Chapter 31 Laboratory Investigations in Diagnosis and Management of Neurological Disease
The history and examination are key to making the diagnosis in a patient with neurological disease (see Chapter 1). Laboratory investigations are becoming increasingly important in diagnosis and management, however, and are discussed in some detail in later chapters on the specific disorders. A test may be diagnostic (e.g., the finding of cryptococci in the cerebrospinal fluid [CSF] of a patient with a subacute meningitis, a low vitamin E level in a patient with ataxia and tremor, a low serum vitamin B12 level in a patient with a combined myelopathy and neuropathy).
Laboratory tests should be directed to prove or disprove the hypothesis that a certain disease is responsible for the condition in the patient. They should not be used as a “fishing expedition.” Sometimes, a physician who cannot formulate a differential diagnosis from the clinical history and examination is tempted to order a wide range of tests to see what is abnormal. In addition to the high costs involved, this approach is likely to add to the confusion because “abnormalities” may be found that have no relevance to the patient’s complaints. For instance, many patients are referred to neurologists to determine whether they have multiple sclerosis (MS) because their physicians requested magnetic resonance imaging (MRI) of the brain for some other purpose such as the investigation of headaches. If the MRI shows small T2-weighted abnormalities in the centrum semiovale (changes that are seen in a proportion of normal older adults and in those with hypertension and diabetes), the neuroradiologist will report that the differential diagnosis includes MS, despite the fact that the patient has no MS symptoms.
Moreover, neuroimaging modalities have expanded remarkably in the past decade, and the neurologist ordering these tests should be familiar with each one, so that appropriate sequences and methods are used to address the particular question presented by the patient’s history. Also, because of the increasing use of pacemakers, deep brain stimulators, and other devices, the neurologist should be aware that certain precautions must be taken before MRI scans are ordered; in many instances, computed tomography (CT) scans or alternative investigations must be used to avoid potential danger to the patient.
Results of laboratory tests can be used to determine response to treatment. For instance, the high erythrocyte sedimentation rate (ESR) typical with cranial arteritis falls with corticosteroid treatment and control of the condition. A rising ESR as the corticosteroid dosage is reduced indicates that the condition is no longer adequately controlled and that headaches and the risk of loss of vision will soon return.
It is important to use laboratory tests judiciously and to understand their sensitivity, specificity, risks, and costs. The physician must understand how to interpret the hematological, biochemical, and bacteriological studies and the specific neurodiagnostic investigations. The latter studies include clinical neurophysiology, neuroimaging, and the pathological study of biopsy tissue. Knowledge of the various DNA tests available and their interpretation is critical before they are ordered; their results may have far-reaching implications not only for the patient but for all other family members. The neurologist also must have a working knowledge of several related disciplines that provide specific investigations to aid in neurological diagnosis. These include neuropsychology, neuro-ophthalmology, neuro-otology, uroneurology, neuroepidemiology, clinical neurogenetics, neuroimmunology and neurovirology, and neuroendocrinology. Chapter 34, Chapter 35, Chapter 36, Chapter 37, Chapter 38, Chapter 39, Chapter 40, Chapter 41, Chapter 42 describe these disciplines and the investigations they offer.
Biopsy of skeletal muscle or peripheral nerve may be needed to diagnose neuromuscular diseases. A brain biopsy may be needed to diagnose a tumor, infection, vasculitis, or (rarely) degenerative disease of the nervous system.
The investigations used to diagnose neurological disease change rapidly. Genetic studies of DNA mutations in the blood now allow the diagnosis of Huntington disease (HD), a growing number of spinocerebellar ataxias and parkinsonian disorders, a form of autosomal dominant dystonia (DYT1), Duchenne and other muscular dystrophies, many forms of Charcot-Marie-Tooth disease, Rett syndrome, fragile X premutation, and a variety of other neurogenetic disorders (see http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests; http://www.genetests.org; http://www.geneclinics.org; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM). Blood tests for human immunodeficiency virus infection (HIV), Lyme disease, and other infections and for various paraneoplastic syndromes affecting the nervous system also can be diagnostic. For example, three types of anti–Purkinje cell antibodies are recognized: anti-Yo (PCA-1), seen with tumors of breast, ovary, and adnexa; atypical anti–cytoplasmic antibody (anti-Tr or PCA-Tr), seen with Hodgkin disease and tumors of the lung and colon; and PCA-2, identified mostly with lung tumors. In addition, three antineuronal antibodies can be detected: anti-Hu (ANNA-1), seen in conjunction with encephalomyelitis, small cell lung tumor, and tumors of breast, prostate, and neuroblastoma; anti-Ri (ANNA-2), found with tumors of breast and ovary; and atypical anti-Hu, seen with tumors of lung, colon, adenocarcinoma, and lymphoma. Anti-CV2 (CRMP) antibody, expressed by oligodendrocytes, is associated with a syndrome of ataxia and optic neuritis and has been seen with small cell lung carcinoma. The role of antineuronal antibodies, such as those presumably directed to components of the basal ganglia, is not established and may be of doubtful pathogenic relevance.
Antibodies directed to a serum protein, Ma (anti-Ma1 and anti-Ma2), have been seen in patients with limbic encephalitis associated with testicular and other tumors. Antibodies directed to amphiphysin have been detected in patients with a cerebellar syndrome and small cell lung carcinoma. Antibodies against a glutamate receptor are seen in rare patients with a pure cerebellar syndrome associated with cancer and a variety of autoimmune diseases. Antibodies against glutamic acid decarboxylase (anti-GAD) have been seen in patients with the stiff person syndrome and in patients with ataxia in a setting of an autoimmune disease such as diabetes, thyroid disease, or vitiligo. Antigliadin antibodies are helpful in evaluating patients with unexplained ataxia. As a result of advances in laboratory technology, genetic, immunological, and other blood tests are expanding the ability of clinicians to confirm the diagnosis of an increasing number of neurological disorders, obviating more invasive studies.
MRI has replaced CT for most conditions, and MR angiography and venography have largely replaced conventional catheter-based blood vessel imaging studies. In general, older, more invasive tests are now used for therapy rather than diagnostics. For example, the diagnosis and cause of an acute stroke may be determined by MRI, but catheter angiography is used to deliver intraarterial tissue plasminogen activator (tPA) or perform embolectomies. The neurologist must know enough about each laboratory test to request it appropriately and to interpret the results intelligently. As a rule, it is inappropriate to order a laboratory test if the result will not influence diagnosis or management. Tests should be used to diagnose and treat disease, not to protect against litigation. When used judiciously, laboratory investigations serve both purposes; when ordered indiscriminately, they serve neither.
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