of ocular or topical medicines. Ironically, medicines for psychiatric and neurologic disorders - anticholinergics, AEDs, antiparkinson agents, opioids, and serotonin agents- readily cross the blood-brain barrier and produce a delirium. In a surprising and paradoxical example, intramuscular injections of olanzapine administered for schizophrenia may produce confusion, agitation, anxiety, sedation, and more severely depressed levels of consciousness rather than calming the patient. Researchers have labeled this reaction the post-injection delirium/sedation syndrome and attribute it to the medicine seeping into the vasculature.Another consideration is medicine withdrawal. Unlike the depressed sensorium typically associated with delirium, withdrawal from benzodiazepines, opioids, or nicotine may cause agitated delirium. In addition, withdrawal from alcohol, barbiturates, and benzodiazepines - but not nicotine - routinely causes seizures.

General Treatments

Even before arriving at an exact diagnosis or instituting Specific treatment, physicians must ascertain that the patient has adequate cerebral oxygen, blood glucose, fluid and electrolytes, nutrition, and other necessities. Physician must control pain with narcotics if indicated, but otherwise reduce or eliminate psychoactive drugs. Other preliminary measures consist of providing orientation clues, such as illumination, clocks, and calendars.

Antipsychotics can reduce dangerous and exhausting Activity, hallucinations, and disordered thinking. Physician should hesitate before prescribing antipsychotics or benzodiazepines to avoid respiratory depression. Sometimes physicians can calm a dangerously disruptive patient by restoring a missing substance or providing a reasonable facsimile, such as methadone, a nicotine patch, or Even, in emergency, an alcoholic beverage.

Hepatic Encephalopathy

A particularly interesting and frequently occurring variety of delirium is hepatic encephalopathy. With hepatic insufficiency, mental function and consciousness steadily decline. Mild confusion with either lethargy or, less frequently, agitation may precede coma and overtly abnormal liver function tests. In classic cases, the neurologic examination demonstrates asterixis and the EEG shows triphasic waves.

Neurologists traditionally attribute hepatic encephalopathy to an elevated serum concentration of ammonia (NH3). This mechanism occurs in the common scenario of gastrointestinal bleeding or high-protein meals precipitating hepatic encephalopathy in patients with cirrhosis. In these situations cirrhosis-induced portal hypertension shunts NH3 released from protein in blood or food directly into the systemic circulation. Because NH3 is a Small and nonionic (uncharged) molecule, it readily penetrates the blood-brain barrier. As a treatment of hepatic encephalopathy, physicians often attempt to convert ammonia (NH3) to ammonium (NH4), which is ionic and unable to penetrate the blood-brain barrier.

An alternative explanation for hepatic encephalopathy is that production of false neurotransmitters binds to benzodiazepine-gamma-aminobutyric acid (GABA) receptors and increases GABA activity. Thus, giving flumazenil, a benzodiazepine antagonist that interferes with benzodiazepine-GABA receptors and carries some risk of precipitating seizures, temporarily reduces hepatic encephalopathy symptoms.

PRECAUTIONS IN DIAGNOSING ALZHEIMER DISEASE

Even though this and other chapters have presented numerous causes of dementia and delirium, Alzheimer disease occupies the default position in the diagnosis of dementia. Physicians should maintain vigilance and mind the red Flags that warn against its diagnosis (Box 7-5).Although they certainly do not preclude a diagnosis of Alzheimer disease, these red flags will help prevent a misdiagnosis in cases of toxic-metabolic encephalopathy, psychiatric disorders, dementia in young adults (see Box 7-2), and neurodegenerative illnesses that strike atmore than the brains cognitive centers.

BOX 7-4 Commode Cited Frequent Causes of Delirium

Fluid or electrolyte imbalance, especially dehydrationHepatic or uremic encephalopathy, i.e., organ failureMajor surgeryMedicadonsNarcotics and alcoholPneumonia, urinary tract, and other nonneurologicinfections

BOX 7-5 Red Flags for an Alzheimer Disease Diagnosis

Age younger than 65 years: see Box 7-2Fluctuating level of consciousness: see toxic-metabolicencephalopathy, Lewy bodies dementiaBehavior, emotional, or personality disturbances over-shadowing cognitive impairment: see frontotemporal dementia and HIV dementiaRapidly - 6-12-month - progressive development, see Creutzfeldt- Jakob disease, vCJD, paraneoplastic limbic encephalitis (Chapter 19), HAD, frontotemporal dementia, Presence of physical abnormalities Gait impairment: see vascular dementia, HIV dementia, NPH Lateral signs, e.g., hemiparesis, spasticity (corticospinal tract signs): see vascular dementia Movement disorders: see Box 18-4 Myoclonus: see Creutzfeldt-Jakob disease, paraneoplastic encephalitis Rigidity, Bradykinesia (Parkinsonism): see dementia with Lewy bodies and Parkinson disease

HIV human immunodeficiency virus; vCjD, variant Crcutzfeldt-Jakob disease; HAD, HIV-associated dementia; NPH, normal-pressure hydrocephalus

REFERENCE

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Alzheimer Disease

Allan LM, Ballard CG, Burn DJ, et al. Prevalence and severity of gait disorders in Alzheimers and non-Alzheimers dementias. J Am Geriatr Soc 2005;53:l68l-7. Ballard C, Hannes ML, Theodoulou M, ct al. The dementia antipsychotic withdrawal trial (DART-AD); Long-term follow up of a randomized placebo-controlled trial. Lancet Neurol 2009;8: 151-7.Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotypefor risk of Alzheimers disease. N Engl J Med 2009;361:245-54.

Larner AJ. Cholinesterase inhibitors. Expert Rev Neurother 2010;10:1699-705.Mayeux R. Early Alzheimers disease. N Engl J Med 2010;362: 2194-201.Meyer GD, Shapiro F, Vanderstichele H, et al. Diagnosis-independentAlzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol 2010;67:949-56.Ott BR, Heindel WC, Papandonatus GD. A survey of voter participation by cognitively impaired elderly patients. Neurology 2003;60: 1546-8.Petersen RC. Mild cognitive impairment. N Engl J Med 2011;364: 2227-34.Querfurth HW, LaFeria FM. Alzheimers disease. N Engl J Med 2010;362:329-44.Rossetti HC, Lacritz LH, Weiner MF. Normative data for the MontrealCognitive Assessment (MoCA) in a population-based sample. Neurology 2011;77:1272-5. . .Schneider LS, Tariot PN, Degerman KS, et al. Effectiveness of atypical antipsychotics drugs in patients with Alzheimers disease. N Engl J Med 2006;355:l525-38.Sultzer DL, David SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer disease. Am J Psychiatry 2008;165:844-54. Yaffe K, Weston A, Graff-Radford NR, et al. Association of plasma beta-amyloid and cognitive reserve with subsequent cognitive decline. JAMA 2011;305:261-6.

HIV-Associated Dementia

Cohen RA, Gongvatana A. The persistence of HIV associated neuro cognitive dysfunction and the effects of comorbidities. Neurology2010;75:2052-3.Heaton RK, Clifford DB, Franklin DR, et al. HlV-associated neuro cognitive disorders persist in the era of potent antiretroviral therapy:CHARTER Study. Neurology 2010;75:2087-96.Rackstraw S. HlV-related neurocognitive impairment a review. Psychol Health Med 2011;l6:548-63.Thompson A, Silverman B, Treisman G. Psychotropic medications andHIV. HIV/AIDS 2006;42:l305-10.

Dementia with Lewy Bodies

Devinsky O. The neurology of Capgras syndrome. Rev Neural Dis2008;5:97-100.Geser F, Wenning GK, Poewe W, et al. How to diagnose dementia with Lewy bodies: State of the art. Mow Disord 2005;12(Suppl 12):S11-20.Goldman JG, Goetz CG, Brandabur M, et al. Effects of dopaminergic medication on psychosis and motor function in dementia with Lewybodies. Mov Disord 2008;23:2248-50.McKeith IG: Dickson DW Lowe J, et al. Diagnosis and managementof dementia with Lewy bodies: Third report of the DLB consortium.Neurology 2005;65:l863-72.Nagahma Y, Okina T, Suzuki N, et al. Neural correlates of psychiatricsymptoms in dementia with Lewy bodies. Brain 2010;133:557-67.

Depression and Pseudodementia

Dotosn VM, Beydoun MA, Zonderman AB. Recurrent depressivesymptoms and the incidence of dementia and mild cognitive impair-ment. Neurology 2010;75:27-34.Goodman WK. Electroconvulsive therapy in the spotlight. N Engl JMed 2011;364:l785-9.Saczyski JS, Beiser A, Seshadri S, et al. Depressive symptoms and riskof dementia: The Framingham Heart Study. Neurology 2010;75:35-41.

Frontal Lobe Disorders

Dubois B, Slachevsky A, Litvan V, et al. The FAB: A Frontal Assessment Battery at bedside. Neurology 2000;55:l621-26.Frontotemporal Dementia

Forman MS, Farmer J, Johnson JK, et al. Frontotemporal dementia.Ann Neurol 2006;59:952-62.Kertesz A, Blair M, McMonagle P, et al. The diagnosis and course offrontotemporal dementia. Alzheimer Dis Assoc Disord 2007;2l:155-63.Kucharski A. History of frontal lobotomy in the United States, 1935-1955. Neurosurgery l984;14:762-72.Rascovsky K, Hodges JR, Knopman D. Sensitivity of revised diagnosticcriteria for the behavioral variant of frontotemporal dementia. Brain2011;l34:2456-77.

Lyme Disease

Fader HM, Johnson BJB, OConnell S, et al. A critical appraisal ofchronic Lyme disease". N Engl J Med 2007;557:l422-30.Halperin JJ. Neurologic manifestations of Lyme disease. Curr infectDis Rep 201l;l3:360-6.

CreutzfeldtJakob Disease and Related illnesses

Binelli S, Agazzi P, Canafoglia L, et al. Myoclonus in Creutzfeldt-Jakobdisease. Mov Dis 20I0;25:2818-27.Heath CA, Cooper SA, Murray K, et al. Validation of diagnostic criteriafor variant Creutzfeldt-Jakob disease. Ann Neurol 2010;67:76l-70.Heath CA, Cooper SA, Murray K, er al. Diagnosing variant Creutzfeldt-Jakob disease: A retrospective analysis of the first 150 cases in theUK. J Neurol Neurosurg Psychiatry 201l;82:646-51.Prusiner SB. Neurodegenerative diseases and prions. N Engl J Med200l;344:l5l6-26. 1Rabinovici GD, Wang PN, Levin J, et al. First symptom in sporadicCreutzfeldt-Jakob disease. Neurology 2006;66:286-7.Schott JM, Reiniger L, Tom M, et al. Brain biopsy in dementia: Clinical indications and diagnostic approach. Acta Neuropathol2010;l20:327-41.Williams ES, Miller MW. Chronic wasting disease in deer and elk. RevSci Tech Off 2002;1:305-16.Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnosticcriteria for sporadic Creutzfeldt-Jakob disease. Brain 2009;l32:2659-68.

Delirium (Toxic-Metabolic Encephalopathy)

Detke HC, McDonnell DP, Brunner E, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olan-zapine long-acting injection: Analysis of cases. BMC Psychiatry 2010;l0:43.Grover S, Malhotra S, Bharadwaj R, et al. Delirium in children andadolescents. Int J Psychiatry Med 2009;39:I79-87.Grover S, Mattoo SK, Gupta N. Usefulness of atypical antipsychoticsand choline esterase inhibitors in delirium: A review. Pharmacopsy chiatry 2011;44:43-54.lnouye SK. Delirium in older persons. N Engl J Med 2006;354:1157-65.Lonergan E, Luxenberg J, Areosa-Sastre A, et al. Benzodiazepines fordelirium. Cochrane Database Syst Rev 2009;l:D006397.Meagher DJ, Leonard M, Donnelly S, et al. A comparison of neuro-psychiatric and cognitive profiles in delirium, dementia, comorbiddelirium-dementia and cognitively intact controls. J Neurol Neuro-Surg Psychiatry 2010;8l:876-81.Ozbolt LB, Paniagua MA, Kaiser RM. Atypical antipsychotics forthe treatment of delirious elders. J Am Med Dir Assoc 2008;9:18-28.Wong CL, Holyrood-Leduc J, Simel DL, et al. Does this patient havedelirium? Value of bedside instruments. JAMA 2010;304:779-86.

Vascular Cognitive Impairment

Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American StrokeAssociation, Stroke 2011;42:2672-713.Malouf R, Birks J. Donepezil for vascular cognitive impairment.Cochrane Database Syst 2004;Rev l:CD004395.Saehdev PS, Brodaty H, Valenzuela MJ, et al. The neuropsychologicalprofile of vascular Cognitive impairment in stroke and TIA patients.Neurology 2004;62:912-9.Solfrizzi V, Scafato E, Capurso C, er al. Metabolic syndrome and therisk of vascular dementia: The Italian Longitudinal Study on Ageing.J Neural Neurosurg Psychiatry 2010;81:433-40.

Miscellaneous

Chahine LM, Khoriaty RN, Tomford WJ, et al. The changing facebof neurosyphilis. Int J Stroke 2011;6:136-43Ghanem KG. Neurosyphilis: A historical perspective and review CNSNeurosci Ther 2010;16:e157-e168.Gutierrezj, Isaacson RS, Koppel BS. Subacute sclerosing panencephalitis: An update. Dev Med Child Neurol 2010;52:901-7Klassen BT, Ahlskog JE. Normal pressure hydrocephalusi How oftendoes the diagnosis hold water? Neurology 2011;77:1119-25.Lair L, Naidech AM. Modern neuropsychiatric presentation of neurosyphilis. Neurology 2004;63:1331--3.Sonia M, Lalit D, Shobha B, et al. Subacute sclerosing panenceplialitisin a tertiary care centre in post measles vaccination era. J CommunDis 2009;41:161-7.Yatabe Y, Hashimoto M, Kaneda K, et al. Neuropsychiatric symptomsOf progressive supranuclear palsy in a dementia clinic. Psychogeriattics 2011;11:54-9.

Chapter 7

Question and Answer

1.Which of the following statements is true regarding individuals with mild cognitive impairment (MCI)?a. They have impairment of their social or occupational activities.b. As with Alzheimer disease, cholinesterase inhibitors slow the cognitive decline in MCI.c. Approximately 10% progress from MCI todementia each year.d. The risk factors associated With MCI progressing to dementia differ from those for developing Alzheimer disease.

Answer: MCI is most often the first clinical sign of alzheimer disease. Because MCI individuals maintain their social and occupational activities, neurologists can not diagnose them as having dementia. However, each year approximately 10% of MCI individuals progressfrom that stage to the next, dementia. The risk factors associated with MCI individuals progressing to dementia are similar to those for individuals developing Alzheimer disease. For example, MCI individuals carrying the E4-E4 alleles and those with a family history of alzheimer disease are likely do progress to dementia. Physicians should have MCI patients undergo tests for correctable causes of dementia. Cholinesterase inhibitors do not slow the cognitive decline or reduce the rate of deterioration of MCI into dementia.

2.Advancing age leads to loss of neurons in the cerebral cortex and many deep structures. Which of the following structures is not subject to age-related neuron loss?a. Locus ceruleus .b. Suprachiasmatic nucleusc. Substantia nigrad. Nucleus basalis of Meynerte. Mamillary bodies

Answer: e. The maxillary bodies resist age-related changes. in contrast, age-related changes in the other structures contribute to disturbances in affect (locus cerulcus), sleep (locus cemleus and suprachiasmaticnucleus), and locomotion (substanda nigra).

3.In a 70-year-old man who has normal cognitive and physical Function, which sensation is most likely to be lost?a. Joint positionb. Vibrationc. Paind. Temperature

Answer: b. In normal individual older than 65 years, vibration sensation declines to a greater degree than other sensations. Although loss of position sense is less pronounced dan vibration sense, that loss is more troublesome because it leads to gait impairment and falls. In contrast, pain and temperature sensations remain remain relatively well preserved. Preservation of pain sensation is well known to physicians who care for elderly patients describing painful feet from osteoarthritis, peripheralvascular disease, and diabetic neuropathy.

4. The diagnosis of normal-pressure hydrocephalus (NPH) has received much attention because instalation of a ventricular peritoneal shunt may correct the dementia. Most cases are idiopathic. Which conditions predispose a patient to NPH?a. Hypothyroidismb. Meningitis and subarachnoid hemorrhagec. Cysticercosisd. Tuberous sclerosis

Answer: b. Both meningitis and subarachnoid hemorrhage can cause communicating hydrocephalus that sometimes leads to NPH. Cysticercosis and tuberous sclerosis cause obstructive hydrocephalus. Nevertheless, most cases of NPH are idiopathic.

5. True or false: A cerebral cortex biopsy is appropriate for the diagnosis of Alzheimer disease.

Answer: False. Although a definitive diagnosis is desirable, a single cerebral cortex biopsy cannot provide it because the histologic changes are quantitative rather than qualitative. For example, normal aged brains contain the characteristic plaques and tangles - although in lesser concentrations and different distributions. Neurologists also do not request a cerebral biopsy for the diagnosis of frontotemporal dementia, dementia with Lewy bodies, or vascular cognitive impairment (VCI), which the preliminary version of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) calls Vascular. Neurocognotive Disorder. All these diseases are incurable and the procedure carries risks of hemorrhage and seizures.A biopsy may have benefits that outweigh the risks in the diagnosis of Creutzfeldt-Jakob disease, variant Creutzfeldt-]akob disease (vCJD), other infections, and neoplasms.

6. With which histologic feature is Alzheimer disease dementia most closely associated?a. Accumulation of taub. lncreased concentration of plaques