Outline - Ch 39 Degenerative Dzs of the Nervous System

From Adams and Victor's Principles of Neurology, Ninth Edition

Part 4: Major Categories of Neurologic Disease, pg 589

Ch 39: Degenerative Diseases of the Nervous System, pg 1011-1080

General Clinical characteristics of Degenerative Diseases

General Pathologic and Pathogenic Features

• Clinical Classification
  
  • Syndrome of progressive dementia, other neurologic signs being absent or inconspicuous
    
    • Diffuse cerebral atrophy
      
      • Alzheimer dz
        
    • Circumscribed cerebral atrophies including primary progressive aphasias and progressive visuospatial disorders
      
      • pick dz (lobar sclerosis)
        
      • frontotemporal dementias including primary progressive aphasias
        
  • Syndrome of progressive dementia in combination with other neurologic abnormalities
    
    • Huntington dz (chorea)
      
    • Lewy-body dz
      
    • some cases of Parkinson dz
      
    • corticobasal ganglionic degeneration
      
    • cortical-striatal-spinal degeneration (Jakob dz)
      
    • Demential-Parkinson-anyotrophic lateral sclerosis complex
      
    • cerebrocerebellar degeneration
      
    • Familial dementia w/ spastic paraparesis, amyotrophy or myoclonus
      
    • Polyglucosan body dz
      
    • Frontotemporal dementia with parkinsonism or ALS
      
  • Syndrome of disordered posture and movement
    
    • Parkinson dz
      
    • multiple system atrophy (striatonigral degeneration and Shy-Drager syndrome
      
    • Progressive spuranuclear palsy
      
    • Dystonia musculorum deformans
      
    • Huntington dz (chorea)
      
    • Acanthocytosis with chora
      
    • Corticobasal ganglionic degeneration
      
    • Lew-body dz
      
    • Restricted dystonias, including spasmodic torticollis and Meige syndrome
      
    • Essential tremor
      
  • Syndrome of progressive ataxia
    
    • Spinocerebellar ataxias (early onset)
      
    • Cerebellar cortical ataxias
      
    • Complicated hereditary and sporadic cerebellar ataxias
      
      • Olivopontocerebellar degenerations (OPCA)
        
      • w/ extrapyramidal and autonomic degeneration
        
      • (Menzel type)
        
    • Dentatorubral degeneration
      
    • Dentatorubropallidoluysian adtrophy (DRPLA)
      
    • Machado-Joseph (Azorean) dz
      
    • Other complicated late onset …
      
  • Syndrome of slowly developing muscular weakness & atrophy
    
    • Motor disorders w/ amyotrophy
      
      • ALS, et. al.
        
    • Spastic paraplegia without amyotrophy
      
      • primary lateral sclerosis
        
      • hereditary spastic paraplegia (Strumpell-Lorrain)
        
  • Sensory and sensorimotor disorders (neuropathies; see ch46)
    
  • Syndrome of progressive blindness or ophthalmoplegia with or without other neurologic disorders (see ch 13)
    
  • Syndromes characterized by degenerative neurosensory deafness (see ch15)
    
• Diseases Characterized Mainly By Progressive Dementia
  
  • Alzheimer Disease – most common and important degenerative disease of the brain …
    
    • Epidemiology – majority of pts are in their 60s or older.
      
    • Clinical Features (see also ch21) – The gradual development of forgetfulness is the major symptom.
      
      • echolalia – a rather dramatic repetition of every spoken phrase
        
      • acalculia or dysalculia – when a pt can no longer carry out the simplest calculations
        
      • ideational and ideomotor apraxia – advanced forms of motor incapacity
        
    • Minimal Cognitive Impairment (MCI)
      
      • 1. Korsakoff amnesic state – a disproportionate failure of retentive memory w/ integrity of other cognitive abilities – immediate memory is essentially a measure of attention – short term and long-term (retentive) memory fails
        
      • 2. Dysnomia – the forgetting of words, especially proper names. Later the difficulty involves common nouns & progresses to the point where fluency of speech is seriously inpaired. Every sentence is broken by a pause and search for the wanted workd; if this is not found, a circumlocution is substituted or the sentence is left unfinished.
        
      • 3. Visuospatial disorientation – Parietooccipital functions are sometimes deranged in the course of Alzheimer dz and may fail while other functions are relatively preserved.
        
      • 4. Paranoia and other personality and mood changes – frequently, at some point in the development of Alzheimer dementia, paranoia or bizarre behavior occasionally assum prominence.
        
    • For research purposes, etc – exclusive criteria for the dx of Alzheimer dz two groups have adopted 5 criteria. The two groups are National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Dz and Related Dz's Association (ADRDA). The 5 criteria are
      
      • 1. dementia defined by clinical examination (the Mini-Mental Scale, see Table 21-6)
        
      • 2. pt older than 40
        
      • 3. deficits in two or more areas of cognition and progressive worsening of memory and other cognitive functions such as language, perception and motor skills (praxis)
        
      • 4. absence of disturbed consciousness
        
      • 5. exclusion of other brain dz
        
    • using these criteria, correct diagnosis is achieved in more than 85 percent of patients.
      
  • Pathology – in advanced stages the brain presents a diffusely strophied appearance and it's weight is usually reduced by 20 percent or more. Cerebral convolutions are narrowed and sulci are widened (I saw an example of this in Neuro lab w/ Dr. Clifford)
    
    • Three microscopic changes give this dz its distinctive character
      
      • 1. presence within the nerve cel cytoplasm of thick, fiber-like strands of silvers-staining material, also in the forms of loops, coils or tangled masses ("tangles")
        
      • 2. spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen w/ periodic acid-schiff (PAS) and silver-staining methods – the core of the aggregates is the protein amyloid surrounded by degenerating nerve terminals (neuritic plaques)
        
      • 3. Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus – probably, this last change is reactive and least important in diagnosis
        
  • Pathogenesis –
    
    • Tau, when talking about a protein in this context is not the Greek letter but rather an acronym for "tubulin associated unit"
      
    • APP – amyloid-protein precursor
      
    • The gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer dz and the duplicated chromosome in Down syndrome – possible overproduction of amylid and all its ABeta residues as being causative factors in the dz. other mechanistic theories exist
      
  • Diagnostic Studies – CT scanning and MRI are useful, but not definitive, ancillary test.
    
    • In advanced stages, the lateral and third ventricles are enlarged to about twice normal size and cerebral sulci are widened.
      
    • SPECT, single-photon emission for study of cerebral blood flow
      
    • PET, positron emission tomography, for metabolism study
      
    • Newer PET ligand agents that bind to amyloid, such as the "Pittsburgh compound" are more sensitive in identifying and plotting the course of Alzheimer disease.
      
  • Differential Diagnosis (see also Table 21-3) – Alzheimer dz is a form of dementia – The potentially treatable forms of dementia are those caused by normal-pressure hydrocephalus; chronic subdural hematoma; the dementia of AIDS; paraneoplastic limbic encephalitis; nutritional definciencies (thiamine – Wernicke-Korsakoff syndrome, Marchiafava-Bignami dz, pellagra, vitamin B12 deficiency); chronic drug intoxication (e.g., alcohol, sedatives); multiple cerebral infarctions; certain endocrine and metabolic disorders (myxedema, Hashimoto encephalopathy, neurosyphilis and other chronic meningitides, Cushing dz, chronic hepatic encephalopathy); frontal and temporal lobe tumors; cerebral vasculitis; sarcoidosis; Whipple dz; multiple sclerosis; and perhaps above all, the pseudodementia of depression. Exclusion of most of these diseases is readily accomplished by sequential outpatient evaluations or by a brief admission to a hospital were examinations of blood CSF, EEG, CT, MRI and neuropsychologic testing can be undertaken.
    
  • Treatment – there is no evidence that any of the previously proposed forms of therapy for Alzheimer dz – cerebral vasodilators, stimulants, L-dopa, massive doses of vitamins B, C and E, gingko biloba and many others has any salutary effect. Trials of oral physostigmine, choline and lecithin have yielded mostly negative or uninterpretable results and the evidence favoring the currently popular cholinergic precursors and agonists and acetylcholinesterase inhibitors, such as donepezil, is valid but only modest. With regard to the latter group of drugs, several large trials have demonstrated a slight prolongation of the pts ability to sustain an independent life, but such evidence generally requires that the medications be taken for 6 to 12 months. ….
    
    • NMDA – N-methyl-D-aspartate – here I'm assuming we're talking about NMDA receptors as mentioned in previous blogs pertaining to neuromusculoskelatal dx (NMS). The NMDA – N-methyl-D-aspartate glutaminergic antagonists, specifically memantine (20mg daily), have also been tried. - …there was no change in three main measures of cognitive performance but, because the side effects were ostensibly minor this drug was approved for use in late-stage Alzheimer dz and in conjunction with cholinergic drugs.
      
  • Associated Pathologic States – Amyloid plaques and tangle deposition are far more common in the brains of pts w/ Parkinson dz (20 to 30 percent) than in the brains of age-matched controls. These findings partly explain the high incidence of dementia in pts w/ Parkinson disease.
    
  • Lobar Atrophies (Pick Disease and Frontotemporal Dementia)
    
    • Clinical Features –
      
  • Frontotemporal Dementia –
    
  • Primary Progressive Aphasia
    
  • Posterior Cortical Atrophy
    
  • Lewy-body Dementia
    
    • Clinical Features
      
  • Other Degenerative Dementias
    
    • Diffuse Cerebral Atrophy of Non-Alzheimer Type
      
    • Argyrophilic Grain Disease
      
    • Thalamic Dementia
      
    • Neuroserpinopathy
      
  • Vascular (Multiinfarct) Dementia
    
  • Denentia Caused by Metabolic Diseases (see ch 37)
    
• Dementing Diseases in Which Other Neurologic Abnormalities are Prominent
  
  • Huntington Disease (Huntington Chorea)
    
    • This disease is distinguished by the triad of dominant inheritance, choreoathetosis and dementia, commemorates the name of George Huntington, a medical of Pomeroy, Ohio. In 1872, his paper, read before the Meigs and Mason Academy of Medicine and published later that year in the Medical and Surgical Reporter of Philadelphia, gave a succinct and graphic account of the disease that was based on observations of patients that his father and grandfather had made in the course of their practice in East Hampton, Long Island.
      
    • A marker linked ot the Huntington gene and localized to the short arm of chromosome 4 was the first important achievement in respect to the biologic understanding of Huntington dz.
      
    • The mutation was an excessively long repeat of the trinucleotide CAG within the Huntington gene – the length of the repeating pattern not only determines the presence of the dz but also the age of onset – the longer the repeating length, the earlier appearance of signs.
      
    • A rare alternative mutation, termed HDL2 (Huntington dzlike-2) is associated with CATCG repeat expansion of the juntophilin-3 gene but it is so rare that few clinicians will encounter it …so, maybe we'll see this on the TV show, House, MD ;)
      
    • Clinical Features
      
    • Pathology and Pathogenesis
      
    • Diagnosis
      
    • Treatment
      
    • Acanthocytosis with Chorea
      
    • Corticostriatospinal Degenerations
      
    • Familia Dementia with Spastic Paraparesis
      
    • Adult Polyglucosan Body Disease
      
• Disease Characterized by Abnormalities of Posture and Movement
  
  • Parkinson Disease
    
    • Genetic Aspects
      
    • Clinical Features
      
    • Diagnosis
      
    • Pathology and Pathogenesis
      
    • Treatment
      
      • L-Dopa & L-Dopa-Modifying Drugs
        
      • Dopamine Agonists
        
      • Adjunctive Medications
        
      • Neuroprotective Agents
        
      • Side Effects of L-Dopa Treatment and Their Management
        
    • Initiating Drug Treatment for Parkinson Disease
      
    • Surgical Measures
      
  • Multiple System Atrophy (Striatonigral Degeneration, Shy-Drager Syndrome, Olivopoontocerebellar Degeneration)
    
  • Progressive Supranuclear Palsy
    
    • Clinical Features
      
  • Corticobasal Degeneration
    
  • Dystonic Disorders
    
    • Dystonia Musculorum Deformans (Torsion Dystonia)
      
  • Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia)
    
  • Torticollis and Other Restricted Dyskinesias and Dystonias (see ch6)
    
  • Other Forms of Hereditary Dystonia
    
• Syndrome of Progressive Ataxia
  
  • Early Onset Spinocerebellar Ataxias (Predominantly Spinal)
    
    • Friedreich Ataxia
      
  • Predominantly Cerebellar (Cortical, Holmes Type) Hereditary and Sporadic Ataxia
    
  • Fragile X Tremor-Ataxic Premutation Syndrome
    
  • Familial and Sporadic Forms of Complicated Cerebellar Atrophy with Brainstem and Extrapyramidal Features
    
  • Cerebellar Atrophy with Prominent Basal Ganglionic Features
    
    • Machado-Joseph-Azorean Desease (SCA3)
      
    • Multiple System Atrophy with Predominant Ataxia
      
    • Dentatorubropallidoluysian Atrophy (DRPLA)
      
    • Dentatorubral Degeneration
      
    • Paroxysmal Ataxias (see ch5)
      
  • Genetics of the Heredodegenerative Ataxias (Table 39-5)
    
  • Differential Diagnosis of the Degenerative Ataxias (see Table 5-1)
    
  • Hereditary Polymyoclonus
    
• Syndrome of Muscular Weakness and Wasting Without Sensory Changes
  
  • Motor System Disease
    
    • Amyotrophic Lateral Sclerosis – a common disease with an annal incidence rate of 0.4 to 1.76 per 100,000 population. Men are affected nearly twice as often as women. Most patients are older than 45 at the onset of symptoms and the incidence increases with each decade of life. The disease occurs in a randome pattern throughout the world except for a dramatic clustering of patients among inhabitants of the Kii peninsula in Japan and in Guam, where ALS is often combined with dementia and parkinsonism. In approximately 10 percent of the cases the disease is familial, being inherited as an autosomal dominant trait with age-dependent penetrance.
      
    • Progressive Muscular Atrophy – this purely lower motor neuron syndrome is more common in men than in women, reportedly in a 4:1 ratio.
      
    • Progressive Bulbar Palsy
      
    • Primary Lateral Sclerosis – PLS
      
    • Laboratory Features of Motor Neuron Disease
      
    • Pathology – The principal finding in ALS is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. Large alpha motor neurons tend to be affected before small ones. In addition to neuronal loss, there is evidence of slight gliosis and proliferation of microglia cells. Many of the surviving nerve cells are small, shrunken and filled with lipofuscin.
      
    • Diagnosis of ALS
      
    • Pathogenesis – the pathogenesis of the sporadic form of motor system disease is not known. Some insight has been afforded by analyses of the 10 percent of ALS cases that are caused by gene mutations.
      
    • Treatment – With the exception of riluzole, there is no specific treatment for any of the motor neuron diseases. The antiglutamate agent riluzole was shown to slow the progression of ALS and improve survival in patients with disease of bulbar onset. However, it adds only 3 months of life at best.
      
  • Heredofamilial Forms of Progressive Muscular Atrophy
    
    • Spinal Muscular Atrophy (Werdnig-Hoffman Disease)
      
    • Kennedy Syndrome (X-Linked Bulbospinal Muscular Atrophy)
      
    • Progressive Bulbar Palsy of Childhood (Fazio-Londe Syndrome)
      
  • Hereditary Forms of Spastic Paraplegia
    
    • Hereditary Spastic Paraplegia (Strumpell-Lorrain Disease)
      
    • Variants of Familial Spastic Paraplegia
      
• Symdrome of Progressive Blindness (see ch 13)
  
  • Hereditary Optic Atrophy of Leber
    
  • Retinitis Pigmentosa (see ch 13)
    
  • Stargardt Disease
    
• Syndrome of Progressive Deafness (see ch 15)
  
  • Hereditary Hearing Loss with Retinal Diseases
    
  • Hereditary Hearing Loss with Diseases of the Nervous System