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InternalMed_Harrison. FIGURE 441e-34 Retropharyngeal soft tissue mass. Sagittal T1-weighted MRI demonstrates a hyperflexion fracture with retropulsion of the posterior wall in the canal at C5 and C6 (arrow). There is also a large retropharyngeal hematoma (∗). The distance from the posterior wall of the airway to the anterior wall of the vertebral body should not measure more than 6 mm at C2 or more than 20 mm at C6 (mnemonic “6 at 2 and 20 at 6”). FIGURE 441e-35 Jefferson fracture. Axial CT demonstrates four fracture lines (arrows) separating C1 in four parts. Jefferson fracture is usually caused by axial impact to the head such as diving in shallow water. FIGURE 441e-36 Ligament injury after trauma. Coronal CT reconstruction demonstrates abnormal asymmetry between the dens and the lateral masses of C1 indicating transverse ligament rupture.


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InternalMed_Harrison. FIGURE 441e-36 Ligament injury after trauma. Coronal CT reconstruction demonstrates abnormal asymmetry between the dens and the lateral masses of C1 indicating transverse ligament rupture. FIGURE 441e-38 Pathologic fracture. Sagittal T1-weighted MRI (A) demonstrates wedge-shaped T6 vertebral body (arrow). Sagittal postcontrast T1-weighted MRI (B) depicts tumor extension into the epidural space and the involvement of the posterior arch (∗), which are highly suggestive of metastatic or primary bone tumor. CHAPTER 441e Atlas of Neuroimaging FIGURE 441e-39 Sacral insufficiency fracture. Axial T2-weighted MRI (A) and T1-weighted MRI (B) demonstrate symmetric high T2 and low T1 signal involving the sacral alae longitudinally (arrows). FIGURE 441e-37 Odontoid fracture. Sagittal CT demonstrates disruption of the main reference cervical lines. 1: Anterior vertebral body line; 2: Posterior vertebral body line; 3: Spinolaminar line.


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InternalMed_Harrison. FIGURE 441e-37 Odontoid fracture. Sagittal CT demonstrates disruption of the main reference cervical lines. 1: Anterior vertebral body line; 2: Posterior vertebral body line; 3: Spinolaminar line. FIGURE 441e-40 Subdural hematoma. Sagittal T2-weighted MRI (A) and axial noncontrast T1-weighted MRI (B) demonstrate subdural collection in the lumbosacral region (∗∗). Note that the epidural fat is compressed but not involved (arrow). FIGURE 441e-41 Teardrop fracture. Sagittal CT (A) demonstrates fracture line separating the anteroinferior corner of C6 (arrow). Sagittal T2-weighted MRI (B) displays cord injury (arrow).


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InternalMed_Harrison. FIGURE 441e-41 Teardrop fracture. Sagittal CT (A) demonstrates fracture line separating the anteroinferior corner of C6 (arrow). Sagittal T2-weighted MRI (B) displays cord injury (arrow). FIGURE 441e-42 Demyelinating disease (multiple sclerosis, Chap. 458). Axial T2-weighted MRI (A, D) and axial T2 FLAIR MRI (B, E) demonstrate multiple hyperintense lesions involving the periventricular and subcortical white matter (arrows). Although not always present, the appearance of a “lesion within and lesion” (arrowheads) is typical of demyelinating disease. Axial T1-weighted postcontrast MRI (C, F) shows partial enhancement of the lesion (arrows), which is often peripheral, incomplete, and “C-shaped” (curved arrow). CHAPTER 441e Atlas of Neuroimaging


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InternalMed_Harrison. CHAPTER 441e Atlas of Neuroimaging FIGURE 441e-43 Neurofibromatosis type 1 (Chap. 118). Axial T2 FLAIR MRI (A, B) demonstrates multiple hyperintense lesions involving the brainstem and basal ganglia (arrows) as well as deep cerebellar hemispheres (arrowheads). Sagittal and corona T1-weighted postcontrast MRI (C, D) shows enlargement of the optic chiasm with an area of enhancement on the left, representing an optic pathway glioma (arrows). Coronal STIR MRI (E) shows thoracolumbar scoliosis and a large paravertebral plexiform neurofibroma (arrows).


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InternalMed_Harrison. FIGURE 441e-44 Neurofibromatosis type 2 (Chap. 118). Axial T1-weighted postcontrast MRI (A, B) shows enhancing expansible lesions in the bilateral cerebellopontine cisterns extending in the internal auditory canals, consistent with vestibular schwannomas (arrows), as well as in the bilateral prepontine cistern, consistent with trigeminal schwannomas (arrowheads). Coronal axial T1-weighted image postgadolinium (C ) demonstrates an intensely enhancing dural-based lesion typical for a small meningioma (arrows). Sagittal (D, E) T1-weighted images postgadolinium show intradural, extramedullary lesions, suggestive of multiple spinal schwannomas (small arrows). The flat dural-based lesion may represent a spinal meningioma (arrowhead). Axial T1-weighted image postgadolinium (F ) shows an enhancing intramedullary lesion, most consistent with an ependymoma. (curved arrow).


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InternalMed_Harrison. FIGURE 441e-45 Tuberous sclerosis (Chap. 118). Coronal T2-weighted MRI (A) shows multiple T2 hyperintense lesions in a cortical and subcortical distribution (arrows). Coronal and axial postcontrast T1-weighted image (B, C) demonstrates an expanding nodule with intense enhancement in the proximity of the right foramen of Monro, consistent with a subependymal giant-cell astrocytoma (SEGA) (arrowheads). Surveillance T1-weighted image (D) and postcontrast T1-weighted image with fat saturation (E) show multiple bilateral renal lesions with signal intensity of fat, consistent with angiomyolipomas (small arrows).


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InternalMed_Harrison. FIGURE 441e-46 Von Hippel–Lindau (VHL) (Chap. 408). Axial postcontrast T1 weighted images (A–C) demonstrates multiple enhancing nodules in the posterior fossa (arrows). Sagittal postcontrast T1-weighted image (D) shows vascular flow voids within the enhancing nodule in the region of the foramen of Magendie (arrow), indicating increased vascularity. Surveillance axial T2-weighted MRI of the abdomen (E) shows multiple small pancreatic cysts (arrowheads). This patient did not have an endolymphatic sac tumor, renal cell carcinoma, neuroendocrine pancreatic tumor, or pheochromocytoma, all of which may also occur in von Hippel–Lindau disease. CHAPTER 441e Atlas of Neuroimaging


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InternalMed_Harrison. CHAPTER 441e Atlas of Neuroimaging FIGURE 441e-47 Neurocutaneous melanosis. Coronal T1 weighted MRI (A–D) shows multiple lesions with intrinsic increased T1 signal in the bilateral amygdalae, right superior temporal gyrus, right cerebellar hemisphere, and right medial occipital cortex (arrows). Sagittal and axial T1-weighted images of the spine (E, F) show intradural, extramedullary lesions, also with intrinsic increased T1 signal, due to malignant melanoma (arrows). FIGURE 441e-48 Sturge-Weber syndrome. Coronal T1-weighted MRI (A) shows enlargement of the sulci in the left parietal lobe, consistent with brain parenchymal volume loss (arrows). Axial susceptibility weighted imaging shows susceptibility effect in this region, consistent with calcifications (arrows). Coronal and axial T1-weighted images postgadolinium (C, D) show increased leptomeningeal enhancement (arrows) and enlargement of the left choroid plexus (curved arrow).


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InternalMed_Harrison. FIGURE 441e-49 Multiple cavernomas (Chap. 446). Axial susceptibility weighted images (A–D) show multiple foci of susceptibility involving the bilateral cerebral hemispheres, pons, and left cerebellum, which in a young patient most likely represents multiple cavernomas (arrows). These lesions have variable signal intensity on T2-weighted (E) and T1-weighted MRI (F), related to the different stages of hemoglobin degradation (arrows). Cavernomas are not seen on the time-of-flight MR angiography (G); thus these are designated as angiographically occult vascular malformations. Of note, in elderly patients, amyloid angiopathy may have a similar appearance. CHAPTER 441e Atlas of Neuroimaging


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InternalMed_Harrison. CHAPTER 441e Atlas of Neuroimaging FIGURE 441e-50 Brainstem glioma (Chap. 118). Axial T2 FLAIR MRI (A) demonstrates increased T2 signal and marked enlargement of the pons (large arrows), which engulfs the basilar artery (small arrow). These findings are characteristic of brainstem glioma. At the time of diagnosis, these lesions are typically low grade without abnormal enhancement, as shown by axial postcontrast T1-weighted image (B). FIGURE 441e-51 Pilocytic astrocytoma (Chap. 118). Axial T2-weighted and T1-weighted postgadolinium images (A, B) show a cystic lesion with peripheral enhancement and an enhancing solid component located in the posterior fossa (arrows). These findings are suggestive of a pilocytic astrocytoma. Note that the lesion exerts mass effect on the fourth ventricle, which is compressed (curved arrows).


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InternalMed_Harrison. FIGURE 441e-52 Fourth ventricle ependymoma causing hydrocephalus (Chap. 118). Unenhanced axial CT images (A, B) demonstrate an expansile mass lesion, isodense with brain parenchyma, filling the fourth ventricle (arrows) and causing obstruction of cerebrospinal fluid flow, dilation of the lateral ventricles, and hydrocephalus (curved arrows). The hypoattenuation within periventricular white matter bilaterally represents transependymal flow (arrowheads). Axial T1-weighted postgadolinium MRI confirms the presence of a heterogeneously enhancing mass filling the fourth ventricle (arrow), which is suggestive of ependymoma.


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InternalMed_Harrison. FIGURE 441e-53 Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (Chap. 462e). Axial T2 FLAIR MRI (A, B) shows areas of increased T2 signal involving the cortex and subcortical white matter in the posterior right frontal lobe and anterior left temporal lobe, consistent with edema (arrows). Axial diffusion-weighted images (C, D) show reduced diffusion from cytotoxic edema, consistent with infarcts (arrows). MR spectroscopy of the right frontal lesion (E) demonstrates markedly increased lactate (arrow), an expected finding in infarction regardless of etiology. However, MR spectroscopy of the normal-appearing contralateral brain parenchyma (F) shows mildly elevated lactate (arrow), which is suggestive of a mitochondrial disorder.


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InternalMed_Harrison. FIGURE 441e-54 Leigh’s disease (subacute necrotizing encephalomyelopathy) (Chap. 85e). Axial T2-weighted MRI (A, B) demonstrates increased T2 signal involving the substantia nigra (white arrows) and dorsal midbrain (black arrows), as well as the putamin bilaterally (curved arrows). This is a common pattern for the mitochondrial disorder Leigh’s disease secondary to cytochrome oxidase (CO IV) deficiency. CHAPTER 441e Atlas of Neuroimaging FIGURE 441e-55 Krabbe’s disease (Chap. 432e). Axial and coronal T2-weighted MRIs (A, B) show increased T2 signal involving predominantly the posterior white matter bilaterally (arrows) with sparing of the subcortical U-fibers (arrowheads). MR spectroscopy of the left parietal white matter (C) shows markedly decreased N-acetylaspartate (large arrow) and increased lactate/lipids (small arrow), consistent with severe neuronal injury.


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InternalMed_Harrison. FIGURE 441e-56 X-linked adrenoleukodystrophy (Chap. 459). Axial unenhanced CT (A) demonstrates areas of attenuation involving the posterior white matter bilaterally (arrows). Axial T2 FLAIR MRI (B) displays increased T2 signal consistent with edema (arrows). Axial T1-weighted image postgadolinium (C) shows peripheral enhancement of the parietal lesions bilaterally (arrows). These findings are typical of adrenoleukodystrophy.


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InternalMed_Harrison. FIGURE 441e-57 Sickle cell disease and moyamoya disease (Chap. 446). Axial T2-weighted MRI (A, B) shows multiple small areas of encephalomalacia from prior infarcts in the watershed zones between the anterior and middle cerebral artery territories (small arrows). There is also an area of edema involving the left basal ganglia from an evolving subacute infarct (arrow). An axial diffusion-weighted image (C) with corresponding ADC map (D) shows an area of restricted diffusion in the right frontoparietal region, consistent with an acute infarct (arrows). Time-of-flight MR angiography (E) shows absence of flow in the distal internal carotid arteries and proximal middle cerebral arteries (arrows) due to moyamoya disease. Also note that this patient is status post–bilateral encephalo-duro-arterio-synangiosis (EDAS) (arrowheads), a surgical procedure to create indirect anastomosis between branches of the external carotid artery with distal branches of the middle cerebral artery.


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InternalMed_Harrison. FIGURE 441e-58 Hepatic encephalopathy (Chap. 330). Axial T1-weighted MRI (A, B) shows increased intrinsic T1 signal involving the basal ganglia bilaterally, particularly the globus pallidus (arrows). FIGURE 441e-59 Guillain-Barré syndrome (Chap. 460). Axial precontrast T1-weighted MRI (A) and axial and sagittal T1-weighted postgadolinium (B, C) images show thickening and increased enhancement of the anterior roots of the cauda equina (arrows). FIGURE 441e-60 Hemiplegic migraine (Chap. 447). Axial noncontrast perfusion MRI using an arterial spin labeling technique (A) demonstrates decreased cerebral blood flow to the left hemisphere (arrows) in a patient with right hemiparesis associated with migraine symptoms. No abnormality was seen on T2-weighted images, diffusion-weighted images, or time-of-flight MR angiography (B–D) to suggest stroke. CHAPTER 441e Atlas of Neuroimaging


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InternalMed_Harrison. CHAPTER 441e Atlas of Neuroimaging Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG Michael J. Aminoff ELECTROENCEPHALOGRAPHY 442e


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InternalMed_Harrison. The electrical activity of the brain (the electroencephalogram [EEG]) is easily recorded from electrodes placed on the scalp. The potential difference between pairs of electrodes on the scalp (bipolar derivation) or between individual scalp electrodes and a relatively inactive common reference point (referential derivation) is amplified and displayed on a computer monitor, oscilloscope, or paper. Digital systems allow the EEG to be reconstructed and displayed with any desired format and to be manipulated for more detailed analysis and also permit computerized techniques to be used to detect certain abnormalities. The characteristics of the normal EEG depend on the patient’s age and level of arousal. The rhythmic activity normally recorded represents the postsynaptic potentials of vertically oriented pyramidal cells of the cerebral cortex and is characterized by its frequency. In normal awake adults lying quietly with the eyes closed, an 8to 13-Hz alpha rhythm is seen posteriorly in


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InternalMed_Harrison. oriented pyramidal cells of the cerebral cortex and is characterized by its frequency. In normal awake adults lying quietly with the eyes closed, an 8to 13-Hz alpha rhythm is seen posteriorly in the EEG, intermixed with a variable amount of generalized faster (beta) activity (>13 Hz); the alpha rhythm is attenuated when the eyes are opened (Fig. 442e-1). During drowsiness, the alpha rhythm is also attenuated; with light sleep, slower activity in the theta (4–7 Hz) and delta (<4 Hz) ranges becomes more conspicuous.


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InternalMed_Harrison. Activating procedures are generally undertaken while the EEG is 442e-1 recorded in an attempt to provoke abnormalities. Such procedures commonly include hyperventilation (for 3 or 4 min), photic stimulation, sleep, and sleep deprivation on the night prior to the recording. Electroencephalography is relatively inexpensive and may aid clinical management in several different contexts.


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InternalMed_Harrison. The EEG is most useful in evaluating patients with suspected epilepsy. The presence of electrographic seizure activity—i.e., of abnormal, repetitive, rhythmic activity having an abrupt onset and termination and a characteristic evolution—clearly establishes the diagnosis. The absence of such electrocerebral accompaniment to an episodic behavioral disturbance does not exclude a seizure disorder, however, because there may be no changes in the scalp-recorded EEG during certain focal seizures. With generalized tonic-clonic seizures, the EEG is always abnormal during the episode. It is often not possible to obtain an EEG during clinical events that may represent seizures, especially when such events occur unpredictably or infrequently. Continuous monitoring for prolonged periods in video-EEG telemetry units has made it easier to capture the electrocerebral accompaniments of such clinical episodes. Monitoring by these means is sometimes helpful in confirming that seizures are occurring,


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InternalMed_Harrison. telemetry units has made it easier to capture the electrocerebral accompaniments of such clinical episodes. Monitoring by these means is sometimes helpful in confirming that seizures are occurring, characterizing the nature of clinically equivocal episodes, and determining the frequency of epileptic events.


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InternalMed_Harrison. The EEG findings in the interictal period may show certain abnormalities that are strongly supportive of a diagnosis of epilepsy. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. The presence of epileptiform activity is not specific for epilepsy, but it has a much greater prevalence in epileptic patients than in normal individuals. However, even in individuals with epilepsy, the initial routine interictal EEG may be normal up to 60% of CHAPTER 442e Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG


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InternalMed_Harrison. FIGuRE 442e-1 A. Normal electroencephalogram (EEG) showing a posteriorly situated 9-Hz alpha rhythm that attenuates with eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient with encephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a patient with a right parietal glioma. D. Periodic complexes occurring once every second in a patient with Creutzfeldt-Jakob disease. Horizontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV in other panels. In this and the following figure, electrode placements are indicated at the left of each panel and accord with the international 10:20 system. A, earlobe; C, central; F, frontal; Fp, frontal polar; P, parietal; T, temporal; O, occipital. Right-sided placements are indicated by even numbers, left-sided placements by odd numbers, and midline placements by Z. (From MJ Aminoff [ed]: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford,


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InternalMed_Harrison. placements are indicated by even numbers, left-sided placements by odd numbers, and midline placements by Z. (From MJ Aminoff [ed]: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford, Elsevier Saunders, 2012.) the time. Thus, the EEG cannot establish the diagnosis of epilepsy in many cases.


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InternalMed_Harrison. The EEG findings have been used in classifying seizure disorders and selecting appropriate anticonvulsant medication for individual patients (Fig. 442e-2). The episodic generalized spike-wave activity that occurs during and between seizures in patients with typical absence epilepsy contrasts with focal interictal epileptiform discharges or ictal patterns found in patients with focal seizures. These latter seizures may have no correlates in the scalp-recorded EEG or may be associated with abnormal rhythmic activity of variable frequency, a localized or generalized distribution, and a stereotyped pattern that varies with the patient. Focal or lateralized epileptogenic lesions are important to recognize, especially if surgical treatment is contemplated. Intensive long-term monitoring of clinical behavior and the EEG is required for operative candidates, however, and this generally also involves recording from intracranial (subdural, extradural, or intracerebral) electrodes.


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InternalMed_Harrison. The EEG findings may indicate the prognosis of seizure disorders: In general, a normal EEG implies a better prognosis than otherwise, whereas an abnormal background or profuse epileptiform activity suggests a poor outlook. The EEG findings are not helpful in determining which patients with head injuries, stroke, or brain tumors will go on to develop seizures, because in such circumstances epileptiform activity is FIGuRE 442e-2 Electrographic seizures. A. Onset of a tonic seizure showing generalized repetitive sharp activity with synchronous onset over both hemispheres. B. Burst of repetitive spikes occurring with sudden onset in the right temporal region during a clinical spell characterized by transient impairment of external awareness.


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InternalMed_Harrison. C. Generalized 3-Hz spike-wave activity occurring synchronously over both hemispheres during an absence (petit mal) attack. Horizontal calibration: 1 s; vertical calibration: 400 µV in A, 200 µV in B, and 750 µV in C. (From MJ Aminoff [ed]: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford, Elsevier Saunders, 2012.) commonly encountered regardless of whether seizures occur. The EEG findings are of limited utility in determining whether anticonvulsant medication can be discontinued after several seizure-free years. Further seizures may occur after withdrawal of anticonvulsant medication despite a normal EEG or, conversely, may not occur despite a continuing EEG abnormality. The decision to discontinue anticonvulsant medication is made on clinical grounds, and the EEG is helpful only for providing guidance when there is clinical ambiguity or the patient requires reassurance about a particular course of action.


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InternalMed_Harrison. The EEG has no role in the management of tonic-clonic status epilepticus except when there is clinical uncertainty about whether seizures are continuing in a comatose patient. In patients treated by drug-induced coma for refractory status epilepticus, the EEG findings indicate the level of anesthesia and whether seizures are occurring. During status epilepticus, the EEG shows repeated electrographic seizures or continuous spike-wave discharges. In nonconvulsive status epilepticus, a disorder that may not be recognized unless an EEG is performed, the EEG may also show continuous spike-wave activity (“spike-wave stupor”) or, less commonly, repetitive electrographic seizures (focal status epilepticus).


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InternalMed_Harrison. The EEG tends to become slower as consciousness is depressed, regardless of the underlying cause (Fig. 442e-1). Other findings may suggest diagnostic possibilities, as when electrographic seizures are found or a focal abnormality indicates a structural lesion. The EEG generally slows in metabolic encephalopathies, and triphasic waves may be present. The findings do not permit differentiation of the underlying metabolic disturbance but help to exclude other encephalopathic processes by indicating the diffuse extent of cerebral dysfunction. An EEG responsive to external stimulation is helpful prognostically because electrocerebral responsiveness implies a lighter level of coma than a nonreactive EEG, and thus a better prognosis. Serial records provide a better guide to prognosis than a single record and supplement the clinical examination in following the course of events. As the depth of coma increases, the EEG becomes nonreactive and may show a burst-suppression pattern, with bursts


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InternalMed_Harrison. record and supplement the clinical examination in following the course of events. As the depth of coma increases, the EEG becomes nonreactive and may show a burst-suppression pattern, with bursts of mixed-frequency activity separated by intervals of relative cerebral inactivity. In other instances there is a reduction in amplitude of the EEG until eventually activity cannot be detected. Such electrocerebral silence does not necessarily reflect irreversible brain damage, because it may occur reversibly in hypothermic patients or with drug overdose. The prognosis of electrocerebral silence, when recorded using an adequate technique, therefore depends on the clinical context in which it is found. In patients with severe cerebral anoxia, for example, electrocerebral silence in a technically satisfactory record implies that useful cognitive recovery will not occur.


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InternalMed_Harrison. In patients with clinically suspected brain death, an EEG recorded using appropriate technical standards may be confirmatory by showing electrocerebral silence, but disorders that may produce a similar but reversible EEG appearance must be excluded. The presence of residual EEG activity in suspected brain death fails to confirm the diagnosis but does not exclude it. The EEG is usually normal in patients with locked-in syndrome (Chap. 446), and helps in distinguishing this disorder from the comatose state with which it is sometimes confused clinically.


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InternalMed_Harrison. In developed countries, computed tomography (CT) scanning and magnetic resonance imaging (MRI) are used as a noninvasive means of screening for focal structural abnormalities of the brain, such as tumors, infarcts, or hematomas (Fig. 442e-1). The EEG is still used for this purpose in many parts of the world, however, although infratentorial or slowly expanding lesions may not be recognized. Focal slow-wave disturbances, a localized loss of electrocerebral activity, or more generalized electrocerebral disturbances are common findings but do not indicate the nature of the underlying pathology.


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InternalMed_Harrison. In patients with an acute encephalopathy, focal or lateralized periodic slow-wave complexes, sometimes with a sharpened outline, suggest a diagnosis of herpes simplex encephalitis, and periodic lateralizing epileptiform discharges (PLEDs) are commonly found with acute hemispheric pathology such as a hematoma, abscess, or rapidly expanding tumor. The EEG findings in dementia are usually nonspecific and do not distinguish reliably between different underlying causes except in rare instances when the presence of complexes occurring with a regular repetition rate (“periodic complexes”) supports a diagnosis of Creutzfeldt-Jakob disease (Fig. 442e-1) or subacute sclerosing panencephalitis. In most patients with dementia, the EEG is normal or diffusely slowed, and the findings alone cannot indicate whether a patient is demented or distinguish between dementia and pseudodementia.


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InternalMed_Harrison. The brief EEG obtained routinely in the laboratory often fails to reveal abnormalities that are transient and infrequent. Continuous monitoring over 12 or 24 hours or longer may detect abnormalities or capture clinical events that otherwise would be missed. The EEG is often recorded continuously in critically ill patients to detect early changes in neurologic status. Continuous EEG recording in this context has been used to detect acute events such as from nonconvulsive seizures or developing cerebral ischemia, to monitor cerebral function in patients with metabolic disorders such as liver failure, and to manage the level of anesthesia in pharmacologically induced coma.


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InternalMed_Harrison. Recording the magnetic field of the electrical activity of the brain (magnetoencephalography [MEG]) provides a means of examining cerebral activity that is less subject to distortion by other biologic tissues than the EEG. MEG is used in only a few specialized centers because of the complexity and expense of the necessary equipment. It permits the source of activity to be localized and coregistered with the MRI in a technique that is known as magnetic source imaging. In patients with focal epilepsy, MEG is useful in localizing epileptogenic foci for surgery and for guiding the placement of intracranial electrodes for electrophysiologic monitoring. MEG has also been used for mapping brain tumors, identifying the central fissure preoperatively, and localizing functionally eloquent cortical areas such as those concerned with language.


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InternalMed_Harrison. The noninvasive recording of spinal or cerebral potentials elicited by stimulation of specific afferent pathways allows the functional integrity of these pathways to be monitored but does not indicate the pathologic basis of lesions involving them. Such evoked potentials (EPs) are small compared to the background EEG activity, and the responses to a number of stimuli are therefore recorded and averaged with a computer to permit their recognition and definition. The background EEG activity, which has no fixed temporal relationship to the stimulus, is averaged out by this procedure.


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InternalMed_Harrison. Visual evoked potentials (VEPs) are elicited by monocular stimulation with a reversing checkerboard pattern and are recorded from the occipital region in the midline and on either side of the scalp. The component of major clinical importance is the so-called P100 response, a positive peak having a latency of approximately 100 ms. Its presence, latency, and symmetry over the two sides of the scalp are noted. Amplitude changes are less helpful for the recognition of pathology. VEPs are most useful in detecting dysfunction of the visual pathways anterior to the optic chiasm. In acute severe optic neuritis, the P100 is frequently lost or grossly attenuated; as clinical recovery occurs, it is restored but with an increased latency that generally remains abnormal indefinitely. The VEP findings are therefore helpful in indicating previous or subclinical optic neuritis. They may also be abnormal with ocular abnormalities and with other causes of optic nerve disease, such as ischemia or


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InternalMed_Harrison. are therefore helpful in indicating previous or subclinical optic neuritis. They may also be abnormal with ocular abnormalities and with other causes of optic nerve disease, such as ischemia or compression by a tumor. Flash-elicited VEPs may be normal in patients with cortical blindness.


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InternalMed_Harrison. Routine VEPs record a mass response over a relatively large cortical area and thus may be insensitive to localized waveform abnormalities. A newer technique, multifocal VEP, measures responses from 120 individual sectors within each affected eye and is more sensitive than routine VEP. Brainstem auditory evoked potentials (BAEPs) are elicited by monaural stimulation with repetitive clicks and are recorded between the vertex of the scalp and the mastoid process or earlobe. A series of potentials, designated by roman numerals, occurs in the first 10 ms after the stimulus and represents in part the sequential activation of different structures in the pathway between the auditory nerve (wave


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InternalMed_Harrison. I) and the inferior colliculus (wave V) in the midbrain. The presence, latency, and interpeak latency of the first five positive potentials recorded at the vertex are evaluated. The findings are helpful in screening for acoustic neuromas, detecting brainstem pathology, and evaluating comatose patients. The BAEPs are often normal in coma due to metabolic/toxic disorders or bihemispheric disease but are typically abnormal in the presence of brainstem pathology. Somatosensory evoked potentials (SSEPs) are recorded over the scalp 442e-3 and spine in response to electrical stimulation of a peripheral (mixed or cutaneous) nerve. The configuration, polarity, and latency of the responses depend on the nerve that is stimulated and on the recording arrangements. SSEPs are used to evaluate proximal (otherwise inaccessible) portions of the peripheral nervous system and the integrity of the central somatosensory pathways, especially in patients who are comatose or suspected to be brain dead.


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InternalMed_Harrison. Clinical utility of EPs EP studies may detect and localize lesions in afferent pathways in the central nervous system (CNS). They have been used particularly to investigate patients with suspected multiple sclerosis (MS), the diagnosis of which requires the recognition of multifocal white-matter lesions. In patients with clinical evidence of a single lesion, the electrophysiologic recognition of abnormalities in other sites helps to support the diagnosis but does not establish it unequivocally. Multimodality EP abnormalities are not specific for MS; they may occur in AIDS, Lyme disease, systemic lupus erythematosus, neurosyphilis, spinocerebellar degenerations, familial spastic paraplegia, and deficiency of vitamin E or B12, among other disorders. The diagnostic utility of the EP findings therefore depends on the circumstances in which they are found. Abnormalities may aid in the localization of lesions to broad areas of the CNS, but attempts at precise localization may be misleading


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InternalMed_Harrison. therefore depends on the circumstances in which they are found. Abnormalities may aid in the localization of lesions to broad areas of the CNS, but attempts at precise localization may be misleading because the generators of many components are unknown.


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InternalMed_Harrison. The EP findings are sometimes of prognostic relevance. Bilateral loss of cortically generated SSEP components implies that cognition may not be regained in posttraumatic or postanoxic coma, and EP studies may also be useful in evaluating patients with suspected brain death. In patients who are comatose for uncertain reasons, preserved BAEPs suggest either a metabolic-toxic etiology or bihemispheric disease. In patients with spinal cord injuries, SSEPs have been used to indicate the completeness of the lesion. The presence or early return of a cortically generated response to stimulation of a nerve below the injured segment of the cord indicates an incomplete lesion and thus a better prognosis for functional recovery than otherwise. In surgery, intraoperative EP monitoring of neural structures placed at risk by the procedure may permit the early recognition of dysfunction and thereby permit a neurologic complication to be averted or minimized.


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InternalMed_Harrison. Visual and auditory acuity may be determined using EP techniques in patients whose age or mental state precludes traditional ophthalmologic or audiologic examinations.


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InternalMed_Harrison. Certain EP components depend on the mental attention of the subject and the setting in which the stimulus occurs, rather than simply on the physical characteristics of the stimulus. Such “event-related” potentials (ERPs) or “endogenous” potentials are related in some manner to the cognitive aspects of distinguishing an infrequently occurring target stimulus from other stimuli occurring more frequently. For clinical purposes, attention has been directed particularly at the so-called P3 component of the ERP, which is also designated the P300 component because of its positive polarity and latency of approximately 300–400 ms after onset of an auditory target stimulus. The P3 component is prolonged in latency in many patients with dementia, whereas it is generally normal in patients with depression or other disorders simulating dementia. ERPs are, therefore, sometimes helpful in making this distinction when there is clinical uncertainty, although a response of normal latency does not


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InternalMed_Harrison. depression or other disorders simulating dementia. ERPs are, therefore, sometimes helpful in making this distinction when there is clinical uncertainty, although a response of normal latency does not exclude dementia.


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InternalMed_Harrison. The electrical potentials recorded from muscle or the spinal cord following stimulation of the motor cortex or central motor pathways are referred to as motor evoked potentials. For clinical purposes, such responses are recorded most often as the compound muscle action potentials elicited by transcutaneous magnetic stimulation of the motor cortex. A strong but brief magnetic field is produced by passing a current through a coil, and this induces stimulating currents in the subjacent neural tissue. The procedure is painless and apparently safe. CHAPTER 442e Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG


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InternalMed_Harrison. CHAPTER 442e Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG Abnormalities have been described in several neurologic disorders with clinical or subclinical involvement of central motor pathways, including MS and motor neuron disease. In addition to a possible role in diagnosis or evaluating the extent of pathologic involvement, the technique provides information of prognostic relevance (e.g., in suggesting the likelihood of recovery of motor function after stroke) and provides a means of monitoring intraoperatively the functional integrity of central motor tracts. Nevertheless, it is not used widely for clinical purposes.


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InternalMed_Harrison. The motor unit is the basic element subserving motor function. It is defined as an anterior horn cell, its axon and neuromuscular junctions, and all the muscle fibers innervated by the axon. The number of motor units in a muscle ranges from approximately 10 in the extraocular muscles to several thousand in the large muscles of the legs. There is considerable variation in the average number of muscle fibers within the motor units of an individual muscle, i.e., in the innervation ratio of different muscles. Thus the innervation ratio is <25 in the human external rectus or platysma muscle and between 1600 and 1700 in the medial head of the gastrocnemius muscle. The muscle fibers of individual motor units are divided into two general types by distinctive contractile properties, histochemical stains, and characteristic responses to fatigue. Within each motor unit, all of the muscle fibers are of the same type.


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InternalMed_Harrison. The pattern of electrical activity in muscle, i.e., the electromyogram (EMG), may be recorded both at rest and during activity from a needle electrode inserted into the muscle. The nature and pattern of abnormalities relate to disorders at different levels of the motor unit.


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InternalMed_Harrison. Relaxed muscle normally is electrically silent except in the end-plate region, but abnormal spontaneous activity (Fig. 442e-3) occurs in various neuromuscular disorders, especially those associated with denervation or inflammatory changes in affected muscle. Fibrillation potentials and positive sharp waves (which reflect muscle fiber irritability) and complex repetitive discharges are most often—but not always—found in denervated muscle and may also occur after muscle injury and in certain myopathic disorders, especially inflammatory disorders such as polymyositis. After an acute neuropathic lesion, they occur earlier in proximal than distal muscles and sometimes do not develop distally in the extremities for 4–6 weeks; once present, they may persist indefinitely unless reinnervation occurs or the muscle degenerates so completely that no viable tissue remains. Fasciculation potentials


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InternalMed_Harrison. FIGuRE 442e-3 Activity recorded during electromyography (EMG). A. Spontaneous fibrillation potentials and positive sharp waves. B. Complex repetitive discharges recorded in partially denervated muscle at rest. C. Normal triphasic motor unit action potential. D. Small, short-duration, polyphasic motor unit action potential such as is commonly encountered in myopathic disorders. E. Long-duration polyphasic motor unit action potential such as may be seen in chronic neuropathic disorders.


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InternalMed_Harrison. (which reflect the spontaneous activity of individual motor units) are characteristic of slowly progressive neuropathic disorders, especially those with degeneration of anterior horn cells (such as amyotrophic lateral sclerosis). Myotonic discharges—high-frequency discharges of potentials derived from single muscle fibers that wax and wane in amplitude and frequency—are the signature of myotonic disorders such as myotonic dystrophy or myotonia congenita but occur occasionally in polymyositis or other, rarer, disorders.


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InternalMed_Harrison. Slight voluntary contraction of a muscle leads to activation of a small number of motor units. The potentials generated by muscle fibers of these units that are within the pickup range of the needle electrode will be recorded (Fig. 442e-3). The parameters of normal motor unit action potentials depend on the muscle under study and age of the patient, but their duration is normally between 5 and 15 ms, amplitude is between 200 μV and 2 mV, and most are bior triphasic. The number of units activated depends on the degree of voluntary activity. An increase in muscle contraction is associated with an increase in the number of motor units that are activated (recruited) and in the frequency of discharge. With a full contraction, so many motor units are normally activated that individual motor unit action potentials can no longer be distinguished, and a complete interference pattern is said to have been produced.


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InternalMed_Harrison. The incidence of small, short-duration, polyphasic motor unit action potentials (i.e., having more than four phases) is usually increased in myopathic muscle, and an excessive number of units is activated for a specified degree of voluntary activity. By contrast, the loss of motor units that occurs in neuropathic disorders leads to a reduction in number of units activated during a maximal contraction and an increase in their firing rate, i.e., there is an incomplete or reduced interference pattern. The configuration and dimensions of the potentials may also be abnormal, depending on the duration of the neuropathic process. The surviving motor units are initially normal in configuration but, as reinnervation occurs, they increase in amplitude and duration and become polyphasic (Fig. 442e-3).


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InternalMed_Harrison. Action potentials from the same motor unit sometimes fire with a consistent temporal relationship to each other, so that double, triple, or multiple discharges are recorded, especially in tetany, hemifacial spasm, or myokymia. Electrical silence characterizes the involuntary, sustained muscle contraction that occurs in phosphorylase deficiency, which is designated a contracture. EMG enables disorders of the motor units to be detected and characterized as either neurogenic or myopathic. In neurogenic disorders, the pattern of affected muscles may localize the lesion to the anterior horn cells or to a specific site as the axons traverse a nerve root, limb plexus, and peripheral nerve to their terminal arborizations. The findings do not enable a specific etiologic diagnosis to be made, however, except in conjunction with the clinical findings and results of other laboratory studies.


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InternalMed_Harrison. The findings may provide a guide to the severity of an acute disorder of a peripheral or cranial nerve (by indicating whether denervation has occurred and the completeness of the lesion) and whether the pathologic process is active or progressive in chronic or degenerative disorders such as amyotrophic lateral sclerosis. Such information is important for prognostic purposes.


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InternalMed_Harrison. Various quantitative EMG approaches have been developed. The most common is to determine the mean duration and amplitude of 20 motor unit action potentials using a standardized technique. The technique of macro-EMG provides information about the number and size of muscle fibers in a larger volume of the motor unit territory and has also been used to estimate the number of motor units in a muscle. Scanning EMG is a computer-based technique that has been used to study the topography of motor unit action potentials and, in particular, the spatial and temporal distribution of activity in individual units. The technique of single-fiber EMG is discussed separately below. Recording of the electrical response of a muscle to stimulation of its motor nerve at two or more points along its course (Fig. 442e-4)


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InternalMed_Harrison. FIGuRE 442e-4 Arrangement for motor conduction studies of the ulnar nerve. Responses are recorded with a surface electrode from the abductor digiti minimi muscle to supramaximal stimulation of the nerve at different sites, and are shown in the lower panel. (From MJ Aminoff: Electromyography in Clinical Practice: Electrodiagnostic Aspects of Neuromuscular Disease, 3rd ed. New York, Churchill Livingstone, 1998.) permits conduction velocity to be determined in the fastest conducting motor fibers between the points of stimulation. The latency and amplitude of the electrical response of muscle (i.e., of the compound muscle action potential) to stimulation of its motor nerve at a distal site are also compared with values defined in normal subjects. Sensory nerve conduction studies are performed by determining the conduction velocity and amplitude of action potentials in sensory fibers when these fibers are stimulated at one point and the responses are recorded at another point along the


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InternalMed_Harrison. by determining the conduction velocity and amplitude of action potentials in sensory fibers when these fibers are stimulated at one point and the responses are recorded at another point along the course of the nerve. In adults, conduction velocity in the arms is normally between 50 and 70 m/s, and in the legs is between 40 and 60 m/s.


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InternalMed_Harrison. Nerve conduction studies complement the EMG examination, enabling the presence and extent of peripheral nerve pathology to be determined. They are particularly helpful in determining whether sensory symptoms are arising from pathology proximal or distal to the dorsal root ganglia (in the former instance, peripheral sensory conduction studies is normal) and whether neuromuscular dysfunction relates to peripheral nerve disease. In patients with a mononeuropathy, they are invaluable as a means of localizing a focal nerve lesion, determining the extent and severity of the underlying pathology, providing a guide to prognosis, and detecting subclinical involvement of other nerves. They enable a polyneuropathy to be distinguished from a mononeuropathy multiplex, which has important etiologic implications. Nerve conduction studies provide a means of following the progression and therapeutic response of peripheral nerve disorders and are used widely for this purpose in clinical trials. They


InternalMed_Harrison

InternalMed_Harrison. Nerve conduction studies provide a means of following the progression and therapeutic response of peripheral nerve disorders and are used widely for this purpose in clinical trials. They may suggest the underlying pathologic basis in individual cases. Conduction velocity is often markedly slowed, terminal motor latencies are prolonged, and compound motor and sensory nerve action potentials may be dispersed in the demyelinative neuropathies (such as in Guillain-Barré syndrome, chronic inflammatory polyneuropathy, metachromatic leukodystrophy, or certain hereditary neuropathies); conduction block is frequent in acquired varieties of 442e-5 these neuropathies. By contrast, conduction velocity is normal or slowed only mildly, sensory nerve action potentials are small or absent, and there is EMG evidence of denervation in axonal neuropathies such as occur in association with metabolic or toxic disorders.


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InternalMed_Harrison. The utility and complementary role of EMG and nerve conduction studies are best illustrated by reference to a common clinical problem. Numbness and paresthesias of the little finger and associated wasting of the intrinsic muscles of the hand may result from a spinal cord lesion, C8/T1 radiculopathy, brachial plexopathy (lower trunk or medial cord), or a lesion of the ulnar nerve. If sensory nerve action potentials can be recorded normally at the wrist following stimulation of the digital fibers in the affected finger, the pathology is probably proximal to the dorsal root ganglia (i.e., there is a radiculopathy or more central lesion); absence of the sensory potentials, by contrast, suggests distal pathology. EMG examination will indicate whether the pattern of affected muscles conforms to radicular or ulnar nerve territory or is more extensive (thereby favoring a plexopathy). Ulnar motor conduction studies will generally also distinguish between a radiculopathy (normal findings) and


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InternalMed_Harrison. radicular or ulnar nerve territory or is more extensive (thereby favoring a plexopathy). Ulnar motor conduction studies will generally also distinguish between a radiculopathy (normal findings) and ulnar neuropathy (abnormal findings) and will often identify the site of an ulnar nerve lesion. The nerve is stimulated at several points along its course to determine whether the compound action potential recorded from a distal muscle that it supplies shows a marked alteration in size or area or a disproportionate change in latency, with stimulation at a particular site. The electrophysiologic findings thus permit a definitive diagnosis to be made and specific treatment instituted in circumstances where there is clinical ambiguity.


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InternalMed_Harrison. Stimulation of a motor nerve causes impulses to travel antidromically (i.e., toward the spinal cord) as well as orthodromically (to the nerve terminals). Such antidromic impulses cause a few of the anterior horn cells to discharge, producing a small motor response that occurs considerably later than the direct response elicited by nerve stimulation. The F wave so elicited is sometimes abnormal (absent or delayed) with proximal pathology of the peripheral nervous system, such as a radiculopathy, and may therefore be helpful in detecting abnormalities when conventional nerve conduction studies are normal. In general, however, the clinical utility of F-wave studies has been disappointing, except perhaps in Guillain-Barré syndrome, where they are often absent or delayed.


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InternalMed_Harrison. The H reflex is easily recorded only from the soleus muscle (S1) in normal adults. It is elicited by low-intensity stimulation of the tibial nerve and represents a monosynaptic reflex in which spindle (Ia) afferent fibers constitute the afferent arc and alpha motor axons the efferent pathway. The H reflexes are often absent bilaterally in elderly patients or with polyneuropathies and may be lost unilaterally in S1 radiculopathies. The size of the electrical response of a muscle to supramaximal electrical stimulation of its motor nerve relates to the number of muscle fibers that are activated. Neuromuscular transmission can be tested by several different protocols, but the most helpful is to record with surface electrodes the electrical response of a muscle to supramaximal stimulation of its motor nerve by repetitive (2–3 Hz) shocks delivered before and at selected intervals after a maximal voluntary contraction.


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InternalMed_Harrison. There is normally little or no change in size of the muscle response to repetitive stimulation of a motor nerve at 2–3 Hz with stimuli delivered at intervals after voluntary contraction of the muscle for about 20–30 s, even though preceding activity in the junctional region influences the release of acetylcholine and thus the size of the end-plate potentials elicited by a test stimulus. This is because more acetylcholine is normally released than is required to bring the motor end-plate potentials to the threshold for generating muscle fiber action potentials. In disorders of neuromuscular transmission this safety


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InternalMed_Harrison. CHAPTER 442e Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG factor is reduced. Thus in myasthenia gravis, repetitive stimulation, particularly at a rate of between 2 and 5 Hz, may lead to a depression of neuromuscular transmission, with a decrement in size of the response recorded from affected muscles. Similarly, immediately after a period of maximal voluntary activity, single or repetitive stimuli of the motor nerve may elicit larger muscle responses than before, indicating that more muscle fibers are responding. This postactivation facilitation of neuromuscular transmission is followed by a longer-lasting period of depression, maximal between 2 and 4 min after the conditioning period and lasting for as long as 10 min or so, during which responses are reduced in size.


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InternalMed_Harrison. Decrementing responses to repetitive stimulation at 2–5 Hz are common in myasthenia gravis but may also occur in the congenital myasthenic syndromes (Chap. 461). In Lambert-Eaton myasthenic syndrome, in which there is defective release of acetylcholine at the neuromuscular junction, the compound muscle action potential elicited by a single stimulus is generally very small. With repetitive stimulation at rates of up to 10 Hz, the first few responses may decline in size, but subsequent responses increase. If faster rates of stimulation are used (20–50 Hz), the increment may be dramatic so that the amplitude of compound muscle action potentials eventually reaches a size that is several times larger than the initial response. In patients with botulism, the response to repetitive stimulation is similar to that in Lambert-Eaton myasthenic syndrome, although the findings are somewhat more variable and not all muscles are affected.


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InternalMed_Harrison. This technique is particularly helpful in detecting disorders of neuromuscular transmission. A special needle electrode is placed within a muscle and positioned to record action potentials from two muscle fibers belonging to the same motor unit. The time interval between the two potentials will vary in consecutive discharges; this is called the neuromuscular jitter. The jitter can be quantified as the mean difference between consecutive interpotential intervals and is normally between 10 and 50 μs. This value is increased when neuromuscular transmission is disturbed for any reason, and in some instances impulses in individual muscle fibers may fail to occur because of impulse blocking at the neuromuscular junction. Single-fiber EMG is more sensitive than repetitive nerve stimulation or determination of acetylcholine receptor antibody levels in diagnosing myasthenia gravis.


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InternalMed_Harrison. Single-fiber EMG can also be used to determine the mean fiber density of motor units (i.e., mean number of muscle fibers per motor unit within the recording area) and to estimate the number of motor units in a muscle, but this is of less immediate clinical relevance. Electrical or mechanical stimulation of the supraorbital nerve on one side leads to two separate reflex responses of the orbicularis oculi—an ipsilateral R1 response having a latency of approximately 10 ms and a bilateral R2 response with a latency in the order of 30 ms. The trigeminal and facial nerves constitute the afferent and efferent arcs of the reflex, respectively. Abnormalities of either nerve or intrinsic lesions of the medulla or pons may lead to unior bilateral loss of the response, and the findings may therefore be helpful in identifying or localizing such pathology.


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InternalMed_Harrison. technique of Lumbar puncture Elizabeth Robbins, Stephen L. Hauser In experienced hands, lumbar puncture (LP) is usually a safe proce-dure. Major complications are extremely uncommon but can include cerebral herniation, injury to the spinal cord or nerve roots, hemor-rhage (spinal hematoma), or infection. Minor complications occur 443e with greater frequency and can include backache, post-LP headache, and radicular pain or numbness.


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InternalMed_Harrison. Patients with an altered level of consciousness, a focal neurologic deficit, new-onset seizure, papilledema, or an immunocompromised state are at increased risk for potentially fatal cerebellar or tentorial herniation following LP. Neuroimaging should be obtained in these patients prior to LP to exclude a focal mass lesion or diffuse swelling. Imaging studies should include the spine in patients with symptoms suggesting spinal cord compression, such as back pain, leg weakness, urinary retention, or incontinence. In patients with suspected meningitis who require neuroimaging prior to diagnostic LP, administration of antibiotics, preferably following blood culture, should precede the neuroimaging study. LP should not be performed through infected skin, as organisms can be introduced into the subarachnoid space (SAS).


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InternalMed_Harrison. LP should not be performed through infected skin, as organisms can be introduced into the subarachnoid space (SAS). Patients with coagulation defects including thrombocytopenia are at increased risk of post-LP spinal subdural or epidural hematomas, either of which can produce permanent nerve injury and/or paralysis. If a bleeding disorder is suspected, the platelet count, international normalized ratio (INR), and partial thromboplastin time should be checked prior to LP. There are no data available to assess the safety of LP in patients with low platelet counts; a count of <20,000/μL is considered to be a contraindication to LP. Bleeding complications rarely occur in patients with platelet counts ≥50,000/μL and an INR ≤1.5. Some institutions recommend that the platelet count be >40,000 prior to LP.


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InternalMed_Harrison. There is an increased risk of bleeding complications if an LP is performed in a patient receiving antiplatelet or anticoagulant medications. The risk is further increased when multiple anticoagulant medications are used or when the level of anticoagulation is high. The most common site of bleeding is the epidural space. Symptoms of bleeding following an LP can include a sensory or motor deficit and/ or bowel/bladder dysfunction; back pain occurs less commonly. For serious deficits such as paraparesis, immediate surgical intervention, ideally within 8 h of onset of weakness, is important to minimize permanent disability; surgical intervention after 24 h is associated with a poor outcome.


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InternalMed_Harrison. Only limited data are available to guide decisions about performing LPs in patients receiving anticoagulant drugs. Information about managing antiplatelet and anticoagulation drugs during invasive surgical procedures is often available from the prescribing information provided by the drug manufacturer. Evidence-based guidelines for management of regional anesthetic procedures including spinal and epidural blocks in patients receiving anticoagulation have been developed by the American Society of Regional Anesthesia and Pain (ASRA); these guidelines can help guide decisions by physicians considering LP in patients receiving anticoagulation. Management of these patients can be complex and needs to consider both the risk of LP-related hemorrhage as well as the risk of reversing therapeutic anticoagulation prior to LP. Guidelines for some commonly used anticoagulants are summarized below.


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InternalMed_Harrison. Unfractionated Heparin, Therapeutic Dosing The ASRA 2010 Practice Advisory recommends discontinuing unfractionated heparin (UFH) 2–4 h prior to removal of spinal or epidural catheters to minimize risk 443e-1 of hematoma. Similar guidelines are reasonable for patients undergoing LP: discontinue UFH 2–4 h prior to LP; document normal partial thromboplastin time (PTT) prior to the procedure; and document a normal platelet count in patients who have received heparin for 4 days or longer because of the risk of heparin-induced thrombocytopenia (HIT). The half-life of heparin is 60–90 min.


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InternalMed_Harrison. Unfractionated Heparin, Prophylactic Dosing There are only a few case reports of spinal hematoma resulting from spinal or epidural anesthetic procedures in patients receiving low-dose subcutaneous UFH; ASRA guidelines state that there is no contraindication to the use of these techniques for anesthesia in patients receiving prophylactic UFH at a dose of 5000 U subcutaneously twice daily. Similarly, LP in patients receiving 5000 U of UFH subcutaneously twice daily is unlikely to cause spinal hematoma. Precautions to minimize risk include the following: document a normal PTT prior to the LP; document a normal platelet count in patients who have received heparin for 4 days or longer; and perform the LP 1–2 h prior to the next heparin dose, when the heparin effect should be minimal.


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InternalMed_Harrison. Low-Molecular-Weight Heparin, Therapeutic Dose (e.g., Enoxaparin 1 mg/kg Subcutaneously q12h) Patients receiving low-molecular-weight heparin (LMWH) are at increased risk of post-LP spinal or epidural hematoma. LMWH dose should be held for at least 24 h before the procedure. Low-Molecular-Weight Heparin, Prophylactic Dose (e.g., Enoxaparin 0.5 mg/kg Subcutaneously q12h) Patients receiving prophylactic-dose LMWH have altered coagulation. ASRA guidelines recommend waiting at least 10–12 h after a prophylactic dose of LMWH before inserting a spinal or epidural catheter to minimize the risk of spinal or epidural hematoma. Similar guidelines are reasonable for patients undergoing LP. Warfarin Spinal puncture is contraindicated during warfarin therapy.


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InternalMed_Harrison. Warfarin Spinal puncture is contraindicated during warfarin therapy. Aspirin and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) ASRA guidelines conclude that use of these drugs does not appear to be associated with an added significant risk of spinal bleeding in patients having spinal or epidural anesthesia. Similarly, LP in patients receiving one of these drugs is unlikely to cause bleeding. Reversal of drug effect on platelet function requires stopping the drug for approximately 10 days for aspirin and for 48 h for NSAIDs. Ticlopidine/Clopidogrel The actual risk of spinal hematoma with these drugs is unknown. Based on drug prescribing information and surgical reviews, ASRA guidelines suggest discontinuing ticlopidine 14 days prior to a spinal or epidural procedure and discontinuing clopidogrel 7 days prior to the procedure. Similar guidelines are reasonable for performing LP. Abciximab, Eptifibatide, and Other Platelet Glycoprotein IIb/IIIa Inhibitors


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InternalMed_Harrison. Abciximab, Eptifibatide, and Other Platelet Glycoprotein IIb/IIIa Inhibitors The actual risk of spinal hematoma with these drugs is unknown. Platelet aggregation remains abnormal for 24–48 h following discontinuation of abciximab and 4–8 h following discontinuation of eptifibatide. ASRA guidelines recommend avoiding spinal or epidural procedures until platelet function is normal. Similar guidelines are reasonable for performing LP. Direct Thrombin Inhibitors (e.g., Argatroban, Bivalirudin) ASRA guidelines recommend against performing spinal or epidural anesthesia in patients receiving thrombin inhibitors. Oral Factor Xa Inhibitor (e.g., Rivaroxaban) Rivaroxaban prescribing information includes a black box warning that epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving spinal or epidural anesthesia or undergoing LP. LP should be avoided in patients receiving this drug.


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InternalMed_Harrison. Anxiety and pain can be minimized prior to beginning the procedure. Anxiety can be allayed by the use of lorazepam, 1–2 mg given PO 30 min prior to the procedure or IV 5 min prior to the procedure. Chapter 443e Technique of Lumbar Puncture Level of the posterior superior iliac crest L3-L4 interspace L5L4L3L5L4L3 FIGURE 443e-1 Proper positioning of a patient in the lateral decubitus position. Note that the shoulders and hips are in a vertical plane; the torso is perpendicular to the bed. (From RP Simon et al [eds]: Clinical Neurology, 7th ed. New York, McGraw-Hill, 2009.) Topical anesthesia can be achieved by the application of a lidocainebased cream. Lidocaine 4% is effective when applied 30 min prior to the procedure; lidocaine/prilocaine requires 60–120 min. The cream should be applied in a thick layer so that it completely covers the skin; an occlusive dressing is used to keep the cream in place.


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InternalMed_Harrison. Proper positioning of the patient is essential. The procedure should be performed on a firm surface; if the procedure is to be performed at the bedside, the patient should be positioned at the edge of the bed and not in the middle. The patient is asked to lie on his or her side, facing away from the examiner, and to “roll up into a ball.” The neck is gently ante-flexed and the thighs pulled up toward the abdomen; the shoulders and pelvis should be vertically aligned without forward or backward tilt (Fig. 443e-1). The spinal cord terminates at approximately the L1 vertebral level in 94% of individuals. In the remaining 6%, the conus extends to the L2–L3 interspace. LP is therefore performed at or below the L3–L4 interspace. A useful anatomic guide is a line drawn between the posterior superior iliac crests, which corresponds closely to the level of the L3–L4 interspace. The interspace is chosen following gentle palpation to identify the spinous processes at each lumbar level.


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InternalMed_Harrison. An alternative to the lateral recumbent position is the seated position. The patient sits at the side of the bed, with feet supported on a chair. The patient is instructed to curl forward, trying to touch the nose to the umbilicus. It is important that the patient not simply lean forward onto a bedside tabletop, as this is not an optimal position for opening up the spinous processes. LP is sometimes more easily performed in obese patients if they are sitting. A disadvantage of the seated position is that measurement of opening pressure is not accurate. In situations in which LP is difficult using palpable spinal landmarks, bedside ultrasound to guide needle placement may be used. In some particularly difficult situations, a computed tomography (CT)-guided needle placement may be necessary.


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InternalMed_Harrison. Once the desired site for needle insertion has been identified, the examiner should put on sterile gloves. A mask is worn if the clinician will be injecting material into the spinal or epidural space to prevent droplet spread of oral flora during the procedure. After cleansing the skin with povidone-iodine or similar disinfectant, the area is draped with a sterile cloth; the needle insertion site is blotted dry using a sterile gauze pad. Proper local disinfection reduces the risk of introducing skin bacteria into the SAS or other sites. Local anesthetic, typically 1% lidocaine, 3–5 mL total, is injected into the subcutaneous tissue; in nonemergency situations, a topical anesthetic cream can be applied (see above). When time permits, pain associated with the injection of lidocaine can be minimized by slow, serial injections, each one progressively deeper than the last, over a period of ~5 min. Approximately 0.5–1 mL of lidocaine is injected at a time; the needle is not usually


InternalMed_Harrison

InternalMed_Harrison. can be minimized by slow, serial injections, each one progressively deeper than the last, over a period of ~5 min. Approximately 0.5–1 mL of lidocaine is injected at a time; the needle is not usually withdrawn between injections. A pause of ~15 s between injections helps to minimize the pain of the subsequent injection. The goal is to inject each mini-bolus of anesthetic into an area of skin that has become numb from the preceding injection. Approximately 5–10 mini-boluses are injected, using a total of ~5 mL of lidocaine.


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InternalMed_Harrison. If possible, the LP should be delayed for 10–15 min following the completion of the injection of anesthetic; this significantly decreases and can even eliminate pain from the procedure. Even a delay of 5 min will help to reduce pain.


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InternalMed_Harrison. The LP needle (typically 20to 22-gauge) is inserted in the midline, midway between two spinous processes, and slowly advanced. The bevel of the needle should be maintained in a horizontal position, parallel to the direction of the dural fibers and with the flat portion of the bevel pointed upward; this minimizes injury to the fibers as the dura is penetrated. When LP is performed in patients who are sitting, the bevel should be maintained in the vertical position. In most adults, the needle is advanced 4–5 cm (1–2 in.) before the SAS is reached; the examiner usually recognizes entry as a sudden release of resistance, a “pop.” If no fluid appears despite apparently correct needle placement, then the needle may be rotated 90°–180°. If there is still no fluid, the stylet is reinserted and the needle is advanced slightly. Some examiners halt needle advancement periodically to remove the stylet and check for flow of cerebrospinal fluid (CSF). If the needle cannot be advanced because it


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InternalMed_Harrison. the needle is advanced slightly. Some examiners halt needle advancement periodically to remove the stylet and check for flow of cerebrospinal fluid (CSF). If the needle cannot be advanced because it hits bone, if the patient experiences sharp radiating pain down one leg, or if no fluid appears (“dry tap”), the needle is partially withdrawn and reinserted at a different angle. If on the second attempt the needle still hits bone (indicating lack of success in introducing it between the spinous processes), then the needle should be completely withdrawn and the patient should be repositioned. The second attempt is sometimes more successful if the patient straightens the spine completely prior to repositioning. The needle can then be reinserted at the same level or at an adjacent one.


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InternalMed_Harrison. Once the SAS is reached, a manometer is attached to the needle and the opening pressure measured. The examiner should look for normal oscillations in CSF pressure associated with pulse and respirations. The upper limit of normal opening pressure with the patient supine is 180 mmH2O in adults but may be as high as 200–250 mmH2O in obese adults.


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InternalMed_Harrison. CSF is allowed to drip into collection tubes; it should not be withdrawn with a syringe. Depending on the clinical indication, fluid is obtained for studies including: (1) cell count with differential; (2) protein and glucose concentrations; (3) culture (bacterial, fungal, mycobacterial, viral); (4) smears (e.g., Gram’s and acid-fast stained smears); (5) antigen tests (e.g., latex agglutination); (6) polymerase chain reaction (PCR) amplification of DNA or RNA of microorganisms (e.g., herpes simplex virus, enteroviruses); (7) antibody levels against microorganisms; (8) immunoelectrophoresis for determination of γ-globulin level and oligoclonal banding; and (9) cytology. Although 15 mL of CSF is sufficient to obtain all of the listed studies, the yield of fungal and mycobacterial cultures and cytology increases when larger volumes are sampled. In general 20–30 mL may be safely removed from adults.


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InternalMed_Harrison. A bloody tap due to penetration of a meningeal vessel (a “traumatic tap”) may result in confusion with subarachnoid hemorrhage (SAH). In these situations a specimen of CSF should be centrifuged immediately after it is obtained; clear supernatant following CSF centrifugation supports the diagnosis of a bloody tap, whereas xanthochromic supernatant suggests SAH. In general, bloody CSF due to the penetration of a meningeal vessel clears gradually in successive tubes, whereas blood due to SAH does not. In addition to SAH, xanthochromic CSF may also be present in patients with liver disease and when the CSF protein concentration is markedly elevated (>1.5–2 g/L [150–200 mg/dL]).


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InternalMed_Harrison. Prior to removing the LP needle, the stylet is reinserted to avoid the possibility of entrapment of a nerve root in the dura as the needle is being withdrawn; entrapment could result in a dural CSF leak, causing headache. Some practitioners question the safety of this maneuver, with its potential risk of causing a needle-stick injury to the examiner. Injury is unlikely, however, given the flexibility of the small-diameter stylet, which tends to bend, rather than penetrate, on contact. Following LP, the patient is customarily positioned in a comfortable, recumbent position for 30–60 min before rising, although this may be unnecessary because it does not appear to affect the development of headache (see below).


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InternalMed_Harrison. The principal complication of LP is headache, occurring in 10–30% of patients. Younger age and female gender are associated with an increased risk of post-LP headache. Headache usually begins within 48 h but may be delayed for up to 12 days. Head pain is dramatically positional; it begins when the patient sits or stands upright; there is relief upon reclining or with abdominal compression. The longer the patient is upright, the longer the latency before head pain subsides. The pain is usually a dull ache but may be throbbing; its location is occipitofrontal. Nausea and stiff neck often accompany headache, and occasionally, patients report blurred vision, photophobia, tinnitus, and vertigo. In more than three-quarters of patients, symptoms completely resolve within a week, but in a minority they can persist for weeks or even months.


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InternalMed_Harrison. Post-LP headache is caused by a drop in CSF pressure related to persistent leakage of CSF at the site where the needle entered the SAS. Loss of CSF volume decreases the brain’s supportive cushion, so that when a patient is upright there is probably dilation and tension placed on the brain’s anchoring structures, the pain-sensitive dural sinuses, resulting in pain. Although intracranial hypotension is the usual explanation for severe LP headache, the syndrome can occur in patients with normal CSF pressure. Because post-LP headache usually resolves without specific treatment, care is largely supportive with oral analgesics (acetaminophen, NSAIDs, opioids [Chap. 18]) and antiemetics. Patients may obtain relief by lying in a comfortable (especially a recumbent or head-down Trendelenburg) position. For some patients, beverages with caffeine can provide temporary pain relief.


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InternalMed_Harrison. For patients with persistent pain, treatment with IV caffeine (500 mg in 500 mL saline administered over 2 h) may be effective; atrial fibrillation is a rare side effect. Alternatively, an epidural blood patch accomplished by injection of 15 mL of autologous whole blood is usually effective; the injection is directed at the epidural space at the level of the initial LP. This procedure is most often performed by a pain specialist or anesthesiologist. The blood patch has an immediate effect, making it unlikely that sealing off a dural hole with blood clot is its sole mechanism of action. The acute benefit may be due to compression of the CSF space by the clot, increasing CSF pressure. Some clinicians reserve epidural blood patch for patients who do not respond to caffeine, while others prefer to use blood patch as initial management for unremitting post-LP symptoms.


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InternalMed_Harrison. Strategies to decrease the incidence of post-LP headache are listed in Table 443e-1. Use of a smaller caliber needle is associated with a lower risk: in one study, the risk of headache following use of a 24to 27-gauge standard (Quincke) needle was 5–12%, compared to 20–40% when a 20-or 22-gauge needle was used. The smallest gauge needles usually require the use of an introducer needle and are associated with a slower CSF flow rate. Use of an “atraumatic” (Sprotte, “pencil Use of small-diameter needle (22-gauge or smaller) Use of atraumatic needle (Sprotte and others) Replacement of stylet prior to removal of needle Insertion of needle with bevel oriented in a cephalad to caudad direction Bed rest (up to 4 h) following LP Supplemental fluids Minimizing the volume of spinal fluid removed Immediate mobilization following LP Abbreviation: LP, lumbar puncture.


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InternalMed_Harrison. Bed rest (up to 4 h) following LP Supplemental fluids Minimizing the volume of spinal fluid removed Immediate mobilization following LP Abbreviation: LP, lumbar puncture. FIGURE 443e-2 Comparison of the standard (“cutting” or Quincke) lumbar puncture (LP) needle with the “atraumatic” (Sprotte). The “atraumatic” needle has its opening on the top surface of the needle, a design intended to reduce the chance of cutting dural fibers that, by protruding through the dura, could be responsible for subsequent cerebrospinal fluid leak and post-LP headache.


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InternalMed_Harrison. (From SR Thomas et al: BMJ 321:986, 2000.) point,” or “noncutting”) needle also reduces the incidence of moderate to severe headache compared with standard LP (Quincke, or “traumatic”) needles (Fig. 443e-2). However, because atraumatic needles are more difficult to use, more attempts may be required to perform the LP, particularly in overweight patients. It may also be necessary to use an introducer with the atraumatic needle, which does not have the customary cutting, beveled tip. There is a low risk of needle damage, e.g., breakage, with the Sprotte atraumatic needle. Another strategy to decrease the incidence of headache is to replace the stylet before removing the LP needle.


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InternalMed_Harrison. Patients are often advised to remain in a recumbent position for up to an hour following LP. However, studies comparing mobilization immediately following LP with bed rest for periods up to 4 h show no significant differences in the incidence of headache, suggesting that the customary practice of remaining in a recumbent position post-LP may be unnecessary. Chapter 443e Technique of Lumbar Puncture Glucose 2.22–3.89 mmol/L 40–70 mg/dL Lactate 1–2 mmol/L 10–20 mg/dL Total protein Lumbar 0.15–0.5 g/L 15–50 mg/dL Cisternal 0.15–0.25 g/L 15–25 mg/dL Ventricular 0.06–0.15 g/L 6–15 mg/dL Albumin 0.066–0.442 g/L 6.6–44.2 mg/dL IgG 0.009–0.057 g/L 0.9–5.7 mg/dL IgG indexb 0.29–0.59 Oligoclonal bands (OGB) <2 bands not present in


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InternalMed_Harrison. Albumin 0.066–0.442 g/L 6.6–44.2 mg/dL IgG 0.009–0.057 g/L 0.9–5.7 mg/dL IgG indexb 0.29–0.59 Oligoclonal bands (OGB) <2 bands not present in Total 0–5 mononuclear cells per mm3 Differential Lymphocytes 60–70% Monocytes 30–50% Neutrophils None aBecause CSF concentrations are equilibrium values, measurements of the same parameters in blood plasma obtained at the same time are recommended. However, there is a time lag in attainment of equilibrium, and cerebrospinal levels of plasma constituents that can fluctuate rapidly (such as plasma glucose) may not achieve stable values until after a significant lag phase. bIgG index = CSF IgG (mg/dL) × Serum albumin (g/dL)/Serum IgG (g/dL) × CSF albumin (mg/dL).


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InternalMed_Harrison. NORMAL VALUES in centrifuged or concentrated CSF specimens such as those used for cytologic examination. Red blood cells (RBCs) are not normally pres (See Table 443e-2) In uninfected CSF, the normal white blood cell ent in CSF; if RBCs are present from a traumatic tap, their numbercount is fewer than five mononuclear cells (lymphocytes and mono-decreases as additional CSF is collected. CSF glucose concentrationscytes) per μL. Polymorphonuclear leukocytes (PMNs) are not found <2.2 mmol/L (<40 mg/dL) are abnormal. in normal unconcentrated CSF; however, rare PMNs can be found noncoding sequences of DNA. For example, large intronic GGGGCC 444e-1 Biology of Neurologic Diseases repeat expansions in a gene of unknown function C9orf 72 (chromo some 9 open reading frame 72) were recently identified as a common Stephen L. Hauser, Stanley B. Prusiner, M. Flint Beal cause of both frontotemporal dementia and amyotrophic lateral scle-


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InternalMed_Harrison. Stephen L. Hauser, Stanley B. Prusiner, M. Flint Beal cause of both frontotemporal dementia and amyotrophic lateral scle- The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. More than one-third of the 23,000 genes encoded in the human genome are expressed in the nervous system. Each mature brain is composed of 100 billion neurons, several million miles of axons and dendrites, and >1015 synapses. Neurons exist within a dense parenchyma of multifunctional glial cells that synthesize myelin, preserve homeostasis, and regulate immune responses. Measured against this background of complexity, the achievements of molecular neuroscience have been extraordinary. This chapter reviews selected themes in neuroscience that provide a context for understanding fundamental mechanisms underlying neurologic disorders.


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InternalMed_Harrison. The landscape of neurology has been transformed by modern molecular genetics. Several hundred neurologic and psychiatric disorders can now be diagnosed through genetic testing (http://www.ncbi.nlm.nih .gov/sites/GeneTests/?db=GeneTests). The vast majority of these represent highly penetrant mutations that cause rare neurologic disorders; alternatively, they represent rare monogenic causes of common phenotypes. Examples of the latter include mutations of the amyloid precursor protein in familial Alzheimer’s disease, the microtubule-associated protein tau (MAPT) in frontotemporal dementia, and α-synuclein in Parkinson’s disease. These discoveries have been profoundly important because the mutated gene in the familial disorder often encodes a protein that is also pathogenetically involved (although not mutated) in the typical, sporadic form. The common mechanism involves disordered processing and, ultimately, aggregation of the protein leading to cell death (see “Protein Aggregation and


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InternalMed_Harrison. not mutated) in the typical, sporadic form. The common mechanism involves disordered processing and, ultimately, aggregation of the protein leading to cell death (see “Protein Aggregation and Neurodegeneration,” below).


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InternalMed_Harrison. There is optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. Genome-wide association studies (GWAS) have been carried out in many complex neurologic disorders, with many hundreds of variants identified, nearly all of which confer only a small increment in disease risk (1.15to 1.5-fold). GWAS studies are rooted in the “common disease, common variant” hypothesis, as they examine potential risk alleles that are relatively frequent (e.g. >5%) in the general population. More than 1500 GWAS studies have been carried out, with notable successes such as the identification of 110 risk alleles for multiple sclerosis (Chap. 458). Furthermore, using bioinformatics tools, risk variants can be aligned in functional biologic pathways to identify novel pathogenic mechanisms as well as to reveal heterogeneity (e.g., different pathways in different individuals). Despite these successes, many experienced


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InternalMed_Harrison. functional biologic pathways to identify novel pathogenic mechanisms as well as to reveal heterogeneity (e.g., different pathways in different individuals). Despite these successes, many experienced geneticists question the real value of common disease-associated variants, particularly whether they are actually causative or merely mark the approximate locations of more important—truly causative—rare mutations.


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InternalMed_Harrison. This debate has set the stage for the next revolution in human genetics, made possible by the development of increasingly efficient and cost-effective high-throughput sequencing methodologies. It is already possible to sequence an entire human genome in approximately an hour, at a cost of only $1300 for the entire coding sequence (“wholeexome”) or $3000 for the entire genome; it is certain that these costs will continue to decline. This makes it feasible to look for disease-causing sequence variations in individual patients with the possibility of identifying rare variants that cause disease. The utility of this approach was demonstrated by whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy, in which compound heterozygous mutations were identified in the SH3TC2 gene, which then were shown to co-segregate with the disease in other members of the family.


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InternalMed_Harrison. It is increasingly recognized that not all genetic diseases or predispositions are caused by simple changes in the linear nucleotide sequence of genes. Disease-causative mutations also occur commonly in rosis (ALS). This mutation is the most common cause of both familial and sporadic ALS identified thus far. It was shown to be associated with TDP-43 (tar DNA binding protein-43) inclusions in both hippocampal and cerebral neurons. Interestingly, despite the absence of a start codon, the three alternate dipeptide sequences consisting of two amino acids are translated and found in postmortem brain tissue of affected patients. Three potential pathogenic mechanisms have been proposed, including (1) haploinsufficiency, (2) repeat RNA-mediated toxicity, and (3) dipeptide protein toxicity. The possibility of RNA toxicity is supported by the finding of intranuclear RNA foci containing C9orf 72 hexanucleotide repeats and specific RNA-binding proteins. The C9orf 72 mRNA forms quadruplexes of DNA


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InternalMed_Harrison. of RNA toxicity is supported by the finding of intranuclear RNA foci containing C9orf 72 hexanucleotide repeats and specific RNA-binding proteins. The C9orf 72 mRNA forms quadruplexes of DNA and RNA, which then can halt transcription and also bind transcription factors. Mutations in both TARDP (transactive region DNA binding protein) and FUS (fused in sarcoma) also encode DNA/RNA-processing polypeptides and are a cause of familial and sporadic ALS.


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InternalMed_Harrison. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes (“gene-dosage” effects) resulting from unequal crossing-over are also likely to be identified. As much as 5–10% of the human genome consists of nonhomologous duplications and deletions, and these appear to occur with a much higher mutational rate than is the case for single base pair mutations. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (Chap. 459). Gene-dosage effects are causative in some cases of Parkinson’s disease (α-synuclein), Alzheimer’s disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset


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InternalMed_Harrison. Alzheimer’s disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is likely that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also already clear that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders. Deletions at ch444eq and ch15q have been associated with schizophrenia, and deletions at 15q and 16p with autism. Interestingly, the 16p deletion is also associated with epilepsy. Duplications of the X-linked MeCP2 gene cause autism in males and psychiatric disorders with anxiety in females, whereas point mutations in this gene produce the neurodevelopmental disorder


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InternalMed_Harrison. epilepsy. Duplications of the X-linked MeCP2 gene cause autism in males and psychiatric disorders with anxiety in females, whereas point mutations in this gene produce the neurodevelopmental disorder Rett’s syndrome. The understanding of the role of copy number variation in human disease is still in its infancy.


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InternalMed_Harrison. The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10–containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne’s, myotonic, and facioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome, among other disorders. It is also likely that subtle


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InternalMed_Harrison. myotonic, and facioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome, among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. A splicing variant of the interleukin 7 receptor α chain, resulting in production of more soluble and less membrane-bound receptor, is associated with susceptibility to multiple sclerosis (MS) in multiple different populations.


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InternalMed_Harrison. Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary Chapter 444e Biology of Neurologic Diseases genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. Category Disorder Type Mutated Gene Chap. Ref. DNA methylation and methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin are key mediators of these events. Epigenetic Ataxias Episodic ataxia-1 K KCNA1 processes appear to be dynamically active even in post- mitotic neurons. Imprinting refers to an epigenetic fea- Spinocerebellar ataxia-6 Ca CACNL1A ture, present for a subset of genes, in which the predomi-Migraine Familial hemiplegic migraine 1 Ca CACNL1A 447 nant expression of one allele is determined by its parent of origin. The distinctive neurodevelopmental disorders


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InternalMed_Harrison. Epilepsy Benign neonatal familial K KCNQ2, KCNQ3 445 Generalized epilepsy with (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of the chromosome of the critical genetic region 15q11-13 is responsible. In a study of discordant monozygotic twins for MS in which the entire DNA sequence, transcriptome (e.g., mRNA levels), and methylome were assessed genome-wide, tantalizing allelic differences in the use of the paternal, Deafness Jervell and Lange-Nielsen syn-K KCNQ1, KCNE1 43 drome (deafness, prolonged compared to maternal, copy for a group of genes were


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InternalMed_Harrison. QT interval, and arrhythmia) identified. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders. Paraneoplastic Limbic encephalitis Kv1 — 122 Another advance is the development of transgenic mouse models of neurologic diseases, which has been particularly fruitful in producing models relevant to


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InternalMed_Harrison. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS. These models are useful in both studying disease pathogenesis and developing and testing new therapies. New transgenic mouse models with conditional expression have fostered investigations in which late gene epilepsy syndromes, and recently such mutations have been identified. expression avoids developmental compensation or in which the revers-These mutations appear to alter the normal gating function of these ibility of a disease phenotype can be examined by turning a gene off channels, increasing the inherent excitability of neuronal membranes after the disease phenotype has manifested. One can also examine in regions where the abnormal channels are expressed. the effects of gene expression in specific subsets of neurons, such as Whereas the specific clinical manifestations of channelopathies entorhinal cortex, or selectively in neurons, astrocytes, or microglia. are quite variable, one common feature is that


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InternalMed_Harrison. neurons, such as Whereas the specific clinical manifestations of channelopathies entorhinal cortex, or selectively in neurons, astrocytes, or microglia. are quite variable, one common feature is that manifestations tend to Models in both Caenorhabditis elegans and Drosophila have also been be intermittent or paroxysmal, such as occurs in epilepsy, migraine, extremely useful, particularly in studying genetic modifiers and thera-ataxia, myotonia, or periodic paralysis. Exceptions are clinically peutic interventions. progressive channel disorders such as autosomal dominant hearing impairment. The genetic channelopathies identified to date are all uncommon disorders caused by obvious mutations in channel genes.


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InternalMed_Harrison. As the full repertoire of human ion channels and related proteins is The resting potential of neurons and the action potentials responsible identified, it is likely that additional channelopathies will be discovfor impulse conduction are generated by ion currents and ion channels. ered. In addition to rare disorders that result from obvious mutations, Most ion channels are gated, meaning that they can transition between it is also likely that less penetrant allelic variations in channel genes conformations that are open or closed to ion conductance. Individual or in their pattern of expression might underlie susceptibility to some ion channels are distinguished by the specific ions they conduct; by apparently sporadic forms of epilepsy, migraine, or other disorders. their kinetics; and by whether they directly sense voltage, are linked to For example, mutations in the potassium channel gene Kir2.6 have receptors for neurotransmitters or other ligands such as neurotroph-been found in


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InternalMed_Harrison. whether they directly sense voltage, are linked to For example, mutations in the potassium channel gene Kir2.6 have receptors for neurotransmitters or other ligands such as neurotroph-been found in many individuals with thyrotoxic hypokalemic periodic ins, or are activated by second messengers. The diverse characteristics paralysis, a disorder similar to hypokalemic periodic paralysis but preof different ion channels provide a means by which neuronal excitabil-cipitated by stress from thyrotoxicosis or carbohydrate loading. ity can be exquisitely modulated at both the cellular and the subcellular levels. Disorders of ion channels—channelopathies—are responsible for a growing list of human neurologic diseases (Table 444e-1). Most Synaptic neurotransmission is the predominant means by which neuare caused by mutations in ion channel genes or by autoantibodies rons communicate with each other. Classic neurotransmitters are syn-against ion channel proteins. One example is epilepsy, a


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InternalMed_Harrison. which neuare caused by mutations in ion channel genes or by autoantibodies rons communicate with each other. Classic neurotransmitters are syn-against ion channel proteins. One example is epilepsy, a syndrome of thesized in the presynaptic region of the nerve terminal; stored in vesdiverse causes characterized by repetitive, synchronous firing of neu-icles; and released into the synaptic cleft, where they bind to receptors ronal action potentials. Action potentials are normally generated by the on the postsynaptic cell. Secreted neurotransmitters are eliminated by opening of sodium channels and the inward movement of sodium ions reuptake into the presynaptic neuron (or glia), by diffusion away from down the intracellular concentration gradient. Depolarization of the the synaptic cleft, and/or by specific inactivation. In addition to the neuronal membrane opens potassium channels, resulting in outward classic neurotransmitters, many neuropeptides have been identified movement of


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InternalMed_Harrison. and/or by specific inactivation. In addition to the neuronal membrane opens potassium channels, resulting in outward classic neurotransmitters, many neuropeptides have been identified movement of potassium ions, repolarization, closure of the sodium as definite or probable neurotransmitters; these include substance P, channel, and hyperpolarization. Sodium or potassium channel subunit neurotensin, enkephalins, β-endorphin, histamine, vasoactive intesgenes have long been considered candidate disease genes in inherited tinal polypeptide, cholecystokinin, neuropeptide Y, and somatostatin.