Alzheimer patients present with a primary cortical dementia with memory impairment as a predominant feature. Parkinsonian features are not uncommon in AD, but often will show in advanced disease when cognitive impairment is severe. In addition, AD patient can inadvertently be treated with antipsychotics for associated behavioral disturbances and develop drug-induced parkinsonism. With Parkinson disease, patients can also have a dementia, but it is predomi- nantly subcortical (slowed thought processes, retrieval, attention, and concen- tration) and is usually not a predominant clinical feature of the disease. CNS infections such as HIV encephalitis or chronic fungal meningitis can present with slowly progressive dementia and motor dysfunction. Often the dementia and motor dysfunction are more global and include multiple cortical and subcortical deficits, extrapyramidal and pyramidal dysfunction, and a more rapid clinical course. Normal pressure hydrocephalus and cerebrovascu- lar disease (particularly ischemic disease of the deep white matter) typically presents as what is called “lower body parkinsonism” with early gait and bal- ance problems, lower body akinesia/bradykinesia, little or no tremor. Urinary abnormalities and the executive frontal lobe dysfunction are common. For both these disorders, neuroimaging often shows characteristic abnormalities. APPROACH TO DIFFUSE LEWY BODY DEMENTIA Definitions Constructional apraxia: Difficulty in performing tasks involved with con- struction, for example, drawing a five-pointed star. Executive function: Mental capacity to control and plan mental skills, the ability to sustain or flexibly direct attention, the inhibition of inappro- priate behavioral or emotional responses, the planning of strategies for future behavior, the initiation and execution of these strategies, and the ability to flexibly switch among problem-solving strategies. It is medi- ated by the prefrontal lobes of the cerebral cortex. Ideomotor apraxia: Disturbance of voluntary movement in which a per- son cannot translate an idea into movement. REM-related disorders: A parasomnia involving dissociation of the char- acteristic stages of sleep. The major feature is loss of motor inhibition leading to a wide spectrum of behavioral release during sleep, that is, “acting out dreams.” Clinical Approach Diffuse Lewy body dementia (DLBD) is felt to represent the second most common cause of dementia in developed countries in the Western Hemisphere. It accounts for 10–20% of dementias; however, the sensitivity and specificity of DLBD and common dementias are poor because pathology and clinical features CLINICAL CASES 183 can overlap between DLBD and dementias, such as AD. In fact, 40% of AD patients have the pathologic alterations felt to be specific for DLBD, the Lewy body. Epidemiologic studies are limited but suggest that men are more affected than woman, and the usual onset is in late 50’s and beyond. Clinical History and Features DLBD is a progressive degenerative dementia but can overlap with other parkinsonian dementias and primary Alzheimer dementia, clinically and pathologically (Table 21–1 for diagnostic features of DLBD). However, when dementia precedes motor signs, particularly with visual hallucinations and episodes of reduced responsiveness, the diagnosis of DLBD should be consid- ered. The following clinical features help distinguish DLBD from Alzheimer dementia: (1) fluctuations in cognitive function with varying levels of alert- ness and attention, (2) visual hallucinations, (3) parkinsonian motor features that appear relatively early in DLBD. Cognitive impairment in DLBD is char- acterized by more executive dysfunction and visual-spatial impairment rather than the anterograde memory loss of AD. It is not unusual for someone with DLBD to have a relative severe dementia by history, but to have relatively pre- served delayed recall with severe constructional dyspraxia. This combination is virtually never seen in AD. When parkinsonism precedes cognitive dys- function by more than 2 years, the disorder is referred to as Parkinson disease dementia. Although this differentiation seems largely semantic, knowing this clinical presentation is useful practically (Table 21–2). Other suggestive fea- tures of DLBD are nonvisual hallucinations, delusions, unexplained syncope, REM-sleep disorders, neuroleptic sensitivity. Pathology Frederick Lewy first described Lewy bodies (LBs) in 1914, which are cyto- plasmic inclusions of the substantia nigra neurons in patients with idiopathic Parkinson disease (PD). By the 1960s, pathologists had described patients with dementia who had LBs of the neocortex. It was not until the mid 1980s, when sensitive immunocytochemical methods to identify LBs were devel- oped, that dementia with LBs (DLB) was then recognized as being far more common than previously thought. However, there is considerable controversy at this point over whether DLB in PD are two different conditions or just part of a spectrum disorder with common underlying pathology. Diagnostic Studies Laboratory studies should include the routine dementia evaluation, including a chemistry panel, complete blood count (CBC), thyroid studies, vitamin B 12 lev- els, syphilis serology, Lyme disease serology, or HIV testing, when appropriate. 184 CASE FILES: NEUROLOGY CLINICAL CASES 185 Table 21–1 DIAGNOSTIC FEATURES OF DEMENTIA WITH LEWY BODIES 1. Central feature (essential for a diagnosis of possible or probable DLB): • Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function; prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression; deficits on tests of attention, executive function, and visuospatial ability may be especially prominent 2. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB) • Fluctuating cognition with pronounced variations in attention and alertness • Recurrent visual hallucinations that are typically well formed and detailed • Spontaneous features of parkinsonism 3. Suggestive features (one or more of these in the presence of one or more core fea- tures is sufficient for a diagnosis of probable DLB; in the absence of any core fea- tures, one or more suggestive features is sufficient for a diagnosis of possible DLB; probable DLB should not be diagnosed on the basis of suggestive features alone) • REM-sleep behavior disorder • Severe neuroleptic sensitivity • Low dopamine-transporter uptake in basal ganglia demonstrated by SPECT or PET imaging 4. Supportive features (commonly present but not proven to have diagnostic specificity) • Repeated falls and syncope • Transient, unexplained loss of consciousness • Severe autonomic dysfunction • Hallucinations in other modalities • Systematized delusions • Depression • Relative preservation of mesial temporal lobe structures on computed tomography/magnetic resonance imaging • Reduced occipital activity on SPECT/PET • Low uptake MIBG myocardial scintigraphy • Prominent slow wave activity on EEG with temporal lobe transient sharp waves DLB, dementia with Lewy bodies; EEG, electroencephalograph; MIBG, metaiodobenzylguani- dine; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography. Source: McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–1872. Imaging studies are important to evaluate for other conditions that can mimic this disorder (vascular dementia, tumor, normal pressure hydrocephalus, etc). Patients with DLBD usually have less hippocampal atrophy than patients with AD (but more than control subjects). Whether this difference is clinically useful is under investigation, as is the diagnostic utility of functional imaging. Single-photon emission CT scanning or positron emission tomography scanning can show decreased occipital lobe blood flow or metabolism in DLB but not in AD. Reduced dopamine transporter activity in the basal ganglia is seen with positron emission tomography scanning or single-photon emission CT scanning. Other Tests In certain circumstances, neuropsychologic testing is helpful to differentiate DLB from AD and to establish a baseline for future comparison. Patients with DLB can have changes on electroencephalography earlier than patients with AD, but whether this difference is diagnostically useful is not clear. Cerebrospinal fluid (CSF) examination is not required in routine cases, but patients with AD have higher levels of tau protein in their CSF than patients with DLB. Patients with both LB variant-AD have intermediate values. CSF levels of beta-amyloid are lower than normal in DLB, AD, and LBV-AD. However, CSF beta-amyloid levels in DLB, LBV-AD, and AD do not differ from each other. Treatment There are no medications that have been shown to delay the degeneration of this disorder. Symptomatically, the anticholinesterase medications (i.e., rivastigmine, donepezil, and galanthamine) have been demonstrated to have 186 CASE FILES: NEUROLOGY Table 21–2 CLINICAL PHENOMENOLOGY OF DEMENTIA WITH LEWY BODIES • Comparison to PD – Less severe parkinsonism – Less tremor – More postural instability • Comparison to AD – More visuospatial deficit – Less language, memory encoding deficit • Comparison to AD & PD – More fluctuation and hallucinations AD, Alzheimer disease; PD, Parkinson disease. cognitive/behavioral symptom improvement. The cortical cholinergic deple- tion in DLB is actually much more severe than AD and so appears to be more responsive to treatment. Cognitive and behavioral symptoms have been shown to improve with this class of medications, however, not depression. Neuroleptic agents should be used with extreme caution in these patients. Patients, often treated for behavioral issues with neuroleptics, have been described to have disastrous responses to this class of medicines, even when using “atypical antipsychotics.” For severe depression, electroconvulsive therapy has been shown to be effective and safe. In addition, parkinsonian motor signs have also been shown to improve with ECT. Comprehension Questions [21.1] A 68-year-old woman is diagnosed with dementia with Lewy bodies. Her medications are mixed up with her husband’s medication bottles. Which of the following is most likely to be her husband’s medication? A. Rivastigmine B. Donepezil C. Haloperidol D. Galanthamine [21.2]. A 61-year-old man is brought into the doctor’s office for memory loss and confusion. Which of the following symptoms are most suggestive of Alzheimer disease as opposed to dementia with Lewy bodies? A. Visual hallucinations B. Dramatic fluctuations in clinical condition C. Early anterograde memory loss D. Early shuffling gait [21.3] A 73-year-old man is noted to have a slow onset of cognitive deficits. The physical examination reveals no obvious etiology. Which of the follow- ing imaging findings are most suggestive of dementia with Lewy bodies? A. Medial temporal lobe atrophy B. Parietal temporal hypometabolism C. Atrophy of the midbrain D. Occipital lobe hypometabolism Answers [21.1] C. Haloperidol is a dopamine-receptor blocking agent that can have severely deleterious consequences in this disorder. The other three are anti- cholinesterases and have evidence for the use presented in the literature. [21.2] C. Cognitive impairment in DLB is characterized by more executive dysfunction and visuospatial impairment more than the anterograde memory loss of AD. CLINICAL CASES 187 [21.3] D. Occipital lobe hypometabolism is most typical of DLB. Medial temporal lobe atrophy and parietal temporal hypometabolism are char- acteristic of AD. Atrophy of the midbrain is characteristic of progres- sive supranuclear palsy. REFERENCES Ballard C, Grace J, McKeith I, et al. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet 1998;351:1032–1033. Bonner LT, Tsuang DW, Cherrier MM, et al. Familial dementia with Lewy bodies with an atypical clinical presentation. J Geriatr Psychiatry Neurol 2003;16:59–64. Geser F, Wenning GK, Poewe W, et al. How to diagnose dementia with Lewy bod- ies: state of the art. Mov Disord 2005 Aug;20(suppl 12):S11–20. Korczyn AD, Reichmann H. Dementia with Lewy bodies. J Neurol Sci 2006;248:3–8. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65: 1863–1872. Miyasaki JM, Shannon K, Voon V, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:996–1002. 188 CASE FILES: NEUROLOGY CLINICAL PEARLS ❖ Lewy bodies are associated with a number of clinical syndromes, including Alzheimer’s dementia and Parkinson disease. ❖ The typical clinical syndrome of DLB is relatively specific for the Lewy body pathology, but the converse is not necessarily so and can constitute part of a spectrum of synucleinopathies. ❖ Compared to AD, DLB is associated with a greater loss of acetyl- choline and a smaller loss of acetylcholine (ACh)-receptors ❖ Levodopa can be effective for the parkinsonism but is often not very rewarding for behavioral or cognitive dysfunction. ❖ REM-related behavior disorders can be one of the first symptoms of DLBD, prior to the onset of significant cognitive or motor disturbance. ❖ CASE 22 A 48-year-old man complained of “numbness and stiffness” in his arms for the past 4 months. His gait has gradually deteriorated because of unsteadiness. On examination the patient appeared older than his stated age. His hair was nearly completely gray. There was slight limitation of head movement to either side, but no pain with neck extension. His tongue was red and depilated. His gait was broad based, and he was unable to walk a straight line. He was able to stand with his feet together with his eyes open, but he nearly fell when his eyes were closed. He had normal arm coordination but was ataxic on the heel-knee-shin maneuver. Deep tendon reflexes (DTRs) were 3+ in the arms, trace at the knees, and absent at the ankles. Both plantar responses were extensor. There was a 2+ jaw jerk and a positive snout reflex. There was a stocking decrease in sensation and a marked decrease in vibration and joint position sense in the toes and ankles. Cranial nerves were normal, and there were mild problems with memory and calculation. T2-weighted MRI of the brain demonstrated extensive areas of high-intensity signal in the periventricular white matter. MRI of the spine showed a hyperintense signal along the posterior column of the spinal cord. ◆ What is the most likely diagnosis? ◆ What is the next diagnostic step? ◆ What is the next step in therapy? ANSWERS TO CASE 22: Subacute Combined Degeneration of Spinal Cord Summary: This is a 48-year-old patient with a progressive gait disorder char- acterized by sensory ataxia caused by impaired position sense and spasticity. His examination is significant for both peripheral and central nervous system involvement, primarily affecting the white matter fibers of the posterior columns of the spinal columns and pyramidal tracts and large myelinated peripheral nerve affecting coordination and muscle tone. ◆ Most likely diagnosis: Vitamin B 12 deficiency ◆ Next diagnostic step: Vitamin B 12 level and if positive, subsequent testing to determine the source of B 12 malabsorption ◆ Next step in therapy: Intramuscular vitamin B 12 Analysis Objectives 1. Understand the range of pathologic and clinical manifestations of vitamin B 12 deficiency. 2. Know the differential diagnosis of vitamin B 12 deficiency. 3. Understand the types of tests to confirm the diagnosis and etiology of vitamin B 12 deficiency. 4. Be aware of the proper mode of repletion of vitamin B 12 . Considerations The pertinent features of this case include the presentation, unsteadiness of gait, and numbness and stiffness. The physical examination helps localize the pathology. There was a stocking decrease in sensation, specifically vibration and joint position sense, which strongly suggests a neuropathy involving myeli- nated fibers. Involvement of the dorsal columns of the spinal cord, at or above the lumbar level is also a possibility. The pathologically increased reflexes in the arms along with the presence of primitive reflexes are “upper motor neuron signs” and suggest involvement of the corticospinal tract above the level of the cervical spinal cord. In this case, one would expect increased reflexes in the legs also, unless there is also a coexistent neuropathy. The ataxic heel knee to shin maneuver, also points to aberrant input to the cerebellum, which comes through large fibers. The mild problems on mental status examination indicate a cortical disorder. All of these findings suggest involvement at multiple levels of the nervous system. The imaging study confirms involvement of myelinated regions in the spinal cord, specifically the dorsal columns and in the brain. 190 CASE FILES: NEUROLOGY Assuming all these signs/symptoms are manifestations of a single entity, a sys- temic disease should be considered, such as HIV-1 associated vacuolar myelopathy, Lyme disease, multiple sclerosis, neurosyphilis, or vitamin B 12 deficiency. Neuropathic conditions would not be expected to give upper motor neuron signs. Another clue on physical diagnosis is the abnormal tongue and prematurely graying hair. APPROACH TO SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD Spinal cord diseases are common, and many are treatable if discovered early. The spinal cord is a tubular structure originating from the medulla of the brain and extending through the bony spine to the coccyx. Ascending sensory and descending motor white matter tracts are located peripherally; posterior columns govern joint position, vibration and pressure, lateral spinothalamic tracts pain and temperature, and ventral corticospinal tracts carry motor signals. Vitamin B 12 Deficiency Vitamin B 12 deficiency usually presents as paresthesias in the hands and feet and loss of vibratory sense. There is a diffuse effect on the spinal cord, prima- rily the posterior lateral columns, explaining the early loss of vibratory sense. Late in the course, optic atrophy and mental changes as well ataxia can occur. The macrocytic anemia is common. Cyanocobalamin is a compound that is metabolized to a vitamin in the B complex commonly known as vitamin B 12 . Vitamin B 12 is the most chemi- cally complex of all the vitamins. The structure of B 12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is cobalt (Co). Once metabolized, cobal- amin is a coenzyme in many biochemical reactions, including DNA synthesis, methionine synthesis from homocysteine, and conversion of propionyl into succinyl coenzyme A from methylmalonate. Dietary cobalamin (Cbl), obtained through animal foods, enters the stomach bound to animal proteins. Absorption requires many factors including stomach acid, R-protein, and intrinsic factor from parietal cells, and the distal 80 cm of the ileum for trans- port. Interference in any of these points can lead to malabsorption of vitamin B 12 . In addition there are a number of inborn errors of metabolism that can both interfere with the absorption and action of vitamin B 12 . The most com- mon cause of vitamin B 12 deficiency is malabsorption because of pernicious anemia, a condition where antibodies are generated to the parietal cells of the stomach, and the necessary proteins are not available. There are many other causes, however, that should be considered. Pathologically, in experimental subacute combined degeneration (SCD), there is edema and destruction of myelin. Thus, the clinical presentation of SCD CLINICAL CASES 191 is caused by dorsal column, lateral corticospinal tract, and sometimes lateral spinothalamic tract dysfunction. The initial symptoms are usually paresthesia in the hands and feet. This condition can progress to sensory loss, gait ataxia, and distal weakness, particularly in the legs. If the disease goes untreated, an ataxic paraplegia can evolve. Specific findings on examination are loss of vibratory and joint position sense, weakness, spasticity, hyperreflexia, and extensor plan- tar responses. The syndrome of sensory loss as well as spastic paresis associated with pathologic lesions in the dorsal columns and lateral corticospinal tracts is referred to as subacute combined degeneration. There are also effects on other body systems, most conspicuously hematologic with the macrocytic anemia. Differential Diagnosis The manifestations of vitamin B 12 deficiency are noted in Table 22–1. The dif- ferential diagnosis for progressive spastic paraplegia includes degenerative, demyelinating, infectious, inflammatory, neoplastic, nutritional, and vascular dis- orders. HIV-1 associated vacuolar myelopathy, Lyme disease, multiple sclerosis neurosyphilis, toxic neuropathy, Friedreich ataxia, and vitamin E deficiency. 192 CASE FILES: NEUROLOGY Table 22–1 CLINICAL MANIFESTATIONS OF VITAMIN B 12 DEFICIENCY Neurologic • Paresthesia • Peripheral neuropathy • Combined systems disease (demyelination of dorsal columns and corticospinal tract) Behavioral • Irritability, personality change • Mild memory impairment, dementia • Depression • Psychosis General • Lemon-yellow waxy pallor, premature whitening of hair • Flabby bulky frame • Mild icterus • Blotchy skin pigmentation in dark-skinned patients Cardiovascular • Tachycardia, congestive heart failure Gastrointestinal • Beefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges Hematologic • Megaloblastic anemia; pancytopenia (leukopenia, thrombocytopenia) [...]... brain lesions suggesting high risk of MS 202 CASE FILES: NEUROLOGY Comprehension Questions [23.1] A 28-year-old man complains of loss of vision to his right eye The examination suggests optic neuritis Which of the following conditions is most likely to be associated? A B C D Sjögren syndrome Influenza A virus infection Diabetes mellitus Syphilis [23.2] A 24-year-old man is noted to have optic neuritis... rubella, chickenpox, herpes zoster, herpes simplex virus I, Epstein-Barr (infectious mononucleosis), measles, mumps, influenza, human T-cell leukemia virus 1 (HTLV-1), Creutzfeldt-Jacob disease g Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related i Primary HIV-related optic neuritis ii Syphilis iii Cat-scratch disease (Bartonella henselae) iv Cryptococcus v Histoplasmosis... admitted for evaluation and management ◆ What is the most likely diagnosis? ◆ What is the prognosis for this condition? ◆ What is the next step in therapy? 216 CASE FILES: NEUROLOGY ANSWERS TO CASE 25: Acute Disseminated Encephalomyelitis Summary: A 20-year-old man developed multiple neurologic symptoms 3 weeks following a viral illness He suddenly complained of headache and had symptoms of spinal cord compromise... myelopathy AJR Am J Roentgenol 2000;174:863–8 65 Reynolds E Vitamin B12, folic acid, and the nervous system Lancet Neurol 2006 Nov ;5( 11):949–960 Scalabrino G Cobalamin (vitamin B[12]) in subacute combined degeneration and beyond: traditional interpretations and novel theories Exp Neurol 20 05; 192:463–479 This page intentionally left blank ❖ CASE 23 A 23-year-old graduate student was studying late at night... risk of development of multiple sclerosis after an episode of isolated optic neuritis was 30% at 5- year follow-up and 38% at 10-year follow-up The prevalence of optic neuritis is highest among white populations of northern European ancestry, and lowest in African, black, or Asian populations CLINICAL CASES ❖ ❖ 203 Optic neuritis is usually associated with pain of eye movement The prognosis for a single... he would seek medical consultation the next day ◆ What is the most likely diagnosis? ◆ What is the next diagnostic step? ◆ What is the next step in therapy? 206 CASE FILES: NEUROLOGY ANSWERS TO CASE 24: Multiple Sclerosis Summary: A 24-year-old man developed multiple neurological symptoms and, in retrospect, recognized that he had had multiple symptoms over the past 1 to 2 years ◆ ◆ Most likely diagnosis:... sleep and went to the infirmary the following day ◆ What is the most likely diagnosis? ◆ What is the next diagnostic step? ◆ What is the next step in therapy? 198 CASE FILES: NEUROLOGY ANSWERS TO CASE 23: Optic Neuritis Summary: A 23-year-old man suddenly developed left monocular visual complaints and left eye pain with ocular movement Otherwise, he had no symptoms ◆ ◆ Most likely diagnosis: Optic... usually idiopathic or caused by demyelinating disease Sometimes, optic neuritis is caused by other disorders, such as noted in Table 24–1 of case 24 Indications for laboratory testing depends on the 200 CASE FILES: NEUROLOGY A BOTH EYES NORMAL Diffuse Illumination 5 mm 5 mm Normal reaction of both pupils Light on Normal Eye 2 mm 2 mm Normal reaction of both pupils B ABNORMAL RIGHT EYE Afferent pupillary... and infectious disease patients, and in 5 10% of other noninflammatory neuralgic diseases Oligoclonal bands by themselves do not diagnose MS MS is a clinical diagnosis that can be supported by brain imaging and cerebrospinal fluid (CSF) investigations Increased CSF white cells can be seen in MS; however, CSF 210 CASE FILES: NEUROLOGY leukocyte counts greater than 50 mm3 of CSF are rare in MS and should... Degeneration of spinal cord in subacute combined degeneration on microscopy (With permission from Lichtam MA, Beutler E, Kaushansky K, et al Williams hematology, 7th ed New York: McGraw-Hill; 20 05: Fig 39–19.) 194 CASE FILES: NEUROLOGY Treatment Treatment of vitamin B12 deficiency involves administering the vitamin in a fashion to bypass the pathologic steps in the transport process This usually involves . thyroid studies, vitamin B 12 lev- els, syphilis serology, Lyme disease serology, or HIV testing, when appropriate. 184 CASE FILES: NEUROLOGY CLINICAL CASES 1 85 Table 21–1 DIAGNOSTIC FEATURES. Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:996–1002. 188 CASE FILES: NEUROLOGY CLINICAL PEARLS ❖. 7th ed. New York: McGraw-Hill; 20 05: Fig. 39–19.) 194 CASE FILES: NEUROLOGY Treatment Treatment of vitamin B 12 deficiency involves administering the vitamin in a fash- ion to bypass the pathologic