The completion of the Human Genome Project and improving methods to link disease pheno-36 FUNDAMENTALS OF NEUROLOGIC DISEASE
Table 3-4 Signal Intensities and Densities of Tissue Types in Neuroimaging
Neuroimaging Bright Dark
MRI Fat Bone or dense calcium
T1 weighted Methemoglobin CSF
Gadolinium contrast Edema or water
Air
Flowing blood
MRI Edema or water Bone or dense calcium
T2 weighted CSF Air
Methemoglobin (extracellular) Fat
Flowing blood Iron-laden tissues Hemosiderin Deoxyhemoglobin
Methemoglobin (within RBC)
CT Bone CSF
Blood not in vessels Edema or water
CT contrast material Fat
Thrombosis of major vessels Air
CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging; RBC = red blood cell.
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types to specific gene loci enable the diagnosis of many neurologic genetic diseases. Most disease-causing mutations consist of single base substitu-tions leading to amino acid substitusubstitu-tions (missense mutations; neurofibromatosis type 1), premature translation stop signals (nonsense mutations; Duchenne and Becker muscular dys-trophies), or abnormal ribonucleic acid (RNA) transcript splicing. Other clinically important mutations come from deoxyribonucleic acid (DNA) deletions, DNA duplications (Down syn-drome), or abnormal expansion of unstable trinu-cleotide repeats (Huntington’s chorea and spinocerebellar atrophy). Recessive genetic dis-eases usually derive from mutations, causing pro-duction of abnormal enzymes from both chromosomes so the normal enzyme from the opposite chromosome cannot compensate. Total or severe loss of important enzyme functions
results in metabolic diseases affecting brain devel-opment or preventing normal turnover of brain proteins, allowing them to abnormally accumulate in neurons. Dominantly inherited genetic diseases are mainly caused by mutations affecting impor-tant proteins.
The genetic mutations of many genetic neuro-logic diseases can be detected using non-CNS host tissues, such as WBCs, skin biopsy, or mouth mucosa cell scrapings. Assays for specific enzymes can be performed, such as hexosaminidase A to diagnose Tay-Sachs disease. Chromosomal band-ing and spectral karyotypband-ing can detect gross dele-tions or duplicadele-tions of chromosomal DNA.
Cellular DNA can be screened for specific genetic mutations by several methods, including poly-merase chain reaction (PCR) assays, automated fluorescent sequencing, Southern blotting, and fluorescence in situ hybridization (FISH).
While these tests are constantly improving and new genetic mutations are being identified, molec-ular genetic tests have limitations: (1) failure to
CHAPTER 3—Common Neurologic Tests 37
Table 3-5 Commonly Ordered Neuroimaging for Neurologic Conditions
Test Commonly Imaging Indications Ordered Head Trauma
Acute CT
Old MRI
Cerebral Hemorrhage CT
CNS Infection MRI with
gadolinium Acute Stroke MRI with
diffusion-weighted images
Seizures MRI
Brain Tumor MRI with
gadolinium Multiple Sclerosis MRI
Dementia MRI
Back Pain with MRI
Radiculopathy
Spinal Cord Disease and MRI Myelopathy
Atypical Headaches MRI
CNS = central nervous system; CT = computed tomog-raphy; MRI = magnetic resonance imaging.
Table 3-6 Comparison of Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) Techniques
Advantages of MRI
• Better imaging of brain located adjacent to bone
• Superior brain anatomy
• Detection of smaller brain lesions
• Better detection of subtle central nervous system pathology such as low-grade tumors
• Can visualize major neck and cerebral arteries and veins (magnetic resonance angiography)
• No ionizing radiation so safer than CT, especially during pregnancy
Advantages of CT
• Faster imaging time so restless, uncooperative patients can be scanned with fewer movement artifacts
• Ferromagnetic objects may be in or on the patient
• Less claustrophobia
• Better detection of subarachnoid hemorrhage, brain calcifications, and bone fractures 023-038_Davis03 3/2/05 4:08 PM Page 37
detect a given mutation does not rule out the sus-pected disease, as the mutation site may be differ-ent from those searched for in the assay; (2) different mutations in the same gene can produce different phenotypes; and (3) mutations in the same gene can produce different phenotypes. In addition, incomplete penetrance, age-dependent onset, and other genes often modify the disease’s phenotypic expression and rate of progression.
A major advance in the diagnosis of infectious agents affecting the CNS is the PCR assay. These assays now exist for many viruses, bacteria, mycobacterium, fungi, and protozoa. Since the PCR assay identifies only a small, but unique, frag-ment of the infectious agent DNA or RNA, the nucleic acid does not have to be fully intact or part of an infectious organism. As such, the PCR test often is positive when culture of the infectious agent is negative. The test is performed on CSF or biopsy tissue. Compared with conventional isola-tion methods, the PCR assay is sensitive, rapid (can be completed in hours to 1 day), less expensive, and safer (does not require infectious organisms).
PCR works on the following basic principles.
First, unique short DNA fragments, called primers, are chemically synthesized as oligonucleotide primers. Second, the primers, free DNA
nucleo-tides, and heat-stable DNA polymerase are added to the DNA mixture, which contains DNA from the microorganism in question. The mixture is heated to melt and separate the double-stranded DNA and then cooled, allowing the primers to hybridize to their complementary sequences on the separated strands of the microorganism’s DNA. The DNA polymerase enzyme adds nucleotide bases to the ends of the primers to create a long segment of double-stranded DNA. Third, another application of heat splits the new DNA fragments apart to allow the cycle to repeat doubling the number of DNA templates. Using automated equipment, it is possible to make millions of copies of the desired template within hours. Fourth, since the DNA tem-plate molecules are all the same length and compo-sition, they can be detected by gel electrophoresis or other methods.
RECOMMENDED READING
Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. (Excellent compendium of nor-mal CSF values and changes that occur in many diseases.)
38 FUNDAMENTALS OF NEUROLOGIC DISEASE 023-038_Davis03 3/2/05 4:08 PM Page 38
Overview
The human body has over 600 muscles; their bulk comprises about 40% of the total body weight.
Muscles are divided into skeletal muscles (respon-sible for voluntary movement and innervated by motor neurons of the anterior horn or brainstem), smooth muscle (involuntary muscles of the gas-trointestinal tract, genitourinary tract, blood ves-sels, and skin innervated by autonomic nerves), and cardiac muscle (heart muscle innervated by autonomic nerves). Each muscle type has distinct morphologic and biochemical characteristics that separate them and enable diseases to involve one or more muscle types. In simple terms, a muscle fiber is a long multinucleated cell that contains myofibrils for contraction and abundant mito-chondria for energy production. Diseases of skele-tal muscle are called by several general names:
myopathy, implying all types of muscle disease;
myositis, implying inflammation in the muscle;
and muscular dystrophy, implying degeneration of muscle, often hereditary.
The first step in diagnosing a muscle disease is to distinguish it from other causes of weakness (Table 4-1). However, there are exceptions to Table 4-1.
For example, some skeletal muscle disorders are episodic (hyper- or hypokalemic periodic
paraly-sis), some involve distal to a greater extent than proximal muscles (distal and myotonic muscular dystrophies), some produce myotonia or sustained muscle contractions (myotonic muscular dystro-phy), and some involve specific muscle groups (lid muscles and swallowing muscles in