CHAPTER 8 Dementia I. Definitions A. Delirium: an acute confusional state, marked by decreased attention and prominent alterations in perception and consciousness and associated with vivid hallucinations, delusions, heightened alertness, and agitation; hyperactivity of psychomotor and autonomic functions; insomnia; and so forth. Symptoms often fluctuate. A hypoactive form may also be seen. B. Dementia: a syndrome characterized by a progressive deterioration of function in memory, plus two other cognitive domains (e.g., executive functioning, praxis, language, visuospatial function, etc.) compared to previous baseline cognitive ability, and severe enough to interfere with usual social functioning and activities of daily life. Defined as longer than 12 months in progression. Less than 12 months in progression is known as rapidly progressive dementia. C. Mild cognitive impairment (MCI): progressive cognitive impairment, in memory or other cognitive domains, not sufficient to cause significant impairment in activities of daily living. Can be separated into amnestic and nonamnestic forms. No specific pathological correlation. Not all patients with MCI progress to dementia; some return to normal cognition. II. Dementia A. Etiologies of dementia. NB: The most common types of dementia are Alzheimer’s dementia (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia. Trauma Chronic traumatic encephalopathy Chronic subdural hematoma (subacutely progressive) Inflammatory/infection Chronic meningitis (tuberculosis, cryptococcus, cysticercosis) Syphilis (general paresis of the insane, gumma, vasculitic) HIV dementia and opportunistic infections Progressive multifocal leukoencephalopathy (subacute, usually focal or multifocal) Creutzfeldt-Jakob disease (CJD) (subacute, often with other neurological deficits (visual, motor, somatosensory, etc.) Lyme disease Cerebral sarcoidosis Subacute sclerosing panencephalitis (SSPE) Whipple’s disease of the brain Neoplastic Benign and malignant tumors Paraneoplastic limbic encephalitis Metabolic Hypothyroid Vitamin B1 deficiency (Wernicke-Korsakoff) (acute to subacute) Vitamin B12 deficiency Vitamin E deficiency (neuropathy, ataxia, encephalopathy) Nicotinic acid (niacin or vitamin B3) deficiency (pellagra) Uremia/dialysis dementia Chronic hepatic encephalopathy Chronic hypoglycemic encephalopathy Chronic hypercapnia/hyperviscosity/hypoxemia Chronic hypercalcemia/electrolyte imbalance Cushing’s disease (usually behavior change or psychosis) Vascular Multi-infarct dementia Binswanger’s encephalopathy Specific vascular syndromes (thalamic, inferotemporal, bifrontal) (post-acute) Triple border-zone watershed infarction (post-acute) Diffuse hypoxic/ischemic injury (post-acute) Mitochondrial disorders (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Autoimmune Systemic lupus erythematosus (lupus cerebritis) Polyarteritis nodosa Temporal arteritis Wegener’s granulomatosis Isolated angiitis of the central nervous system Autoimmune dementia (dementia with autoantibody markers) Drugs/toxins Medications: β-blockers, neuroleptics, antidepressants, histamine receptor blockers, dopamine receptor blockers Substances of abuse: alcohol, phencyclidine, mescaline, marijuana psychosis, etc. Toxins: lead, mercury, arsenic Bismuth containing medications Demyelinating Multiple sclerosis, Schilder’s disease, Baló concentric sclerosis (usually MRI is diagnostic) Electric injury-induced demyelination (circumstances diagnostic) Decompression sickness demyelination (circumstances diagnostic) Adrenoleukodystrophy Metachromatic leukodystrophy Other inflammatory/infectious processes Cerebrospinal fluid (CSF) processes Normal pressure hydrocephalus Obstructive hydrocephalus Degenerative—adult Alzheimer’s dementia (AD) Parkinson’s disease (PD) Huntington’s disease Frontotemporal dementia (also known as frontotemporal lobar degeneration or FTLD) Progressive supranuclear palsy (PSP) Dementia with Lewy bodies (DLB) Multiple system atrophy (MSA) Corticobasal (ganglionic) degeneration (CBD or CBGD) Hallervorden-Spatz disease (now known as pantothenate kinase-associated neurodegeneration [PKAN] or neurodegeneration with brain iron accumulation–1 [NBIA1]) Primary progressive aphasia (PPA) Degenerative—pediatric Mitochondrial diseases (myoclonic epilepsy with ragged red fibers [MERRF] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]) Adrenoleukodystrophy Metachromatic leukodystrophy Kufs’ disease (neuronal ceroid lipofuscinosis) GM1 and GM2 gangliosidoses Niemann-Pick II-C Krabbe’s disease (globoid cell leukodystrophy) Alexander’s disease Lafora’s disease Cerebrotendinous xanthomatosis B. Diagnostic workup Basic Blood tests may include: complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid function tests, vitamin B12 level, serum folate, erythrocyte sedimentation rate (ESR) Urinalysis, chest X-ray. Brain imaging: either computed tomography (CT) of the head or brain MRI (with contrast if suspecting an enhancing lesion) Expanded Brain MRI with gadolinium Spinal tap—cells, protein, glucose, fungus, tuberculosis, virus, cytology, oligoclonal banding, immunoglobulin G, 14-3-3, lactate Electroencephalography Neuropsychology assessment for executive function, language, processing speed, visuospatial function, memory (recall, registration) Toxin screen (drugs, poisons, metals) Labs for infection: HIV, syphilis, others Vitamins B1, B3, B6, E Quantitative plasma amino acids (in children and young adults) Quantitative urine amino acids (in children and young adults) Vasculitis workup: C-reactive protein (CRP), anti–double-stranded DNA, Ro, La, Sm, ribonucleoprotein, antineutrophil cytoplasmic antibodies, C3, C4, CH50 Tumor screen, paraneoplastic serum antibodies Consider CSF for a beta 42/total and phosphorylated tau (May be helpful in diagnosing Alzheimer’s disease with biomarker; however, does not change management.) If necessary PET/single-photon emission computed tomography (SPECT) Consider amyloid PET imaging (for Alzheimer pathology; does not change treatment, may not be covered by insurance) Cerebral angiography for vasculitis (low sensitivity, specificity) Genetic counseling and testing for Alzheimer’s dementia (AD), frontotemporal dementia (FTD) dominant gene markers Biopsy: brain, meninges, nerve, muscle, skin, liver, kidney (rarely necessary, often nondiagnostic) C. Suggested evaluations for dementia of undetermined cause (rare causes) Low-serum ceruloplasmin and copper, high-urine and liver copper Wilson’s disease Plasma very-long-chain fatty acids Adrenoleukodystrophy White blood cell arylsulfatase A Metachromatic leukodystrophy Serum hexosaminidase A and B Tay-Sachs disease (Hex A) Sandhoff disease (Hex A and B) Muscle biopsy (ragged red fibers on trichrome; polysaccharide non-membrane-bound structures) Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes(MELAS) Myoclonic epilepsy with ragged red fibers (MERRF) Lafora disease White blood cell count for galactocerebroside β-galactosidase Krabbe’s disease Serum cholestanol or urine bile acids Cerebrotendinous xanthomatosis White blood cell for β-galactosidase GM1 gangliosidosis Skin biopsy for biochemical testing of fibroblasts Niemann-Pick II-C X-ray of hands for bone cysts, bone or skin biopsy for fat cells Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy Urine mucopolysaccharides elevated, serum α-N-acetyl glucosaminidase deficient Mucopolysaccharidoses Indications for biopsy Focal, relevant lesion(s) of undetermined etiology Central nervous system vasculitis Subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease (CJD), progressive multifocal leukoencephalopathy Krabbe’s disease (periodic acid-Schiff–positive histiocytes) Kufs’ disease (intranuclear fingerprint pattern) Neuronal intranuclear (eosinophilic) inclusion disease D. Alzheimer’s dementia: the most common degenerative disease of the brain; incidence increases sharply with age after 65; age is the most important and common risk factor (10% of people >65 years old [y/o], 50% of people >85 y/o); other risk factors: Down syndrome (patient 30–45 y/o shows similar pathologic changes), midlife obesity, diabetes mellitus, current tobacco use, head injury, apolipoprotein E4 genotype; reported protective factors: education, Mediterranean-type diet, low or moderate alcohol intake, physical activity, inheritance of apolipoprotein E2 allele. Dominant AD can occur with multiple genetic mutations (presenilin-1 [PS1] most common, presenilin-2 [PS2], amyloid precursor protein [APP], C9 open reading frame 72, Trem2, etc.)
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