs such as tremor or rigidity. Creutzfeldt-Jakob disease is characterized by rapidly progressive dementia with myoclonus or seizures.


Treatment


To date, only three cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and one N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) have been demonstrated to have therapeutic efficacy with acceptable side effects in multiple large randomized controlled clinical trials (see Therapeutic Appendix Dementia). Cholinesterase inhibitors potentiate the activity of acetylcholine released by surviving neurons, though unfortunately, only have a modest degree of clinical effect. Memantine is typically used in moderate to severe AD and in conjunction with cholinesterase inhibitors, or when cholinesterase inhibitors are poorly tolerated, and serves to combat glutamatergic neuronal excitotoxicity while still preserving the receptor.


While there is currently no medication that has been found to slow progression of AD, there is ongoing research into therapies that inhibit amyloid production, directly target Aβ or tau proteins, and reduce inflammation and oxidative stress in the hopes that they may decrease amyloid-β load in the brain and slow disease progression.


Symptom Management


Much of treatment is therefore focused on symptom management. Behavioral symptoms can be disruptive and require careful investigation. Treatment for any underlying medical condition (e.g., urinary tract infection) and thorough review of the medication list should be sought before starting any psychoactive drugs. Depression can be treated with tricyclic antidepressants (e.g., imipramine or amitriptyline) or selective serotonin reuptake inhibitors (e.g., fluoxetine or sertraline). If psychosis is present, neuroleptics should always be used with extreme caution in the elderly. As a class, all antipsychotics are associated with an increased risk of death when used to treat psychosis in elderly patients with dementia. These medications carry a black box warning to this effect. Counseling and social planning in the face of increasing disability are important facets of long-term management.


Vascular dementia


Vascular dementia refers to dementia caused by vascular disease. This is the second most common cause of dementia, accounting for approximately 20% of cases. Patients diagnosed as having vascular dementia, however, do not constitute a homogeneous group. Lacunar infarcts, cortical infarcts, intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), subarachnoid hemorrhage (SAH), leukoaraiosis, and neuronal loss in the hippocampus, neocortex, and basal ganglia after global cerebral anoxia or ischemia can all lead to vascular dementia. Diagnostic criteria for ischemic vascular dementia therefore include the following:



  1. I. Dementia involving memory loss, executive dysfunction, focal cortical signs, personality changes, and affective changes
  2. II. Cerebrovascular disease demonstrated by history, clinical examination, or brain imaging
  3. III. Evidence that the two conditions are causally related by a temporal relationship, abrupt or stepwise deterioration, or specific brain imaging findings, indicating damage to regions important for higher cerebral function

Supportive clinical features include history of cerebrovascular risk factors, early appearance of gait disturbance and urinary incontinence, and frontal lobe, extrapyramidal and pseudobulbar features. Subtypes of vascular dementia worth mentioning include the following:



  1. I. Multi-infarct dementia (MID) is caused by multiple infarcts affecting both the cortical or subcortical areas and by multiple lacunar infarcts. The modified Hachinski ischemic scale (Table 48) may help to differentiate MID from AD.

    Table 48















































    Clinical features of ischemic score (Modified hachinski scale)
    Feature Point Value
    Abrupt onset 2
    Stepwise deterioration 1
    Fluctuating course 2
    Nocturnal confusion 1
    Relative preservation of personality 1
    Depression 1
    Somatic complaints 1
    Emotional incontinence 1
    History of presence of hypertension 1
    History of strokes 2
    Evidence of associated atherosclerosis 1
    Focal neurologic symptoms 2
    Focal neurologic signs 2

    Score 4 suggests primary degenerative dementia; score 7 suggests vascular dementia.


    Modified from Rosen, W. G., Terry, R. D., Fuld, P. A., et al. (1980). Pathological verification of ischemic score in differentiation of dementias. Ann Neurol, 7(5), 486–488.

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