Harrison Neurology in Clinical Medicine Second Edition

SECTION I Introduction to Neurology32 junction. Single-fiber EMG is more sensitive than repet- may lead to uni- or bilateral loss of the response, and the itive nerve stimulation or determination of acetylcholine findings may therefore be helpful in identifying or local- receptor antibody levels in diagnosing myasthenia gravis. izing such pathology. Single-fiber EMG can also be used to determine the mean fiber density of motor units (i.e., mean number of FURTHER READINGS muscle fibers per motor unit within the recording area) and to estimate the number of motor units in a muscle, AMINOFF MJ: Electromyography in Clinical Practice: Electrodiagnostic but this is of less immediate clinical relevance. Aspects of Neuromuscular Disease, 3d ed. New York, Churchill Livingstone, 1998 Blink Reflexes ——— (ed): Electrodiagnosis in Clinical Neurology, 5th ed. New York, Electrical or mechanical stimulation of the supraorbital Churchill Livingstone, 2005 nerve on one side leads to two separate reflex responses of the orbicularis oculi—an ipsilateral R1 response hav- BROWN WF et al (eds): Neuromuscular Function and Disease. Philadel- ing a latency of approximately 10 ms and a bilateral R2 phia, Saunders, 2002 response with a latency in the order of 30 ms. The trigeminal and facial nerves constitute the afferent and EBERSOLE JS, PEDLEY TA (eds): Current Practice of Clinical Electroen- efferent arcs of the reflex, respectively. Abnormalities of cephalography, 3d ed. Philadelphia, Lippincott Williams & Wilkins, either nerve or intrinsic lesions of the medulla or pons 2003 HOLMES GL et al: Clinical Neurophysiology of Infancy, Childhood, and Adolescence. Philadelphia, Butterworth Heinemann, 2006 KIMURA J: Electrodiagnosis in Diseases of Nerve and Muscle, 3d ed. New York, Oxford University Press, 2001

CHAPTER 4 LUMBAR PUNCTURE Elizabeth Robbins I Stephen L. Hauser Imaging and Laboratory Studies Prior to LP . . . . . . . . . . . . . . 33 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Post-LP Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Normal Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 In experienced hands, lumbar puncture (LP) is usually a permanent nerve injury and/or paralysis. If a bleeding safe procedure. Major complications are extremely disorder is suspected, the platelet count, international uncommon but can include cerebral herniation, injury normalized ratio (INR), and partial thromboplastin time to the spinal cord or nerve roots, hemorrhage, or infec- should be checked prior to lumbar puncture. There are tion. Minor complications occur with greater frequency no data available to assess the safety of LP in patients and can include backache, post-LP headache, and radic- with low platelet counts; a count of <20,000/μL is con- ular pain or numbness. sidered to be a contraindication to LP. Bleeding compli- cations rarely occur in patients with platelet counts IMAGING AND LABORATORY STUDIES >50,000/μL and an INR ≤1.5. Patients receiving low- PRIOR TO LP molecular-weight heparin are at increased risk of post- LP spinal or epidural hematoma, and doses should be Patients with an altered level of consciousness, a focal held for 24 h before the procedure. neurologic deficit, new-onset seizure, papilledema, or an immunocompromised state are at increased risk for LP should not be performed through infected skin as potentially fatal cerebellar or tentorial herniation fol- organisms can be introduced into the subarachnoid lowing LP. Neuroimaging should be obtained in these space (SAS). patients prior to LP to exclude a focal mass lesion or diffuse swelling. Imaging studies should include the spine ANALGESIA in patients with symptoms suggesting cord compression, such as back pain, leg weakness, urinary retention, or Anxiety and pain can be minimized prior to beginning the incontinence. In patients with suspected meningitis who procedure. Anxiety can be allayed by the use of lorazepam, require neuroimaging prior to diagnostic LP, administra- 1–2 mg given PO 30 min prior to the procedure or IV 5 tion of antibiotics, preferably following blood culture, min prior to the procedure. Topical anesthesia can be should precede the neuroimaging study. achieved by the application of a lidocaine-based cream. Lidocaine 4% is effective when applied 30 min prior to the Patients receiving therapeutic anticoagulation or procedure; lidocaine/prilocaine requires 60–120 min. The those with coagulation defects including thrombocy- cream should be applied in a thick layer so that it com- topenia are at increased risk of post-LP spinal subdural pletely covers the skin; an occlusive dressing is used to keep or epidural hematomas, either of which can produce the cream in place. 33

SECTION I Introduction to Neurology34 POSITIONING After cleansing the skin with povidone-iodine or similar Proper positioning of the patient is essential.The proce- disinfectant, the area is draped with a sterile cloth; the dure should be performed on a firm surface; if the pro- needle insertion site is blotted dry using a sterile gauze cedure is to be performed at the bedside, the patient pad. Proper local disinfection reduces the risk of intro- should be positioned at the edge of the bed and not in ducing skin bacteria into the SAS or other sites. Local the middle.The patient is asked to lie on his or her side, anesthetic, typically 1% lidocaine, 3–5 mL total, is facing away from the examiner, and to “roll up into a injected into the subcutaneous tissue; in nonemergency ball.” The neck is gently ante-flexed and the thighs situations a topical anesthetic cream can be applied (see pulled up toward the abdomen; the shoulders and pelvis above). When time permits, pain associated with the should be vertically aligned without forward or back- injection of lidocaine can be minimized by slow, serial ward tilt (Fig. 4-1). The spinal cord terminates at injections, each one progressively deeper than the last, approximately the L1 vertebral level in 94% of individ- over a period of ~5 min. Approximately 0.5–1 mL of uals. In the remaining 6%, the conus extends to the L2- lidocaine is injected at a time; the needle is not usually L3 interspace. LP is therefore performed at or below withdrawn between injections. A pause of ~15 s the L3-L4 interspace. A useful anatomic guide is a line between injections helps to minimize the pain of the drawn between the posterior superior iliac crests, which subsequent injection. The goal is to inject each mini- corresponds closely to the level of the L3-L4 inter- bolus of anesthetic into an area of skin that has become space. The interspace is chosen following gentle palpa- numb from the preceding injection.Approximately 5–10 tion to identify the spinous processes at each lumbar mini-boluses are injected, using a total of ~5 mL of level. lidocaine. An alternative to the lateral recumbent position is the seated position. The patient sits at the side of the bed, If possible, the LP should be delayed for 10–15 min with feet supported on a chair. The patient is instructed following the completion of the injection of anesthetic; to curl forward, trying to touch the nose to the umbili- this significantly decreases and can even eliminate pain cus. It is important that the patient not simply lean for- from the procedure. Even a delay of 5 min will help to ward onto a bedside table top, as this is not an optimal reduce pain. position for opening up the spinous processes. LP is sometimes more easily performed in obese patients if The LP needle (typically 20- to 22-gauge) is inserted they are sitting. A disadvantage of the seated position is in the midline, midway between two spinous processes, that measurement of opening pressure may not be accu- and slowly advanced. The bevel of the needle should be rate. In situations in which LP is difficult using palpable maintained in a horizontal position, parallel to the direc- spinal landmarks, bedside ultrasound to guide needle tion of the dural fibers and with the flat portion of the placement may be employed. bevel pointed upward; this minimizes injury to the fibers as the dura is penetrated. When lumbar puncture is per- TECHNIQUE formed in patients who are sitting, the bevel should be maintained in the vertical position. In most adults, the Once the desired target for needle insertion has been needle is advanced 4–5 cm (1–2 in.) before the SAS is identified, the examiner should put on sterile gloves. reached; the examiner usually recognizes entry as a sud- den release of resistance, a “pop.” If no fluid appears Vertical alignment of despite apparently correct needle placement, then the shoulders and pelvis needle may be rotated 90°–180°. If there is still no fluid, the stylet is reinserted and the needle is advanced slightly. L3-L4 Some examiners halt needle advancement periodically to Inner space remove the stylet and check for flow of cerebrospinal fluid (CSF). If the needle cannot be advanced because it FIGURE 4-1 hits bone, if the patient experiences sharp radiating pain Proper positioning of a patient in the lateral decubitus posi- down one leg, or if no fluid appears (“dry tap”), the nee- tion. Note that the shoulders and hips are in a vertical plane; dle is partially withdrawn and reinserted at a different the torso is perpendicular to the bed. (From Straus et al.) 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 reposi- tioning. The needle can then be reinserted at the same level or at an adjacent one. 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 are associated with an increased risk of post-LP 35 CHAPTER 4 Lumbar Puncture pressure associated with pulse and respirations. The headache. Headache usually begins within 48 h but may upper limit of normal opening pressure with the patient be delayed for up to 12 days. Head pain is dramatically supine is 180 mm H2O in adults but may be as high as positional; it begins when the patient sits or stands 200–250 mm H2O in obese adults. upright; there is relief upon reclining or with abdominal compression. The longer the patient is upright, the CSF is allowed to drip into collection tubes; it should longer the latency before head pain subsides.The pain is not be withdrawn with a syringe. Depending on the usually a dull ache but may be throbbing; its location is clinical indication, fluid is then obtained for studies occipitofrontal. Nausea and stiff neck often accompany including: (1) cell count with differential, (2) protein and headache, and occasionally, patients report blurred glucose concentrations, (3) culture (bacterial, fungal, vision, photophobia, tinnitus, and vertigo. Symptoms mycobacterial, viral), (4) smears (e.g., Gram’s and acid- usually resolve over a few days but may on occasion per- fast stained smears), (5) antigen tests (e.g., latex aggluti- sist for weeks to months. nation) (6) polymerase chain reaction (PCR) amplification of DNA or RNA of microorganisms (e.g., herpes sim- Post-LP headache is caused by a drop in CSF pressure plex virus, enteroviruses), (7) antibody levels against related to persistent leakage of CSF at the site where the microorganisms, (8) immunoelectrophoresis for deter- needle entered the subarachnoid space. Loss of CSF vol- mination of γ-globulin level and oligoclonal banding, ume decreases the brain’s supportive cushion, so that and (9) cytology. Although 15 mL of CSF is sufficient to when a patient is upright there is probably dilation and obtain all of the listed studies, the yield of fungal and tension placed on the brain’s anchoring structures, the mycobacterial cultures and cytology increases when pain-sensitive dural sinuses, resulting in pain. Although larger volumes are sampled. In general 20–30 mL may intracranial hypotension is the usual explanation for be safely removed from adults. severe LP headache, the syndrome can occur in patients with normal CSF pressure. A bloody tap due to penetration of a meningeal ves- sel (a “traumatic tap”) may result in confusion with Post-LP headache usually resolves without specific subarachnoid hemorrhage (SAH). In these situations a treatment, and care is largely supportive with oral anal- specimen of CSF should be centrifuged immediately gesics [acetaminophen, nonsteroidal anti-inflammatory after it is obtained; clear supernatant following CSF drugs, opioids (Chap. 5)] and antiemetics. Patients may centrifugation supports the diagnosis of a bloody tap, obtain relief by lying in a comfortable position. For whereas xanthochromic supernatant suggests SAH. In some patients beverages with caffeine can provide tem- general, bloody CSF due to the penetration of a porary pain relief. meningeal vessel clears gradually in successive tubes, whereas blood due to SAH does not. In addition to For patients with persistent pain, treatment with IV SAH, xanthochromic CSF may also be present in caffeine (500 mg in 500 mL saline administered over 2 h) patients with liver disease and when the CSF protein may be effective; atrial fibrillation is an uncommon side concentration is markedly elevated [>1.5–2.0 g/L effect. For patients who do not respond to caffeine, an (150–200 mg/dL)]. epidural blood patch accomplished by injection of 15 mL of autologous whole blood is usually effective. Prior to removing the LP needle, the stylet is rein- This procedure is usually performed by a pain specialist serted to avoid the possibility of entrapment of a or anesthesiologist. The mechanism for these treatment nerve root in the dura as the needle is being with- effects is not straightforward. The blood patch has an drawn; entrapment could result in a dural CSF leak, immediate effect, making it unlikely that sealing off a causing headache. Some practitioners question the safety dural hole with blood clot is its sole mechanism of of this maneuver, with its potential risk of causing a action. needle-stick injury to the examiner. Injury is unlikely, however, given the flexibility of the small-diameter Strategies to decrease the incidence of post-LP stylet, which tends to bend, rather than penetrate, on headache are listed in Table 4-1. Use of a smaller cal- contact. Following LP, the patient is customarily posi- iber needle is associated with a lower risk: in one study, tioned in a comfortable, recumbent position for 1 h the risk of headache following use of a 20- or 22-gauge before rising, although recent data suggest that assum- standard (Quinke) needle was 20–40%, compared to 5–12% ing a recumbent position may be unnecessary as it when a 24- to 27-gauge needle was used. The smallest does not appear to affect the development of headache gauge needles usually require the use of an introducer (see below). needle and are associated with a slower CSF flow rate. Use of an “atraumatic” (Sprotte, “pencil point,” or “non- POST-LP HEADACHE cutting”) needle also reduces the incidence of moderate to severe headache compared with standard LP (Quinke, The principal complication of LP is headache, occurring or “traumatic”) needles (Fig. 4-2). However, because in 10–30% of patients. Younger age and female gender atraumatic needles are more difficult to use, more attempts may be required to perform the LP, particularly

36 TABLE 4-1 TABLE 4-2 CEREBROSPINAL FLUIDa REDUCING THE INCIDENCE OF POST-LP HEADACHE SECTION I Introduction to Neurology CONSTITUENT SI UNITS CONVENTIONAL Effective Strategies UNITS Glucose 2.22–3.89 mmol/L 40–70 mg/dL Use of small-diameter needle (22-gauge or smaller) Lactate 1–2 mmol/L 10–20 mg/dL Use of atraumatic needle (Sprotte and others) Total protein Replacement of stylet prior to removal of needle 0.15–0.5 g/L 15–50 mg/dL Insertion of needle with bevel oriented in a cephalad to Lumbar 0.15–0.25 g/L 15–25 mg/dL Cisternal 0.06–0.15 g/L 6–15 mg/dL caudad direction (when using standard needle) Ventricular 0.066–0.442 g/L 6.6–44.2 mg/dL Ineffective Strategies Albumin 0.009–0.057 g/L 0.9–5.7 mg/dL IgG 0.29–0.59 Bed rest (up to 4 h) following LP IgG indexb <2 bands not 25–80 μg/dL Supplemental fluids Oligoclonal 50–180 mm H2O Minimizing the volume of spinal fluid removed present in Immediate mobilization following LP bands (OGB) matched serum 0 sample in overweight patients. It may also be necessary to use Ammonia 15–47 μmol/L an introducer with the atraumatic needle, which does CSF pressure not have the customary cutting, beveled tip. There is a CSF volume ~150 mL low risk of needle damage, e.g., breakage, with the Sprotte atraumatic needle. (adult) 0 Red blood cells Another strategy to decrease the incidence of headache Leukocytes 0–5 mononuclear is to replace the stylet before removing the LP needle. cells per mm3 Studies comparing mobilization immediately following Total LP with bed rest for up to 4 h show no significant dif- 60–70% ferences in the incidence of headache, suggesting that Differential 30–50% the customary practice of remaining in a recumbent posi- Lymphocytes None tion post-LP may be unnecessary. Monocytes Neutrophils NORMAL VALUES aSince cerebrospinal fluid concentrations are equilibrium values, (See Table 4-2) In uninfected CSF, the normal white measurements of the same parameters in blood plasma obtained at blood cell count is fewer than five mononuclear cells the same time are recommended. However, there is a time lag in (lymphocytes and monocytes) per μL. Polymor- attainment of equilibrium, and cerebrospinal levels of plasma con- phonuclear leukocytes (PMNs) are not found in nor- stituents that can fluctuate rapidly (such as plasma glucose) may not mal unconcentrated CSF; however, rare PMNs can be achieve stable values until after a significant lag phase. found in centrifuged or concentrated CSF specimens bIgG index = CSF IgG(mg/dL) × serum albumin(g/dL)/Serum IgG(g/dL) × CSF albumin(mg/dL). such as those utilized for cytologic examination. Red blood cells (RBCs) are not normally present in CSF; if RBCs are present from a traumatic tap, their num- ber decreases as additional CSF is collected. CSF glucose concentrations <2.2 mmol/L (<40 mg/dL) are abnormal. FIGURE 4-2 FURTHER READINGS Comparison of the standard (“traumatic” or Quinke) LP needle with the “atraumatic” (Sprotte). The atraumatic ARMON C, EVANS RW: Addendum to assessment: Prevention of needle has its opening on the top surface of the needle, a post-lumbar puncture headaches: Report of the Therapeutics design intended to reduce the chance of cutting dural fibers and Technology Assessment Subcommittee of the American that, by protruding through the dura, could be responsible Academy of Neurology. Neurology 65:510, 2005 for subsequent CSF fluid leak and post-LP headache. (From Thomas et al.) ELLENBY MS et al: Lumbar puncture (video). N Engl J Med 355:e12, 2006 EVANS RW et al: Assessment: Prevention of post-lumbar puncture headaches: Report of the Therapeutics and Technology Assess- ment Subcommittee of the American Academy of Neurology. Neurology 55:909, 2000

FERRE RM, SWEENEY TW: Emergency physicians can easily obtain STRUPP M et al: Incidence of post-lumbar puncture syndrome 37 CHAPTER 4 Lumbar Puncture ultrasound images of anatomical landmarks relevant to lumbar puncture.Am J Emerg Med 25: 291, 2007 reduced by reinserting the stylet:A randomized prospective study of 600 patients. J Neurol 245:589, 1998 LAVI R et al: Standard vs atraumatic Whitacre needle for diagnostic THOMAS SF et al: Randomised controlled trial of atraumatic versus lumbar puncture: A randomized trial. Neurology 67:1492, 2006 standard needles for diagnostic lumbar puncture. BMJ 321:986, 2000 RICHMAN JM et al: Bevel direction and postdural puncture TURNBULL DK, SHEPHERD DB: Post-dural puncture headache: headache:A meta-analysis. Neurologist 12:224, 2006 Pathogenesis, prevention and treatment. Br J Anaesth 91:718, 2003 STRAUS SE et al: How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis? JAMA 296:2012, 2006

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SECTION II CLINICAL MANIFESTATIONS OF NEUROLOGIC DISEASE

CHAPTER 5 PAIN: PATHOPHYSIOLOGY AND MANAGEMENT Howard L. Fields ■ Joseph B. Martin ■ The Pain Sensory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Peripheral Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Central Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Pain Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 ■ Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 The task of medicine is to preserve and restore health stress response consisting of increased blood pressure, and to relieve suffering. Understanding pain is essential heart rate, pupil diameter, and plasma cortisol levels. In to both these goals. Because pain is universally under- addition, local muscle contraction (e.g., limb flexion, stood as a signal of disease, it is the most common symp- abdominal wall rigidity) is often present. tom that brings a patient to a physician’s attention. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, PERIPHERAL MECHANISMS localizing, and identifying tissue-damaging processes. Since The Primary Afferent Nociceptor different diseases produce characteristic patterns of tissue A peripheral nerve consists of the axons of three different damage, the quality, time course, and location of a patient’s pain complaint and the location of tenderness provide types of neurons: primary sensory afferents, motor neu- important diagnostic clues and are used to evaluate the rons, and sympathetic postganglionic neurons (Fig. 5-1). response to treatment. Once this information is obtained, The cell bodies of primary sensory afferents are located in it is the obligation of the physician to provide rapid and the dorsal root ganglia in the vertebral foramina.The pri- effective pain relief. mary afferent axon bifurcates to send one process into the spinal cord and the other to innervate tissues. Primary affer- ents are classified by their diameter, degree of myelination, THE PAIN SENSORY SYSTEM and conduction velocity. The largest-diameter fibers, A-beta (Aβ), respond maximally to light touch and/or Pain is an unpleasant sensation localized to a part of the moving stimuli; they are present primarily in nerves that body. It is often described in terms of a penetrating or innervate the skin. In normal individuals, the activity of tissue-destructive process (e.g., stabbing, burning, twist- these fibers does not produce pain. There are two other ing, tearing, squeezing) and/or of a bodily or emotional classes of primary afferents: the small-diameter myelinated reaction (e.g., terrifying, nauseating, sickening). Further- A-delta (Aδ) and the unmyelinated (C fiber) axons more, any pain of moderate or higher intensity is accom- (Fig. 5-1). These fibers are present in nerves to the skin panied by anxiety and the urge to escape or terminate and to deep somatic and visceral structures. Some tissues, the feeling.These properties illustrate the duality of pain: such as the cornea, are innervated only by Aδ and C it is both sensation and emotion. When acute, pain is afferents. Most Aδ and C afferents respond maximally only characteristically associated with behavioral arousal and a to intense (painful) stimuli and produce the subjective 40

Dorsal root 41 ganglion Peripheral nerve Spinal cord Aβ Sympathetic CHAPTER 5 Pain: Pathophysiology and Management preganglionic Aδ ganglion. Primary afferents include those with large- C diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmyelinated (C) axons. All sympathetic postganglionic Sympathetic fibers are unmyelinated. postganglionic FIGURE 5-1 Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion, and sympa- thetic postganglionic fibers with cell bodies in the sympathetic experience of pain when they are electrically stimulated; noninflamed tissue. That is, they cannot be activated by this defines them as primary afferent nociceptors (pain known mechanical or thermal stimuli and are not sponta- receptors). The ability to detect painful stimuli is com- neously active. However, in the presence of inflammatory pletely abolished when Aδ and C axons are blocked. mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, Individual primary afferent nociceptors can respond and their characteristic properties may explain how under to several different types of noxious stimuli. For exam- pathologic conditions the relatively insensitive deep struc- ple, most nociceptors respond to heating, intense cold, tures can become the source of severe and debilitating pain intense mechanical stimuli such as a pinch, and applica- and tenderness. Low pH, prostaglandins, leukotrienes, and tion of irritating chemicals including ATP, serotonin, other inflammatory mediators such as bradykinin play a bradykinin and histamine. significant role in sensitization. Sensitization Nociceptor-Induced Inflammation When intense, repeated, or prolonged stimuli are applied Primary afferent nociceptors also have a neuroeffector func- to damaged or inflamed tissues, the threshold for activat- tion. Most nociceptors contain polypeptide mediators ing primary afferent nociceptors is lowered and the fre- that are released from their peripheral terminals when quency of firing is higher for all stimulus intensities. they are activated (Fig. 5-2). An example is substance P, an Inflammatory mediators such as bradykinin, nerve growth 11-amino-acid peptide. Substance P is released from pri- factor, some prostaglandins, and leukotrienes contribute mary afferent nociceptors and has multiple biologic activi- to this process, which is called sensitization. In sensitized ties. It is a potent vasodilator, degranulates mast cells, is a tissues, normally innocuous stimuli can produce pain. chemoattractant for leukocytes, and increases the produc- Sensitization is a clinically important process that con- tion and release of inflammatory mediators. Interestingly, tributes to tenderness, soreness, and hyperalgesia. A strik- depletion of substance P from joints reduces the severity ing example of sensitization is sunburned skin, in which of experimental arthritis. Primary afferent nociceptors are severe pain can be produced by a gentle slap on the not simply passive messengers of threats to tissue injury back or a warm shower. but also play an active role in tissue protection through these neuroeffector functions. Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively CENTRAL MECHANISMS insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate significant discomfort The Spinal Cord and Referred Pain when distended. In contrast, when affected by a disease process with an inflammatory component, deep structures The axons of primary afferent nociceptors enter the spinal such as joints or hollow viscera characteristically become cord via the dorsal root. They terminate in the dorsal exquisitely sensitive to mechanical stimulation. horn of the spinal gray matter (Fig. 5-3). The terminals of primary afferent axons contact spinal neurons that A large proportion of Aδ and C afferents innervating viscera are completely insensitive in normal noninjured,

42 Primary activation Skin SECTION II Clinical Manifestations of Neurologic Disease K+ PG BK H+ Viscus Anterolateral tract axon FIGURE 5-3 A The convergence-projection hypothesis of referred pain. Secondary activation According to this hypothesis, visceral afferent nociceptors con- verge on the same pain-projection neurons as the afferents from the somatic structures in which the pain is perceived. The brain has no way of knowing the actual source of input and mistakenly “projects” the sensation to the somatic structure. Mast cell SP calcitonin gene-related peptide, which produce a slower SP H BK and longer-lasting excitation of the dorsal horn neurons. The axon of each primary afferent contacts many spinal 5HT neurons, and each spinal neuron receives convergent Platelet inputs from many primary afferents. B The convergence of sensory inputs to a single spinal pain-transmission neuron is of great importance because FIGURE 5-2 it underlies the phenomenon of referred pain. All spinal Events leading to activation, sensitization, and spread of neurons that receive input from the viscera and deep sensitization of primary afferent nociceptor terminals. musculoskeletal structures also receive input from the A. Primary activation by intense pressure and consequent cell skin. The convergence patterns are determined by the damage. Cell damage induces lower pH (H+) and leads to spinal segment of the dorsal root ganglion that supplies release of potassium (K+) and to synthesis of prostaglandins the afferent innervation of a structure. For example, the (PG) and bradykinin (BK). Prostaglandins increase the sensitiv- afferents that supply the central diaphragm are derived ity of the terminal to bradykinin and other pain-producing sub- from the third and fourth cervical dorsal root ganglia. stances. B. Secondary activation. Impulses generated in the Primary afferents with cell bodies in these same ganglia stimulated terminal propagate not only to the spinal cord but supply the skin of the shoulder and lower neck. Thus, also into other terminal branches where they induce the release sensory inputs from both the shoulder skin and the cen- of peptides, including substance P (SP). Substance P causes tral diaphragm converge on pain-transmission neurons in vasodilation and neurogenic edema with further accumulation the third and fourth cervical spinal segments. Because of of bradykinin. Substance P also causes the release of hista- this convergence and the fact that the spinal neurons are most mine (H) from mast cells and serotonin (5HT) from platelets. often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the transmit the pain signal to brain sites involved in pain patient to a place that is roughly coextensive with the region of perception.When primary afferents are activated by nox- skin innervated by the same spinal segment. Thus, inflamma- ious stimuli, they release neurotransmitters from their tion near the central diaphragm is usually reported as dis- terminals that excite the spinal cord neurons.The major comfort near the shoulder. This spatial displacement of neurotransmitter they release is glutamate, which rapidly pain sensation from the site of the injury that produces it excites dorsal horn neurons. Primary afferent nociceptor is known as referred pain. terminals also release peptides, including substance P and Ascending Pathways for Pain A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral

F SS dimension of pain. This affective dimension of pain pro- 43 CHAPTER 5 Pain: Pathophysiology and Management C Hypothalamus duces suffering and exerts potent control of behavior. Because of this dimension, fear is a constant companion Thalamus Midbrain of pain. Spinothalamic Medulla PAIN MODULATION tract The pain produced by injuries of similar magnitude is Injury remarkably variable in different situations and in differ- ent individuals. For example, athletes have been known Spinal to sustain serious fractures with only minor pain, and cord Beecher’s classic World War II survey revealed that many AB soldiers in battle were unbothered by injuries that would FIGURE 5-4 have produced agonizing pain in civilian patients. Fur- Pain transmission and modulatory pathways. A. Transmis- thermore, even the suggestion of relief can have a signifi- sion system for nociceptive messages. Noxious stimuli acti- cant analgesic effect (placebo). On the other hand, many vate the sensitive peripheral ending of the primary afferent patients find even minor injuries (such as venipuncture) nociceptor by the process of transduction. The message is frightening and unbearable, and the expectation of pain then transmitted over the peripheral nerve to the spinal cord, has been demonstrated to induce pain without a noxious where it synapses with cells of origin of the major ascending stimulus. pain pathway, the spinothalamic tract. The message is relayed in the thalamus to the anterior cingulate (C), frontal insular (F), The powerful effect of expectation and other psycho- and somatosensory cortex (SS). B. Pain-modulation network. logical variables on the perceived intensity of pain implies Inputs from frontal cortex and hypothalamus activate cells in the existence of brain circuits that can modulate the the midbrain that control spinal pain-transmission cells via activity of the pain-transmission pathways. One of these cells in the medulla. circuits has links in the hypothalamus, midbrain, and medulla, and it selectively controls spinal pain-transmis- thalamus.These axons form the contralateral spinothala- sion neurons through a descending pathway (Fig. 5-4). mic tract, which lies in the anterolateral white matter of the spinal cord, the lateral edge of the medulla, and the Human brain imaging studies have implicated this lateral pons and midbrain. The spinothalamic pathway is pain-modulating circuit in the pain-relieving effect of crucial for pain sensation in humans. Interruption of this attention, suggestion, and opioid analgesic medications. pathway produces permanent deficits in pain and tem- Furthermore, each of the component structures of the perature discrimination. pathway contains opioid receptors and is sensitive to the direct application of opioid drugs. In animals, Spinothalamic tract axons ascend to several regions of lesions of the system reduce the analgesic effect of sys- the thalamus.There is tremendous divergence of the pain temically administered opioids such as morphine. Along signal from these thalamic sites to broad areas of the with the opioid receptor, the component nuclei of this cerebral cortex that subserve different aspects of the pain pain-modulating circuit contain endogenous opioid experience (Fig. 5-4). One of the thalamic projections is peptides such as the enkephalins and β-endorphin. to the somatosensory cortex. This projection mediates the purely sensory aspects of pain, i.e., its location, inten- The most reliable way to activate this endogenous sity, and quality. Other thalamic neurons project to corti- opioid-mediated modulating system is by prolonged pain cal regions that are linked to emotional responses, such as and/or fear.There is evidence that pain-relieving endoge- the cingulate gyrus and other areas of the frontal lobes, nous opioids are released following surgical procedures including the insular cortex.These pathways to the frontal and in patients given a placebo for pain relief. cortex subserve the affective or unpleasant emotional Pain-modulating circuits can enhance as well as suppress pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and control spinal pain-transmission neurons. Since pain-transmission neurons can be activated by modulatory neurons, it is theoretically possible to gener- ate a pain signal with no peripheral noxious stimulus. In fact, human functional imaging studies have demonstrated increased activity in this circuit during migraine headache. A central circuit that facilitates pain could account for the finding that pain can be induced by suggestion or enhanced by expectation, and it could provide a framework for understanding how psychological factors can contribute to chronic pain.

SECTION II Clinical Manifestations of Neurologic Disease44 NEUROPATHIC PAIN rapidly relieved by blocking the sympathetic nervous sys- tem. This implies that sympathetic activity can activate Lesions of the peripheral or central nervous pathways for undamaged nociceptors when inflammation is present. pain typically result in a loss or impairment of pain sen- Signs of sympathetic hyperactivity should be sought in sation. Paradoxically, damage to or dysfunction of these patients with posttraumatic pain and inflammation and pathways can produce pain. For example, damage to no other obvious explanation. peripheral nerves, as occurs in diabetic neuropathy, or to primary afferents, as in herpes zoster, can result in pain Treatment : that is referred to the body region innervated by the ACUTE PAIN damaged nerves.Though rare, pain may also be produced by damage to the central nervous system, particularly the The ideal treatment for any pain is to remove the cause; spinothalamic pathway or thalamus. Such neuropathic thus, diagnosis should always precede treatment plan- pains are often severe and are notoriously intractable to ning. Sometimes treating the underlying condition does standard treatments for pain. not immediately relieve pain. Furthermore, some condi- tions are so painful that rapid and effective analgesia is Neuropathic pains typically have an unusual burning, essential (e.g., the postoperative state, burns, trauma, tingling, or electric shock–like quality and may be trig- cancer, sickle cell crisis). Analgesic medications are a first gered by very light touch.These features are rare in other line of treatment in these cases, and all practitioners types of pain. On examination, a sensory deficit is char- should be familiar with their use. acteristically present in the area of the patient’s pain. Hyperpathia is also characteristic of neuropathic pain; ASPIRIN, ACETAMINOPHEN, AND NONS- patients often complain that the very lightest moving TEROIDAL ANTI-INFLAMMATORY AGENTS stimuli evoke exquisite pain (allodynia). In this regard it (NSAIDS) These drugs are considered together is of clinical interest that a topical preparation of 5% because they are used for similar problems and may have lidocaine in patch form is effective for patients with pos- a similar mechanism of action (Table 5-1). All these com- therpetic neuralgia who have prominent allodynia. pounds inhibit cyclooxygenase (COX), and, except for acetaminophen, all have anti-inflammatory actions, espe- A variety of mechanisms contribute to neuropathic pain. cially at higher dosages. They are particularly effective for As with sensitized primary afferent nociceptors, damaged mild to moderate headache and for pain of muscu- primary afferents, including nociceptors, become highly loskeletal origin. sensitive to mechanical stimulation and begin to generate impulses in the absence of stimulation.There is evidence Since they are effective for these common types of that this increased sensitivity and spontaneous activity is pain and are available without prescription, COX due to an increased concentration of sodium channels. inhibitors are by far the most commonly used analgesics. Damaged primary afferents may also develop sensitivity to They are absorbed well from the gastrointestinal tract norepinephrine. Interestingly, spinal cord pain-transmission and, with occasional use, have only minimal side effects. neurons cut off from their normal input may also become With chronic use, gastric irritation is a common side spontaneously active.Thus, both central and peripheral ner- effect of aspirin and NSAIDs and is the problem that vous system hyperactivity contribute to neuropathic pain. most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause Sympathetically Maintained Pain erosion and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irreversibly Patients with peripheral nerve injury can develop a acetylates platelets and thereby interferes with coagula- severe burning pain (causalgia) in the region innervated tion of the blood, gastrointestinal bleeding is a particular by the nerve. The pain typically begins after a delay of risk. Increased age and history of gastrointestinal disease hours to days or even weeks.The pain is accompanied by increase the risks of aspirin and NSAIDs. In addition to swelling of the extremity, periarticular osteoporosis, and NSAIDs’ well-known gastrointestinal toxicity, nephrotoxi- arthritic changes in the distal joints.The pain is dramati- city is a significant problem for patients using them on a cally and immediately relieved by blocking the sympa- chronic basis, and patients at risk for renal insufficiency thetic innervation of the affected extremity. Damaged should be monitored closely. NSAIDs also cause an primary afferent nociceptors acquire adrenergic sensitiv- increase in blood pressure in a significant number of ity and can be activated by stimulation of the sympa- individuals. Long-term treatment with NSAIDs requires thetic outflow.A similar syndrome called reflex sympathetic regular blood pressure monitoring and treatment if nec- dystrophy can be produced without obvious nerve dam- essary. Although toxic to the liver when taken in a high age by a variety of injuries, including fractures of bone, dose, acetaminophen rarely produces gastric irritation soft tissue trauma, myocardial infarction, and stroke. and does not interfere with platelet function. Although the pathophysiology of this condition is poorly understood, the pain and the signs of inflammation are

TABLE 5-1 45 DRUGS FOR RELIEF OF PAIN GENERIC NAME DOSE, mg INTERVAL COMMENTS Nonnarcotic Analgesics: Usual Doses and Intervals Enteric-coated preparations available Side effects uncommon Acetylsalicylic acid 650 PO q4h Available without prescription CHAPTER 5 Pain: Pathophysiology and Management Acetaminophen 650 PO q4h Delayed effects may be due to long half-life Ibuprofen 400 PO q 4–6 h Contraindicated in renal disease Naproxen 250–500 PO q 12 h Gastrointestinal side effects common Fenoprofen 200 PO q 4–6 h Available for parenteral use Indomethacin 25–50 PO q8h Useful for arthritis Ketorolac 15–60 IM/IV q 4–6 h Removed from U.S. market in 2005 Celecoxib 100–200 PO q 12–24 h Valdecoxib 10–20 PO q 12–24 h GENERIC NAME PARENTERAL DOSE, mg PO DOSE, mg COMMENTS Narcotic Analgesics: Usual Doses and Intervals Codeine 30–60 q 4 h 30–60 q 4 h Nausea common Oxycodone — 5–10 q 4–6 h Usually available with acetaminophen or aspirin Morphine 10 q 4 h 60 q 4 h Morphine sustained — 30–200 bid Oral slow-release preparation release to tid Hydromorphone 1–2 q 4 h 2–4 q 4 h Shorter acting than morphine sulfate Levorphanol 2 q 6–8 h 4 q 6–8 h Longer acting than morphine sulfate; absorbed well PO Methadone 10 q 6–8 h 20 q 6–8 h Delayed sedation due to long half-life Meperidine 75–100 q 3–4 h 300 q 4 h Poorly absorbed PO; normeperidine a toxic metabolite Butorphanol — 1–2 q 4 h Intranasal spray Fentanyl 25–100 μg/h — 72-h Transdermal patch Tramadol — 50–100 q 4–6 h Mixed opioid/adrenergic action UPTAKE BLOCKADE SEDATIVE ANTICHOLINERGIC ORTHOSTATIC CARDIAC AVE. DOSE, RANGE, GENERIC NAME 5-HT NE POTENCY POTENCY HYPOTENSION ARRHYTHMIA mg/d mg/d Antidepressantsa Doxepin ++ + High Moderate Moderate Less 200 75–400 Amitriptyline ++++ ++ High Highest Moderate Yes 150 25–300 Imipramine ++++ ++ Moderate Moderate High Yes 200 75–400 Nortriptyline +++ ++ Moderate Moderate Low Yes 100 40–150 Desipramine +++ ++++ Low Low Low Yes 150 50–300 Venlafaxine +++ ++ Low None None No 150 75–400 Duloxetine +++ +++ Low None None No 40 30–60 GENERIC NAME PO DOSE, mg INTERVAL GENERIC NAME PO DOSE, mg INTERVAL Anticonvulsants and Antiarrhythmicsa daily/qhs Clonazepam 1 q6h q6h Gabapentinb 600–1200 q8h Phenytoin 300 bid Pregabalin 150–600 bid Carbamazepine 200–300 Oxcarbazepine 300 aAntidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treat- ment of pain. bGabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia. Note: 5-HT, serotonin; NE, norepinephrine. The introduction of a parenteral form of NSAID, There are two major classes of COX: COX-1 is constitu- ketorolac, extends the usefulness of this class of com- tively expressed, and COX-2 is induced in the inflamma- pounds in the management of acute severe pain. tory state. COX-2–selective drugs have moderate anal- Ketorolac is sufficiently potent and rapid in onset to gesic potency and produce less gastric irritation than supplant opioids for many patients with acute severe the nonselective COX inhibitors. It is not yet clear headache and musculoskeletal pain. whether the use of COX-2–selective drugs is associated

SECTION II Clinical Manifestations of Neurologic Disease46 with a lower risk of nephrotoxicity compared to nonse- side effects. Because of this, initiation of therapy requires titration to optimal dose and interval. The most impor- lective NSAIDs. On the other hand, COX-2–selective tant principle is to provide adequate pain relief. This drugs offer a significant benefit in the management of requires determining whether the drug has adequately acute postoperative pain because they do not affect relieved the pain and the duration of the relief. The blood coagulation. This is a situation in which the nonse- most common error made by physicians in manag- lective COX inhibitors would be contraindicated because ing severe pain with opioids is to prescribe an inade- they impair platelet-mediated blood clotting and are quate dose. Since many patients are reluctant to thus associated with increased bleeding at the operative complain, this practice leads to needless suffering. In site. COX-2 inhibitors, including celecoxib (Celebrex), and the absence of sedation at the expected time of peak valdecoxib (Bextra), are associated with increased cardio- effect, a physician should not hesitate to repeat the ini- vascular risk. It is possible that this is a class effect of tial dose to achieve satisfactory pain relief. NSAIDs, excluding aspirin. These drugs are contraindi- cated in patients in the immediate period after coronary An innovative approach to the problem of achieving artery bypass surgery and should be used with caution adequate pain relief is the use of patient-controlled anal- in patients having a history of or significant risk factors gesia (PCA). PCA requires a device that can deliver a base- for cardiovascular disease. line continuous dose of an opioid drug, as well as prepro- grammed additional doses whenever the patient pushes OPIOID ANALGESICS Opioids are the most a button. The patient can then titrate the dose to the potent pain-relieving drugs currently available. Further- optimal level. This approach is used most extensively for more, of all analgesics, they have the broadest range of the management of postoperative pain, but there is no efficacy, providing the most reliable and effective reason why it should not be used for any hospitalized method for rapid pain relief. Although side effects are patient with persistent severe pain. PCA is also used for common, they are usually not serious except for respi- short-term home care of patients with intractable pain, ratory depression and can be reversed rapidly with the such as that caused by metastatic cancer. narcotic antagonist naloxone. The physician should not hesitate to use opioid analgesics in patients with acute Because of patient variability in analgesia requirement, severe pain. Table 5-1 lists the most commonly used intravenous PCA is generally begun after the patient’s opioid analgesics. pain has been controlled. The bolus dose of the drug (typically 1 mg morphine or 40 μg fentanyl) can then be Opioids produce analgesia by actions in the central delivered repeatedly as needed. To prevent overdosing, nervous system. They activate pain-inhibitory neurons PCA devices are programmed with a lockout period after and directly inhibit pain-transmission neurons. Most of each demand dose is delivered (5–10 min) and a limit on the commercially available opioid analgesics act at the the total dose delivered per hour.While some have advo- same opioid receptor (μ-receptor), differing mainly in cated the use of a simultaneous background infusion of potency, speed of onset, duration of action, and optimal the PCA drug, this increases the risk of respiratory route of administration. Although the dose-related side depression and has not been shown to increase the effects (sedation, respiratory depression, pruritus, con- overall efficacy of the technique. stipation) are similar among the different opioids, some side effects are due to accumulation of nonopioid Many physicians, nurses, and patients have a certain metabolites that are unique to individual drugs. One trepidation about using opioids that is based on an striking example of this is normeperidine, a metabolite exaggerated fear of addiction. In fact, there is a vanish- of meperidine. Normeperidine produces hyperexcitabil- ingly small chance of patients becoming addicted to ity and seizures that are not reversible with naloxone. narcotics as a result of their appropriate medical use. Normeperidine accumulation is increased in patients with renal failure. The availability of new routes of administration has extended the usefulness of opioid analgesics. Most The most rapid relief with opioids is obtained by important is the availability of spinal administration. intravenous administration; relief with oral administra- Opioids can be infused through a spinal catheter placed tion is significantly slower. Common side effects include either intrathecally or epidurally. By applying opioids nausea, vomiting, constipation, and sedation. The most directly to the spinal cord, regional analgesia can be serious side effect is respiratory depression. Patients with obtained using a relatively low total dose. In this way, any form of respiratory compromise must be kept under such side effects as sedation, nausea, and respiratory close observation following opioid administration; an depression can be minimized. This approach has been oxygen saturation monitor may be useful. The opioid used extensively in obstetric procedures and for lower- antagonist naloxone should be readily available. Opioid body postoperative pain. Opioids can also be given effects are dose-related, and there is great variability intranasally (butorphanol), rectally, and transdermally among patients in the doses that relieve pain and produce (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medication.

The fentanyl transdermal patch has the advantage of physical or sexual abuse; and past or present substance 47 CHAPTER 5 Pain: Pathophysiology and Management providing fairly steady plasma levels, which maximizes abuse. patient comfort. On examination, special attention should be paid to OPIOID AND COX INHIBITOR COMBINA- whether the patient guards the painful area and whether TIONS When used in combination, opioids and COX certain movements or postures are avoided because of pain. inhibitors have additive effects. Because a lower dose of Discovering a mechanical component to the pain can be each can be used to achieve the same degree of pain useful both diagnostically and therapeutically. Painful areas relief, and their side effects are nonadditive, such combi- should be examined for deep tenderness, noting whether nations can be used to lower the severity of dose- this is localized to muscle, ligamentous structures, or related side effects. Fixed-ratio combinations of an opi- joints. Chronic myofascial pain is very common, and in oid with acetaminophen carry a special risk. Dose these patients deep palpation may reveal highly localized escalation as a result of increased severity of pain or trigger points that are firm bands or knots in muscle. decreased opioid effect as a result of tolerance may lead Relief of the pain following injection of local anesthetic to levels of acetaminophen that are toxic to the liver. into these trigger points supports the diagnosis. A neuro- pathic component to the pain is indicated by evidence of CHRONIC PAIN nerve damage, such as sensory impairment, exquisitely sen- sitive skin, weakness and muscle atrophy, or loss of deep Managing patients with chronic pain is intellectually and tendon reflexes. Evidence suggesting sympathetic nervous emotionally challenging. The patient’s problem is often system involvement includes the presence of diffuse swelling, difficult to diagnose; such patients are demanding of the changes in skin color and temperature, and hypersensitive physician’s time and often appear emotionally distraught. skin and joint tenderness compared with the normal side. The traditional medical approach of seeking an obscure Relief of the pain with a sympathetic block is diagnostic. organic pathology is usually unhelpful. On the other hand, psychological evaluation and behaviorally based treatment A guiding principle in evaluating patients with chronic paradigms are frequently helpful, particularly in the setting pain is to assess both emotional and organic factors before of a multidisciplinary pain-management center. initiating therapy. Addressing these issues together, rather than waiting to address emotional issues after organic There are several factors that can cause, perpetuate, or causes of pain have been ruled out, improves compliance in exacerbate chronic pain. First, of course, the patient may part because it assures patients that a psychological evalua- simply have a disease that is characteristically painful for tion does not mean that the physician is questioning the which there is presently no cure. Arthritis, cancer, migraine validity of their complaint. Even when an organic cause for headaches, fibromyalgia, and diabetic neuropathy are exam- a patient’s pain can be found, it is still wise to look for other ples of this. Second, there may be secondary perpetuating factors. For example, a cancer patient with painful bony factors that are initiated by disease and persist after that metastases may have additional pain due to nerve damage disease has resolved. Examples include damaged sensory and may also be depressed. Optimal therapy requires that nerves, sympathetic efferent activity, and painful reflex mus- each of these factors be looked for and treated. cle contraction. Finally, a variety of psychological condi- tions can exacerbate or even cause pain. Treatment: CHRONIC PAIN There are certain areas to which special attention should be paid in the medical history. Because depression is the Once the evaluation process has been completed and most common emotional disturbance in patients with chronic the likely causative and exacerbating factors identified, pain, patients should be questioned about their mood, an explicit treatment plan should be developed. An appetite, sleep patterns, and daily activity.A simple standard- important part of this process is to identify specific and ized questionnaire, such as the Beck Depression Inventory, realistic functional goals for therapy, such as getting a can be a useful screening device. It is important to remember good night’s sleep, being able to go shopping, or return- that major depression is a common, treatable, and poten- ing to work. A multidisciplinary approach that utilizes tially fatal illness. medications, counseling, physical therapy, nerve blocks, and even surgery may be required to improve the Other clues that a significant emotional disturbance is patient’s quality of life. There are also some newer, rela- contributing to a patient’s chronic pain complaint include: tively invasive procedures that can be helpful for some pain that occurs in multiple unrelated sites; a pattern of patients with intractable pain. These procedures include recurrent, but separate, pain problems beginning in child- implanting intraspinal cannulae to deliver morphine or hood or adolescence; pain beginning at a time of emotional intraspinal electrodes for spinal stimulation. There are trauma, such as the loss of a parent or spouse; a history of no set criteria for predicting which patients will respond

SECTION II Clinical Manifestations of Neurologic Disease48 to these procedures. They are generally reserved for that block both serotonin and norepinephrine reuptake, appear to retain most of the pain-relieving effect of patients who have not responded to conventional phar- TCAs with a side-effect profile more like that of the sero- macologic approaches. Referral to a multidisciplinary tonin-selective reuptake inhibitors. These drugs may be pain clinic for a full evaluation should precede any inva- particularly useful in patients who cannot tolerate the sive procedures. Such referrals are clearly not necessary side effects of tricyclics. for all chronic pain patients. For some, pharmacologic management alone can provide adequate relief. ANTICONVULSANTS AND ANTIARRHYTH- MICS These drugs are useful primarily for patients ANTIDEPRESSANT MEDICATIONS The tricyclic with neuropathic pain. Phenytoin (Dilantin) and carba- anti- depressants [amitriptyline, imipramine, nortripty- mazepine (Tegretol) were first shown to relieve the pain line, desipramine (TCAs; Table 5-1)] are extremely useful of trigeminal neuralgia. This pain has a characteristic for the management of patients with chronic pain. brief, shooting, electric shock–like quality. In fact, anti- Although developed for the treatment of depression, the convulsants seem to be helpful largely for pains that tricyclics have a spectrum of dose-related biologic activi- have such a lancinating quality. Newer anticonvulsants, ties that include the production of analgesia in a variety gabapentin (Neurontin) and pregabalin (Lyrica), are of clinical conditions. Although the mechanism is effective for a broad range of neuropathic pains. unknown, the analgesic effect of TCAs has a more rapid onset and occurs at a lower dose than is typically Antiarrhythmic drugs such as low-dose lidocaine and required for the treatment of depression. Furthermore, mexiletine (Mexitil) can also be effective for neuropathic patients with chronic pain who are not depressed obtain pain. These drugs block the spontaneous activity of pain relief with antidepressants. There is evidence that damaged primary afferent nociceptors. tricyclic drugs potentiate opioid analgesia, so they may be useful adjuncts for the treatment of severe persistent CHRONIC OPIOID MEDICATION The long- pain such as occurs with malignant tumors. Table 5-2 term use of opioids is accepted for patients with pain lists some of the painful conditions that respond to tri- due to malignant disease. Although opioid use for cyclics. TCAs are of particular value in the management chronic pain of nonmalignant origin is controversial, it is of neuropathic pain such as occurs in diabetic neuropa- clear that for many such patients opioid analgesics are thy and postherpetic neuralgia, for which there are few the best available option. This is understandable since other therapeutic options. opioids are the most potent and have the broadest range of efficacy of any analgesic medications. The TCAs that have been shown to relieve pain have Although addiction is rare in patients who first use opi- significant side effects (Table 5-1; Chap. 49). Some of oids for pain relief, some degree of tolerance and physi- these side effects, such as orthostatic hypotension, cal dependence are likely with long-term use. Therefore, drowsiness, cardiac conduction delay, memory impair- before embarking on opioid therapy, other options ment, constipation, and urinary retention, are particu- should be explored, and the limitations and risks of opi- larly problematic in elderly patients, and several are oids should be explained to the patient. It is also impor- additive to the side effects of opioid analgesics. The tant to point out that some opioid analgesic medica- serotonin-selective reuptake inhibitors such as fluoxe- tions have mixed agonist-antagonist properties (e.g., tine (Prozac) have fewer and less serious side effects pentazocine and butorphanol). From a practical stand- than TCAs, but they are much less effective for relieving point, this means that they may worsen pain by induc- pain. It is of interest that venlafaxine (Effexor) and dulox- ing an abstinence syndrome in patients who are physi- etine (Cymbalta), which are nontricyclic antidepressants cally dependent on other opioid analgesics. TABLE 5-2 With long-term outpatient use of orally administered opioids, it is desirable to use long-acting compounds such PAINFUL CONDITIONS THAT RESPOND TO as levorphanol, methadone, or sustained-release mor- TRICYCLIC ANTIDEPRESSANTS phine (Table 5-1). Transdermal fentanyl is another excel- lent option. The pharmacokinetic profile of these drug Postherpetic neuralgiaa preparations enables prolonged pain relief, minimizes Diabetic neuropathya side effects such as sedation that are associated with high Tension headachea peak plasma levels, and reduces the likelihood of rebound Migraine headachea pain associated with a rapid fall in plasma opioid concen- Rheumatoid arthritisa,b tration. Constipation is a virtually universal side effect of Chronic low back painb opioid use and should be treated expectantly. Cancer Central post-stroke pain TREATMENT OF NEUROPATHIC PAIN It is important to individualize treatment for patients with aControlled trials demonstrate analgesia. bControlled studies indicate benefit but not analgesia.

neuropathic pain. Several general principles should dependence. Drugs of different classes can be used in 49 guide therapy: the first is to move quickly to provide combination to optimize pain control. relief; a second is to minimize drug side effects. For CHAPTER 5 Pain: Pathophysiology and Management example, in patients with postherpetic neuralgia and It is worth emphasizing that many patients, espe- significant cutaneous hypersensitivity, topical lidocaine cially those with chronic pain, seek medical attention (Lidoderm patches) can provide immediate relief with- primarily because they are suffering and because only out side effects. Anticonvulsants (gabapentin or prega- physicians can provide the medications required for balin, see earlier) or antidepressants can be used as first- pain relief. A primary responsibility of all physicians is to line drugs for patients with neuropathic pain. minimize the physical and emotional discomfort of their Antiarrhythmic drugs such as lidocaine and mexiletene patients. Familiarity with pain mechanisms and anal- can be effective (see earlier). There is no consensus on gesic medications is an important step toward accom- which class of drug should be used as a first-line treat- plishing this aim. ment for any chronically painful condition. However, because relatively high doses of anticonvulsants are FURTHER READINGS required for pain relief, sedation is very common. Seda- tion is also a problem with the tricyclic antidepressants CRAIG AD: How do you feel? Interoception: The sense of the but is much less of a problem with serotonin/norepi- physiological condition of the body. Nat Rev Neurosci 8:655, nephrine reuptake inhibitors (SNRIs, e.g., venlafaxine 2002 and duloxetine). Thus, in the elderly or in those patients whose daily activities require high-level mental activity, FIELDS HL: Should we be reluctant to prescribe opioids for chronic these drugs should be considered as the first line. In nonmalignant pain? Pain 129:233, 2007 contrast, opioid medications should be used as a second- or third-line drug class. While highly effective for many KELTNER JR et al: Isolating the modulatory effect of expectation on painful conditions, opioids are sedating, and their effect pain transmission: A functional magnetic resonance imaging tends to lessen over time, leading to dose escalation study. J Neurosci 26:4437, 2006 and, occasionally, a worsening of pain due to physical MACINTYRE PE: Safety and efficacy of patient-controlled analgesia. Br J Anaesth 87:36, 2001 WAGER TD et al: Placebo-induced changes in FMRI in the anticipa- tion and experience of pain. Science 303:1162, 2004

CHAPTER 6 HEADACHE Peter J. Goadsby I Neil H. Raskin I General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 I Primary Headache Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 52 Anatomy and Physiology of Headache . . . . . . . . . . . . . . . . . . 50 Migraine Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Clinical Evaluation of Acute, New-Onset Headache . . . . . . . . . 51 Tension-Type Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Trigeminal Autonomic Cephalalgias, Including Cluster I Secondary Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Chronic Daily Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Other Primary Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Brain Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Temporal Arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Headache is among the most common reasons that patients other factors (Chap. 5). In such situations, pain perception seek medical attention. Diagnosis and management is based is a normal physiologic response mediated by a healthy on a careful clinical approach that is augmented by an nervous system. Pain can also result when pain-producing understanding of the anatomy, physiology, and pharma- pathways of the peripheral or central nervous system cology of the nervous system pathways that mediate the (CNS) are damaged or activated inappropriately. Headache various headache syndromes. may originate from either or both mechanisms. Relatively few cranial structures are pain-producing; these include GENERAL PRINCIPLES the scalp, middle meningeal artery, dural sinuses, falx cere- bri, and proximal segments of the large pial arteries. The A classification system developed by the International ventricular ependyma, choroid plexus, pial veins, and Headache Society characterizes headache as primary or much of the brain parenchyma are not pain-producing. secondary (Table 6-1). Primary headaches are those in which headache and its associated features are the disor- The key structures involved in primary headache appear der in itself, whereas secondary headaches are those caused to be by exogenous disorders. Primary headache often results in considerable disability and a decrease in the patient’s • the large intracranial vessels and dura mater quality of life. Mild secondary headache, such as that • the peripheral terminals of the trigeminal nerve that seen in association with upper respiratory tract infec- tions, is common but rarely worrisome. Life-threatening innervate these structures headache is relatively uncommon, but vigilance is required • the caudal portion of the trigeminal nucleus, which extends in order to recognize and appropriately treat patients with this category of head pain. into the dorsal horns of the upper cervical spinal cord and receives input from the first and second cervical nerve roots (the trigeminocervical complex) • the pain modulatory systems in the brain that receive input from trigeminal nociceptors ANATOMY AND PHYSIOLOGY OF HEADACHE The innervation of the large intracranial vessels and Pain usually occurs when peripheral nociceptors are stim- dura mater by the trigeminal nerve is known as the trigemi- ulated in response to tissue injury, visceral distension, or novascular system. Autonomic symptoms, such as lacrimation 50

TABLE 6-1 TABLE 6-2 51 COMMON CAUSES OF HEADACHE HEADACHE SYMPTOMS THAT SUGGEST A SERIOUS PRIMARY HEADACHE SECONDARY HEADACHE UNDERLYING DISORDER TYPE % TYPE % “Worst” headache ever CHAPTER 6 Headache First severe headache Migraine 16 Systemic infection 63 Subacute worsening over days or weeks Tension-type 69 Head injury 4 Abnormal neurologic examination Cluster Vascular disorders 1 Fever or unexplained systemic signs Idiopathic 0.1 Subarachnoid Vomiting that precedes headache 2 <1 Pain induced by bending, lifting, cough stabbing hemorrhage Pain that disturbs sleep or presents immediately upon Exertional 1 Brain tumor 0.1 awakening Source: After J Olesen et al: The Headaches. Philadelphia, Lippincott, Known systemic illness Williams & Wilkins, 2005. Onset after age 55 Pain associated with local tenderness, e.g., region of temporal artery and nasal congestion, are prominent in the trigeminal auto- The psychological state of the patient should also be nomic cephalalgias, including cluster headache and parox- evaluated since a relationship exists between head pain ysmal hemicrania, and may also be seen in migraine.These and depression. Many patients in chronic daily pain cycles autonomic symptoms reflect activation of cranial parasym- become depressed, although depression itself is rarely a pathetic pathways, and functional imaging studies indicate cause of headache. Drugs with antidepressant actions are that vascular changes in migraine and cluster headache, also effective in the prophylactic treatment of both when present, are similarly driven by these cranial auto- tension-type headache and migraine. nomic systems. Migraine and other primary headache types are not “vascular headaches”; these disorders do not Underlying recurrent headache disorders may be acti- reliably manifest vascular changes, and treatment outcomes vated by pain that follows otologic or endodontic surgi- cannot be predicted by vascular effects. cal procedures.Thus, pain about the head as the result of diseased tissue or trauma may reawaken an otherwise qui- CLINICAL EVALUATION OF ACUTE, escent migrainous syndrome. Treatment of the headache NEW-ONSET HEADACHE is largely ineffective until the cause of the primary prob- lem is addressed. The patient who presents with a new, severe headache has a differential diagnosis that is quite different from the Serious underlying conditions that are associated with patient with recurrent headaches over many years. In headache are described below. Brain tumor is a rare cause new-onset and severe headache, the probability of find- of headache and even less commonly a cause of severe ing a potentially serious cause is considerably greater pain.The vast majority of patients presenting with severe than in recurrent headache. Patients with recent onset of headache have a benign cause. pain require prompt evaluation and often treatment. Serious causes to be considered include meningitis, sub- SECONDARY HEADACHE arachnoid hemorrhage, epidural or subdural hematoma, glaucoma, and purulent sinusitis. When worrisome The management of secondary headache focuses on symptoms and signs are present (Table 6-2), rapid diag- diagnosis and treatment of the underlying condition. nosis and management is critical. MENINGITIS A complete neurologic examination is an essential first step in the evaluation. In most cases, patients with an abnor- Acute, severe headache with stiff neck and fever suggests mal examination or a history of recent-onset headache meningitis. LP is mandatory. Often there is striking accen- should be evaluated by a CT or MRI study. As an initial tuation of pain with eye movement. Meningitis can be screening procedure for intracranial pathology in this set- easily mistaken for migraine in that the cardinal symptoms ting, CT and MRI methods appear to be equally sensitive. of pounding headache, photophobia, nausea, and vomiting In some circumstances a lumbar puncture (LP) is also are present. Meningitis is discussed in Chaps. 35 and 36. required, unless a benign etiology can be otherwise estab- lished.A general evaluation of acute headache might include INTRACRANIAL HEMORRHAGE the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; eyes by fun- Acute, severe headache with stiff neck but without fever doscopy, intraocular pressure measurement, and refraction; suggests subarachnoid hemorrhage. A ruptured aneurysm, cranial arteries by palpation; and cervical spine by the effect of passive movement of the head and by imaging.

SECTION II Clinical Manifestations of Neurologic Disease52 arteriovenous malformation, or intraparenchymal hem- Most patients can recognize that the origin of their head orrhage may also present with headache alone. Rarely, if pain is superficial, external to the skull, rather than the hemorrhage is small or below the foramen magnum, originating deep within the cranium (the pain site for the head CT scan can be normal. Therefore, LP may be migraineurs). Scalp tenderness is present, often to a required to definitively diagnose subarachnoid hemorrhage. marked degree; brushing the hair or resting the head on Intraparenchymal hemorrhage is discussed in Chap. 21 and a pillow may be impossible because of pain. Headache is subarachnoid hemorrhage in Chap. 22. usually worse at night and often aggravated by exposure to cold. Additional findings may include reddened, ten- BRAIN TUMOR der nodules or red streaking of the skin overlying the temporal arteries, and tenderness of the temporal or, less Approximately 30% of patients with brain tumors consider commonly, the occipital arteries. headache to be their chief complaint. The head pain is usually nondescript—an intermittent deep, dull aching of The erythrocyte sedimentation rate (ESR) is often, moderate intensity, which may worsen with exertion or though not always, elevated; a normal ESR does not change in position and may be associated with nausea and exclude giant cell arteritis. A temporal artery biopsy fol- vomiting.This pattern of symptoms results from migraine lowed by treatment with prednisone 80 mg daily for the far more often than from brain tumor. The headache of first 4–6 weeks should be initiated when clinical suspi- brain tumor disturbs sleep in about 10% of patients.Vomit- cion is high. The prevalence of migraine among the ing that precedes the appearance of headache by weeks is elderly is substantial, considerably higher than that of highly characteristic of posterior fossa brain tumors. A his- giant cell arteritis. Migraineurs often report amelioration tory of amenorrhea or galactorrhea should lead one to of their headaches with prednisone; thus, caution must question whether a prolactin-secreting pituitary adenoma be used when interpreting the therapeutic response. (or the polycystic ovary syndrome) is the source of headache. Headache arising de novo in a patient with GLAUCOMA known malignancy suggests either cerebral metastases or carcinomatous meningitis, or both. Head pain appearing Glaucoma may present with a prostrating headache asso- abruptly after bending, lifting, or coughing can be due to a ciated with nausea and vomiting. The headache often posterior fossa mass (or a Chiari malformation). Brain starts with severe eye pain. On physical examination, the tumors are discussed in Chap. 32. eye is often red with a fixed, moderately dilated pupil. Glaucoma is discussed in Chap. 17. TEMPORAL ARTERITIS PRIMARY HEADACHE SYNDROMES Temporal (giant cell) arteritis is an inflammatory disorder of arteries that frequently involves the extracranial carotid Primary headaches are disorders in which headache and circulation. It is a common disorder of the elderly; its annual associated features occur in the absence of any exoge- incidence is 77 per 100,000 individuals aged 50 years and nous cause (Table 6-1).The most common are migraine, older. The average age of onset is 70 years, and women tension-type headache, and cluster headache. account for 65% of cases. About half of patients with untreated temporal arteritis develop blindness due to MIGRAINE HEADACHE involvement of the ophthalmic artery and its branches; indeed, the ischemic optic neuropathy induced by giant Migraine, the second most common cause of headache, cell arteritis is the major cause of rapidly developing bilat- afflicts approximately 15% of women and 6% of men. It eral blindness in patients >60 years. Because treatment is usually an episodic headache that is associated with with glucocorticoids is effective in preventing this com- certain features such as sensitivity to light, sound, or plication, prompt recognition of the disorder is important. movement; nausea and vomiting often accompany the headache. A useful description of migraine is a benign Typical presenting symptoms include headache, poly- and recurring syndrome of headache associated with myalgia rheumatica, jaw claudication, fever, and weight other symptoms of neurologic dysfunction in varying loss. Headache is the dominant symptom and often admixtures (Table 6-3). Migraine can often be recog- appears in association with malaise and muscle aches. nized by its activators, referred to as triggers. Head pain may be unilateral or bilateral and is located temporally in 50% of patients but may involve any and The brain of the migraineur is particularly sensitive all aspects of the cranium. Pain usually appears gradually to environmental and sensory stimuli; migraine-prone over a few hours before peak intensity is reached; occa- patients do not habituate easily to sensory stimuli. This sionally, it is explosive in onset. The quality of pain is sensitivity is amplified in females during the menstrual only seldom throbbing; it is almost invariably described cycle. Headache can be initiated or amplified by various as dull and boring, with superimposed episodic stabbing triggers, including glare, bright lights, sounds, or other pains similar to the sharp pains that appear in migraine. afferent stimulation; hunger; excess stress; physical

TABLE 6-3 be useful in management strategies involving lifestyle 53 adjustments. SYMPTOMS ACCOMPANYING SEVERE MIGRAINE ATTACKS IN 500 PATIENTS Pathogenesis SYMPTOM PATIENTS AFFECTED, % The sensory sensitivity that is characteristic of migraine CHAPTER 6 Headache is probably due to dysfunction of monoaminergic sen- Nausea 87 sory control systems located in the brainstem and thala- Photophobia 82 mus (Fig. 6-1). Lightheadedness 72 Scalp tenderness 65 Activation of cells in the trigeminal nucleus results in Vomiting 56 the release of vasoactive neuropeptides, particularly cal- Visual disturbances 36 citonin gene-related peptide (CGRP), at vascular termi- 26 nations of the trigeminal nerve. Recently, antagonists of Photopsia 10 CGRP have shown some early promise in the therapy Fortification spectra 33 of migraine. Centrally, the second-order trigeminal neu- Paresthesias 33 rons cross the midline and project to ventrobasal and Vertigo 18 posterior nuclei of the thalamus for further processing. Alteration of consciousness 10 Additionally, there are projections to the periaqueductal Syncope 4 gray and hypothalamus, from which reciprocal descending Seizure 4 systems have established anti-nociceptive effects. Other Confusional state 16 brainstem regions likely to be involved in descending Diarrhea modulation of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla. Source: From NH Raskin, Headache, 2d ed. New York, Churchill Livingston, 1988; with permission. Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also exertion; stormy weather or barometric pressure changes; known as serotonin) in migraine. Approximately 50 years hormonal fluctuations during menses; lack of or excess ago, methysergide was found to antagonize certain peripheral sleep; and alcohol or other chemical stimulation. Knowl- edge of a patient’s susceptibility to specific triggers can Cortex Thalamus Hypothalamus Dorsal raphe nucleus Dura Locus coeruleus Superior salivatory nucleus Magnus raphe nucleus Trigeminal ganglion FIGURE 6-1 Pterygopalatine Brainstem pathways that modulate sensory input. The ganglion key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the project in the quintothalamic tract and, after decussating in trigeminal ganglion and synapses on second-order neurons the brainstem, synapse on neurons in the thalamus. Impor- in the trigeminocervical complex. These neurons in turn tant modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus.

54 SECTION II Clinical Manifestations of Neurologic Disease FIGURE 6-2 Moreover, lateralization of changes in this region of the brain- Positron emission tomography (PET) activation in migraine. stem correlates with lateralization of the head pain in hemicra- In spontaneous attacks of episodic migraine (A) there is activa- nial migraine; the scans shown in panels B and C are of tion of the region of the dorsolateral pons (intersection of dark patients with acute migraine headache on the right and left blue lines); an identical pattern is found in chronic migraine (not side, respectively. (From S Afridi et al: Arch Neurol 62:1270, shown). This area, which includes the noradrenergic locus 2005; Brain 128:932, 2005.) coeruleus, is fundamental to the expression of migraine. actions of 5-HT and was introduced as the first drug FHM 2, are responsible for about 20% of FHM. Muta- capable of preventing migraine attacks. The triptans are tions in the neuronal voltage-gated sodium channel designed to selectively stimulate subpopulations of SCN1A cause FHM 3. Functional neuroimaging has 5-HT receptors; at least 14 different 5-HT receptors exist suggested that brainstem regions in migraine (Fig. 6-2) in humans. The triptans are potent agonists of 5-HT1B, and the posterior hypothalamic gray matter region close 5-HT1D, and 5-HT1F receptors and are less potent at the to the human circadian pacemaker cells of the suprachi- 5-HT1A receptor. A growing body of data indicates that asmatic nucleus in cluster headache (Fig. 6-3) are good the antimigraine efficacy of the triptans relates to their candidates for specific involvement in primary headache. ability to stimulate 5-HT1B/1D receptors, which are located on both blood vessels and nerve terminals. FIGURE 6-3 Posterior hypothalamic gray matter activation on positron Data also support a role for dopamine in the patho- emission tomography (PET) in a patient with acute cluster physiology of certain subtypes of migraine. Most migraine headache. (From A May et al: Lancet 352:275, 1998.) symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawn- ing, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal involvement of ion channels, suggesting that alterations in membrane excitability can predispose to migraine. Mutations involv- ing the Cav2.1 (P/Q) type voltage-gated calcium chan- nel CACNA1A gene are now known to cause FHM 1; this mutation is responsible for about 50% of FHM. Mutations in the Na+-K+ATPase ATP1A2 gene, designated

TABLE 6-4 migraine (see Chronic Daily Headache, below). Migraine 55 must be differentiated from tension-type headache (dis- SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE cussed below), the most common primary headache syn- drome seen in clinical practice. Migraine at its most basic level Repeated attacks of headache lasting 4–72 h in patients is headache with associated features, and tension-type headache is headache that is featureless. Most patients with disabling headache with a normal physical examination, no other reasonable probably have migraine. cause for the headache, and: Patients with acephalgic migraine experience recur- rent neurologic symptoms, often with nausea or vomit- At least 2 of the following Plus at least 1 of the ing, but with little or no headache.Vertigo can be promi- nent; it has been estimated that one-third of patients features: following features: referred for vertigo or dizziness have a primary diagnosis of migraine. Unilateral pain Nausea/vomiting Treatment: Throbbing pain Photophobia and MIGRAINE HEADACHES phonophobia Once a diagnosis of migraine has been established, it is CHAPTER 6 Headache important to assess the extent of a patient’s disease and Aggravation by movement disability.The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool (Fig. 6-4). Moderate or severe intensity Patient education is an important aspect of migraine Source: Adapted from the International Headache Society Classifi- management. Information for patients is available at cation (Headache Classification Committee of the International www.achenet.org, the website of the American Council Headache Society, 2004). for Headache Education (ACHE). It is helpful for patients to understand that migraine is an inherited tendency to Diagnosis and Clinical Features headache; that migraine can be modified and con- trolled by lifestyle adjustments and medications, but it Diagnostic criteria for migraine headache are listed in cannot be eradicated; and that, except in some occasions Table 6-4. A high index of suspicion is required to diag- nose migraine: the migraine aura, consisting of visual dis- turbances with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported in only 20–25% of patients.A headache diary can often be helpful in making the diagnosis; this is also helpful in assessing disability and the frequency of treatment for acute attacks. Patients with episodes of migraine that occur daily or near-daily are considered to have chronic *MIDAS Questionnaire INSTRUCTIONS: Please answer the following questions about ALL headaches you have had over the last 3 months. Write zero if you did not do the activity in the last 3 months. 1. On how many days in the last 3 months did you miss work or school because days of your headaches?............................................................................................... days 2. How many days in the last 3 months was your productivity at work or school days reduced by half or more because of your headaches (do not include days you counted in question 1 where you missed work or school)? ............................ days days 3. On how many days in the last 3 months did you not do household work because of your headaches? ................................................................................ 4. How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches (do not include days you counted in question 3 where you did not do household work)? ..................... 5. On how many days in the last 3 months did you miss family, social, or leisure activities because of your headaches? ................................................................. A. On how many days in the last 3 months did you have a headache? (If a days headache lasted more than one day, count each day.) ......................................... B. On a scale of 0–10, on average how painful were these headaches? (Where 0 = no pain at all, and 10 = pain as bad as it can be.) .......................................... *Migraine Disability Assessment Score (Questions 1−5 are used to calculate the MIDAS score.) Grade I—Minimal or Infrequent Disability: 0–5 Grade II—Mild or Infrequent Disability: 6–10 Grade III—Moderate Disability: 11–20 Grade IV—Severe Disability: > 20 FIGURE 6-4 MIDAS Questionnaire. (From Innovative Medical Research 1997.)

SECTION II Clinical Manifestations of Neurologic Disease56 in women on oral estrogens or contraceptives, migraine attack can be reduced significantly by anti-inflammatory agents (Table 6-5). Indeed, many undiagnosed migraineurs is not associated with serious or life-threatening ill- are self-treated with nonprescription NSAIDs. A general nesses. Recent studies have demonstrated an increased consensus is that NSAIDs are most effective when taken number of cerebellar white matter lesions of uncertain early in the migraine attack. However, the effectiveness of significance in those with migraine with aura. anti-inflammatory agents in migraine is usually less than optimal in moderate or severe migraine attacks. The com- Nonpharmacologic Management Migraine bination of acetaminophen, aspirin, and caffeine has been can often be managed to some degree by a variety of approved for use by the U.S. Food and Drug Administration nonpharmacologic approaches. Most patients benefit (FDA) for the treatment of mild to moderate migraine. The by the identification and avoidance of specific headache combination of aspirin and metoclopramide has been triggers. A regulated lifestyle is helpful, including a shown to be equivalent to a single dose of sumatriptan. healthful diet, regular exercise, regular sleep patterns, Important side effects of NSAIDs include dyspepsia and avoidance of excess caffeine and alcohol, and avoidance gastrointestinal irritation. of acute changes in stress levels. 5-HT1 Agonists The measures that benefit a given individual should Oral Stimulation of 5-HT1B/1D receptors can stop an be used routinely since they provide a simple, cost- acute migraine attack. Ergotamine and dihydroergota- effective approach to migraine management. Patients mine are nonselective receptor agonists, while the trip- with migraine do not encounter more stress than tans are selective 5-HT1B/1D receptor agonists. A variety headache-free individuals; overresponsiveness to stress of triptans (e.g., naratriptan, rizatriptan, eletriptan, suma- appears to be the issue. Since the stresses of everyday triptan, zolmitriptan, almotriptan, frovatriptan) are now living cannot be eliminated, lessening one’s response to available for the treatment of migraine. stress by various techniques is helpful for many patients. These may include yoga, transcendental medi- Each drug in the triptan class has similar pharmaco- tation, hypnosis, and conditioning techniques such as logic properties but varies slightly in terms of clinical biofeedback. For most patients, this approach is, at best, efficacy. Rizatriptan and eletriptan are the most effica- an adjunct to pharmacotherapy. Nonpharmacologic cious of the triptans currently available in the United measures are unlikely to prevent all migraine attacks. States. Sumatriptan and zolmitriptan have similar rates When these measures fail to prevent an attack, pharma- of efficacy as well as time to onset, whereas naratriptan cologic approaches are then needed to abort an attack. and frovatriptan are the slowest-acting and least effica- cious. Clinical efficacy appears to be related more to Acute Attack Therapies for Migraine The the tmax (time to peak plasma level) than to the potency, mainstay of pharmacologic therapy is the judicious use half-life, or bioavailability. This observation is consistent of one or more of the many drugs that are effective in with a large body of data indicating that faster-acting migraine (Table 6-5). The selection of the optimal regi- analgesics are more effective than slower-acting agents. men for a given patient depends on a number of factors, the most important of which is the severity of the Unfortunately, monotherapy with a selective oral 5- attack. Mild migraine attacks can usually be managed by HT1B/1D agonist does not result in rapid, consistent, and oral agents; the average efficacy rate is 50–70%. Severe complete relief of migraine in all patients. Triptans are migraine attacks may require parenteral therapy. Most not effective in migraine with aura unless given after drugs effective in the treatment of migraine are mem- the aura is completed and the headache initiated. Side bers of one of three major pharmacologic classes: anti- effects are common though often mild and transient. inflammatory agents, 5HT1B/1D receptor agonists, and Moreover, 5-HT1B/1D agonists are contraindicated in indi- dopamine receptor antagonists. viduals with a history of cardiovascular and cerebrovas- cular disease. Recurrence of headache is another impor- In general, an adequate dose of whichever agent is tant limitation of triptan use and occurs at least chosen should be used as soon as possible after the occasionally in most patients. onset of an attack. If additional medication is required within 60 min because symptoms return or have not Ergotamine preparations offer a nonselective means abated, the initial dose should be increased for subse- of stimulating 5-HT1 receptors. A nonnauseating dose of quent attacks. Migraine therapy must be individualized; ergotamine should be sought since a dose that pro- a standard approach for all patients is not possible. A vokes nausea is too high and may intensify head pain. therapeutic regimen may need to be constantly refined Except for a sublingual formulation of ergotamine, oral until one is identified that provides the patient with formulations of ergotamine also contain 100 mg caf- rapid, complete, and consistent relief with minimal side feine (theoretically to enhance ergotamine absorption effects (Table 6-6). and possibly to add additional analgesic activity). The average oral ergotamine dose for a migraine attack is 2 mg. Nonsteroidal Anti-Inflammatory Drugs Since the clinical studies demonstrating the efficacy of (NSAIDs) Both the severity and duration of a migraine

TABLE 6-5 57 TREATMENT OF ACUTE MIGRAINE DRUG TRADE NAME DOSAGE Simple Analgesics Excedrin Migraine Two tablets or caplets q6h (max 8 per day) CHAPTER 6 Headache Acetaminophen, aspirin, Aleve, Anaprox, generic 220–550 mg PO bid caffeine Advil, Motrin, Nuprin, 400 mg PO q3–4h generic NSAIDs Clotam Rapid 200 mg PO. May repeat x 1 after 1–2 h Naproxen Ergomar One 2 mg sublingual tablet at onset and q1/2h (max 3 per day, Ibuprofen Ercaf, Wigraine 5 per week) Amerge One or two tablets at onset, then one tablet q1/2h Tolfenamic acid Maxalt (max 6 per day,10 per week) 5-HT1 Agonists Maxalt-MLT 2.5 mg tablet at onset; may repeat once after 4 h Oral Imitrex 5–10 mg tablet at onset; may repeat after 2 h (max 30 mg/d) Ergotamine Frova Axert 50–100 mg tablet at onset; may repeat after 2 h (max 200 mg/d) Ergotamine 1 mg, Relpax 2.5 mg tablet at onset, may repeat after 2 h (max 5 mg/d) caffeine 100 mg Zomig 12.5 mg tablet at onset, may repeat after 2 h (max 25 mg/d) Naratriptan Zomig Rapimelt 40 or 80 mg Rizatriptan Migranal Nasal Spray 2.5 mg tablet at onset; may repeat after 2 h (max 10 mg/d) Imitrex Nasal Spray Sumatriptan Zomig Prior to nasal spray, the pump must be primed 4 times; 1 spray Frovatriptan (0.5 mg) is administered, followed in 15 min by a second spray Almotriptan DHE-45 5–20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg Eletriptan Imitrex Injection spray (may repeat once after 2 h, not to exceed a dose of 40 mg/d) Zolmitriptan 5 mg intranasal spray as one spray (may repeat once after 2 h, Reglan,a generica not to exceed a dose of 10 mg/d) Nasal Compazine,a generica Dihydroergotamine Generica 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week) Reglan,a generic 6 mg SC at onset (may repeat once after 1 h for max of 2 doses Sumatriptan Compazine,a generica in 24 h) Zolmitriptan Midrin, Duradrin, generic 5–10 mg/d 1–25 mg/d Parenteral Stadola Dihydroergotamine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d Sumatriptan 10 mg IV 10 mg IV Dopamine Antagonists Two capsules at onset followed by 1 capsule q1h Oral (max 5 capsules) Metoclopramide Prochlorperazine 1 mg (1 spray in 1 nostril), may repeat if necessary in 1–2 h Parenteral Chlorpromazine Multiple preparations and dosages; see Table 5-1 Metoclopramide Prochlorperazine Other Oral Acetaminophen, 325 mg, plus dichloralphenazone, 100 mg, plus isometheptene, 65 mg Nasal Butorphanol Parenteral Narcotics aNot all drugs are specifically indicated by the FDA for migraine. Local regulations and guidelines should be consulted. Note: Antiemetics (e.g., domperidone 10 mg or ondansetron) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts. NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine.

58 TABLE 6-6 the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min CLINICAL STRATIFICATION OF ACUTE SPECIFIC after intravenous dosing, 30 min after intramuscular MIGRAINE TREATMENTS dosing, and 45 min after subcutaneous dosing. If an attack has not already peaked, subcutaneous or intra- CLINICAL SITUATION TREATMENT OPTIONS muscular administration of 1 mg dihydroergotamine suffices for about 80–90% of patients. Sumatriptan, 6 mg SECTION II Clinical Manifestations of Neurologic Disease Failed NSAIDS/ First tier subcutaneously, is effective in ~70–80% of patients. analgesics Sumatriptan 50 mg or 100 mg PO Almotriptan 12.5 mg PO Dopamine Antagonists Early nausea or Rizatriptan 10 mg PO Oral Oral dopamine antagonists should be consid- difficulties taking Eletriptan 40 mg PO ered as adjunctive therapy in migraine. Drug absorption tablets Zolmitriptan 2.5 mg PO is impaired during migraine because of reduced gas- trointestinal motility. Delayed absorption occurs even in Headache recurrence Slower effect/better tolerability the absence of nausea and is related to the severity of Naratriptan 2.5 mg PO the attack and not its duration. Therefore, when oral Tolerating acute Frovatriptan 2.5 mg PO NSAIDs and/or triptan agents fail, the addition of a treatments poorly dopamine antagonist such as metoclopramide, 10 mg, Infrequent headache should be considered to enhance gastric absorption. In Early vomiting Ergotamine 1–2 mg PO addition, dopamine antagonists decrease nausea/vomit- Dihydroergotamine nasal spray ing and restore normal gastric motility. Menses-related 2 mg headache Parenteral Parenteral dopamine antagonists (e.g., Zolmitriptan 5 mg nasal spray chlorpromazine, prochlorperazine, metoclopramide) can Very rapidly Sumatriptan 20 mg nasal spray also provide significant acute relief of migraine; they can developing Rizatriptan 10 mg MLT wafer be used in combination with parenteral 5-HT1B/1D ago- symptoms Ergotamine 2 mg (most effective nists. A common intravenous protocol used for the treat- PR/usually with caffeine) ment of severe migraine is the administration over Naratriptan 2.5 mg PO 2 min of a mixture of 5 mg of prochlorperazine and Almotriptan 12.5 mg PO 0.5 mg of dihydroergotamine. Eletriptan 40 mg Naratriptan 2.5 mg Other Medications for Acute Migraine Almotriptan 12.5 mg Zolmitriptan 5 mg nasal spray Oral The combination of acetaminophen, dichlo- Sumatriptan 25 mg PR ralphenazone, and isometheptene, one to two capsules, Sumatriptan 6 mg SC has been classified by the FDA as “possibly” effective in Prevention the treatment of migraine. Since the clinical studies demonstrating the efficacy of this combination anal- Ergotamine PO at night gesic in migraine predated the clinical trial methodolo- Estrogen patches gies used with the triptans, it is difficult to compare the Treatment efficacy of this sympathomimetic compound to other Triptans agents. Dihydroergotamine nasal spray Zolmitriptan 5 mg nasal spray Nasal A nasal preparation of butorphanol is available Sumatriptan 6 mg SC for the treatment of acute pain. As with all narcotics, the Dihydroergotamine 1 mg IM use of nasal butorphanol should be limited to a select group of migraineurs, as described below. ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to Parenteral Narcotics are effective in the acute treat- assess the clinical efficacy of ergotamine versus the trip- ment of migraine. For example, intravenous meperidine tans. In general, ergotamine appears to have a much (50–100 mg) is given frequently in the emergency room. higher incidence of nausea than triptans, but less This regimen “works” in the sense that the pain of headache recurrence. migraine is eliminated. However, this regimen is clearly suboptimal for patients with recurrent headache. Nar- Nasal The fastest-acting nonparenteral antimigraine cotics do not treat the underlying headache mecha- therapies that can be self-administered include nasal for- nism; rather, they act to alter the pain sensation. More- mulations of dihydroergotamine (Migranal), zolmitriptan over, in patients taking oral narcotics such as oxycodone (Zomig nasal), or sumatriptan. The nasal sprays result in or hydrocodone, narcotic addiction can greatly confuse substantial blood levels within 30–60 min. Although in theory nasal sprays might provide faster and more effec- tive relief of a migraine attack than oral formulations, their reported efficacy is only ~50–60%. Parenteral Parenteral administration of drugs such as dihydroergotamine and sumatriptan is approved by

the treatment of migraine. Narcotic craving and/or with- adequately with low-dose amitriptyline, propranolol, 59 drawal can aggravate and accentuate migraine. There- topiramate, gabapentin, or valproate. If these agents fail fore, it is recommended that narcotic use in migraine be or lead to unacceptable side effects, second-line agents CHAPTER 6 Headache limited to patients with severe, but infrequent, headaches such as methysergide or phenelzine can be used. Once that are unresponsive to other pharmacologic approaches. effective stabilization is achieved, the drug is continued for 5–6 months and then slowly tapered to assess the Medication-Overuse Headache Acute attack continued need. Many patients are able to discontinue medications, particularly codeine or barbiturate- medication and experience fewer and milder attacks for containing compound analgesics, have a propensity to long periods, suggesting that these drugs may alter the aggravate headache frequency and induce a state of natural history of migraine. refractory daily or near-daily headache called medication- overuse headache. This condition is likely not a separate TENSION-TYPE HEADACHE headache entity but a reaction of the migraine patient to a particular medicine. Migraine patients who have Clinical Features two or more headache days a week should be cautioned about frequent analgesic use (see Chronic Daily The term tension-type headache (TTH) is commonly used Headache, below). to describe a chronic head-pain syndrome characterized by bilateral tight, bandlike discomfort.The pain typically Preventive Treatments for Migraine Patients builds slowly, fluctuates in severity, and may persist more with an increasing frequency of migraine attacks, or or less continuously for many days. The headache may with attacks that are either unresponsive or poorly be episodic or chronic (present >15 days per month). responsive to abortive treatments, are good candidates for preventive agents. In general, a preventive medica- A useful clinical approach is to diagnose TTH in patients tion should be considered in the subset of patients with whose headaches are completely without accompanying five or more attacks a month. Significant side effects are features such as nausea, vomiting, photophobia, phono- associated with the use of many of these agents; fur- phobia, osmophobia, throbbing, and aggravation with thermore, determination of dose can be difficult since movement. Such an approach neatly separates migraine, the recommended doses have been derived for condi- which has one or more of these features and is the main tions other than migraine. The mechanism of action of differential diagnosis, from TTH. However, the Interna- these drugs is unclear; it seems likely that the brain sen- tional Headache Society’s definition of TTH allows an sitivity that underlies migraine is modified. Patients are admixture of nausea, photophobia, or phonophobia in usually started on a low dose of a chosen treatment; the various combinations, illustrating the difficulties in distin- dose is then gradually increased, up to a reasonable guishing these two clinical entities. Patients whose headaches maximum to achieve clinical benefit. fit the TTH phenotype and who have migraine at other times, along with a family history of migraine, migrain- Drugs that have the capacity to stabilize migraine are ous illnesses of childhood, or typical migraine triggers listed in Table 6-7. Drugs must be taken daily, and there to their migraine attacks, may be biologically different is usually a lag of at least 2–12 weeks before an effect is from those who have TTH headache with none of the seen. The drugs that have been approved by the FDA for features. the prophylactic treatment of migraine include propra- nolol, timolol, sodium valproate, topiramate, and methy- Pathophysiology sergide (not available in the United States). In addition, a number of other drugs appear to display prophylactic The pathophysiology of TTH is incompletely understood. efficacy. This group includes amitriptyline, nortriptyline, It seems likely that TTH is due to a primary disorder of flunarizine, phenelzine, gabapentin, topiramate, and CNS pain modulation alone, unlike migraine, which cyproheptadine. Phenelzine and methysergide are usu- involves a more generalized disturbance of sensory modu- ally reserved for recalcitrant cases because of their seri- lation. Data suggest a genetic contribution to TTH, but ous potential side effects. Phenelzine is a monoamine this may not be a valid finding: given the current diagnos- oxidase inhibitor (MAOI); therefore, tyramine-containing tic criteria, the studies undoubtedly included many foods, decongestants, and meperidine are contraindi- migraine patients. The name tension-type headache implies cated. Methysergide may cause retroperitoneal or car- that pain is a product of nervous tension, but there is no diac valvular fibrosis when it is used for >6 months, and clear evidence for tension as an etiology. Muscle contrac- thus monitoring is required for patients using this drug; tion has been considered to be a feature that distinguishes the risk of fibrosis is about 1:1500 and is likely to reverse TTH from migraine, but there appear to be no differences after the drug is stopped. in contraction between the two headache types. The probability of success with any one of the antimi- graine drugs is 50–75%. Many patients are managed

60 TABLE 6-7 PREVENTIVE TREATMENTS IN MIGRAINEa DRUG DOSE SELECTED SIDE EFFECTS Pizotifenb 0.5–2 mg qd Weight gain Drowsiness Beta blocker Propranolol 40–120 mg bid Reduced energy Tiredness SECTION II Clinical Manifestations of Neurologic Disease Postural symptoms Contraindicated in asthma Tricyclics Amitriptyline 10–75 mg at night Drowsiness Dothiepin 25–75 mg at night Nortriptyline 25–75 mg at night Note: Some patients may only need a total dose of 10 mg, although generally 1–1.5 mg/kg body weight is required Anticonvulsants Topiramate 25–200 mg/d Paresthesias Valproate 400–600 mg bid Cognitive symptoms Gabapentin 900–3600 mg qd Weight loss Glaucoma Caution with nephrolithiasis Drowsiness Weight gain Tremor Hair loss Fetal abnormalities Hematologic or liver abnormalities Dizziness Sedation Serotonergic drugs Methysergide 1–4 mg qd Drowsiness Flunarizineb 5–15 mg qd Leg cramps Hair loss Retroperitoneal fibrosis (1-month drug holiday is required every 6 months) Drowsiness Weight gain Depression Parkinsonism No convincing evidence from controlled trials Verapamil Controlled trials demonstrate no effect Nimodipine Clonidine SSRIs: fluoxetine aCommonly used preventives are listed with reasonable doses and common side effects. Not all listed medicines are approved by the FDA; local regulations and guidelines should be consulted. bNot available in the United States.

Treatment: Because of the associated nasal congestion or rhinorrhea, 61 CHAPTER 6 Headache TENSION-TYPE HEADACHE patients are often misdiagnosed with “sinus headache” and treated with decongestants, which are ineffective. The pain of TTH can generally be managed with simple analgesics such as acetaminophen, aspirin, or NSAIDs. TACs must be differentiated from short-lasting head- Behavioral approaches including relaxation can also be aches that do not have prominent cranial autonomic syn- effective. Clinical studies have demonstrated that triptans dromes, notably trigeminal neuralgia, primary stabbing in pure TTH are not helpful, although triptans are effective headache, and hypnic headache.The cycling pattern and in TTH when the patient also has migraine. For chronic length, frequency, and timing of attacks are useful in TTH, amitriptyline is the only proven treatment (Table 6-7); classifying patients. Patients with TACs should undergo other tricyclics, selective serotonin reuptake inhibitors, and pituitary imaging and pituitary function tests as there is the benzodiazepines have not been shown to be effective. an excess of TAC presentations in patients with pituitary There is no evidence for the efficacy of acupuncture. tumor–related headache Placebo controlled trials of botulinum toxin type A in chronic TTH have not shown benefit. Cluster Headache TRIGEMINAL AUTONOMIC CEPHALALGIAS, Cluster headache is a rare form of primary headache INCLUDING CLUSTER HEADACHE with a population frequency of 0.1%. The pain is deep, usually retroorbital, often excruciating in intensity, non- The trigeminal autonomic cephalalgias (TACs) are a group fluctuating, and explosive in quality. A core feature of of primary headaches that includes cluster headache, cluster headache is periodicity. At least one of the daily paroxysmal hemicrania, and SUNCT (short-lasting uni- attacks of pain recurs at about the same hour each day lateral neuralgiform headache attacks with conjunctival for the duration of a cluster bout. The typical cluster injection and tearing). TACs are characterized by rela- headache patient has daily bouts of one to two attacks of tively short-lasting attacks of head pain associated with relatively short-duration unilateral pain for 8–10 weeks cranial autonomic symptoms, such as lacrimation, con- a year; this is usually followed by a pain-free interval that junctival injection, or nasal congestion (Table 6-8). Pain averages 1 year. Cluster headache is characterized as is usually severe and may occur more than once a day. chronic when there is no period of sustained remission. Patients are generally perfectly well between episodes. TABLE 6-8 CLINICAL FEATURES OF THE TRIGEMINAL AUTONOMIC CEPHALALGIAS Gender CLUSTER HEADACHE PAROXYSMAL HEMICRANIA SUNCT Pain F=M F~M M>F Type Throbbing, boring, stabbing Burning, stabbing, sharp Severity Stabbing, boring Excruciating Severe to excruciating Site Excruciating Orbit, temple Periorbital Attack frequency Orbit, temple 1–40/d (>5/d for more than 3–200/d 1/alternate day–8/d half the time) 2–30 min 5–240 s Duration of attack 15–180 min Yes Yes (prominent conjunctival Autonomic features Yes Yes injection and lacrimation)a Migrainous featuresb Yes No Yes Alcohol trigger Yes No No Cutaneous triggers No Yesc Yes Indomethacin effect — No effective treatment — Abortive treatment Sumatriptan injection Lidocaine (IV) or nasal spray Prophylactic Oxygen Indomethacin Lamotrigine treatment Verapamil Topiramate Methysergide Gabapentin Lithium aIf conjunctival injection and tearing not present, consider SUNA. bNausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain. cIndicates complete response to indomethacin. Note: SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

62 Onset is nocturnal in about 50% of patients, and men TABLE 6-9 are affected three times more often than women. PREVENTIVE MANAGEMENT OF CLUSTER HEADACHE Patients with cluster headache tend to move about dur- ing attacks, pacing, rocking, or rubbing their head for SHORT-TERM PREVENTION LONG-TERM PREVENTION relief; some may even become aggressive during attacks. This is in sharp contrast to patients with migraine, who Episodic Cluster Episodic Cluster Headache & prefer to remain motionless during attacks. Headache Prolonged Chronic Cluster headache is associated with ipsilateral symp- Cluster Headache toms of cranial parasympathetic autonomic activation: SECTION II Clinical Manifestations of Neurologic Disease conjunctival injection or lacrimation, rhinorrhea or nasal Prednisone 1 mg/kg up Verapamil 160–960 mg/d congestion, or cranial sympathetic dysfunction such as to 60 mg qd, tapering ptosis.The sympathetic deficit is peripheral and likely to over 21 days Lithium 400–800 mg/d be due to parasympathetic activation with injury to ascend- ing sympathetic fibers surrounding a dilated carotid artery Methysergide 3–12 mg/d Methysergide 3–12 mg/d as it passes into the cranial cavity. When present, photo- Verapamil 160–960 mg/d Topiramatea 100–400 mg/d phobia and phonophobia are far more likely to be unilat- Greater occipital nerve Gabapentina 1200–3600 mg/d eral and on the same side of the pain, rather than bilateral, Melatonina 9–12 mg/d as is seen in migraine. This phenomenon of unilateral injection photophobia/phonophobia is characteristic of TACs. Cluster headache is likely to be a disorder involving aUnproven but of potential benefit. central pacemaker neurons in the region of the posterior hypothalamus (Fig. 6-2). is used, it is most effective when given 1–2 h before an expected attack. Patients who use ergotamine daily Treatment: must be educated regarding the early symptoms of CLUSTER HEADACHE ergotism, which may include vomiting, numbness, tin- gling, pain, and cyanosis of the limbs; a weekly limit of The most satisfactory treatment is the administration of 14 mg should be adhered to. Lithium (600–900 mg qd) drugs to prevent cluster attacks until the bout is over. appears to be particularly useful for the chronic form of However, treatment of acute attacks is required for all the disorder. cluster headache patients at some time. Many experts favor verapamil as the first-line preven- ACUTE ATTACK TREATMENT Cluster headache tive treatment for patients with chronic cluster headache attacks peak rapidly, and thus a treatment with quick or prolonged bouts. While verapamil compares favorably onset is required. Many patients with acute cluster with lithium in practice, some patients require verapamil headache respond very well to oxygen inhalation. This doses far in excess of those administered for cardiac disor- should be given as 100% oxygen at 10–12 L/min for ders. The initial dose range is 40–80 mg twice daily; effec- 15–20 min. It appears that high flow and high oxygen tive doses may be as high as 960 mg/d. Side effects such content are important. Sumatriptan 6 mg subcuta- as constipation and leg swelling can be problematic. Of neously is rapid in onset and will usually shorten an paramount concern, however, is the cardiovascular safety attack to 10–15 min; there is no evidence of tachyphy- of verapamil, particularly at high doses. Verapamil can laxis. Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal cause heart block by slowing conduction in the atrioven- sprays are both effective in acute cluster headache, tricular node, a condition that can be monitored by fol- offering a useful option for patients who may not wish lowing the PR interval on a standard ECG. Approximately to self-inject daily. Oral sumatriptan is not effective for 20% of patients treated with verapamil develop ECG prevention or for acute treatment of cluster headache. abnormalities, which can be observed with doses as low as 240 mg/d; these abnormalities can worsen over time in PREVENTIVE TREATMENTS (Table 6-9) The patients on stable doses. A baseline ECG is recommended choice of a preventive treatment in cluster headache for all patients. The ECG is repeated 10 days after a dose depends in part on the length of the bout. Patients with change in those patients whose dose is being increased long bouts or those with chronic cluster headache above 240 mg daily. Dose increases are usually made in require medicines that are safe when taken for long 80-mg increments. For patients on long-term verapamil, periods. For patients with relatively short bouts, limited ECG monitoring every 6 months is advised. courses of oral glucocorticoids or methysergide (not available in the United States) can be very useful. A 10- NEUROSTIMULATION THERAPY When med- day course of prednisone, beginning at 60 mg daily for 7 ical therapies fail in chronic cluster headache, neu- days and followed by a rapid taper, may interrupt the rostimulation therapy strategies can be employed. pain bout for many patients. When ergotamine (1–2 mg) Deep-brain stimulation of the region of the posterior hypothalamic gray matter has proven successful in a substantial proportion of patients. Favorable results have also been reported with the less-invasive approach of occipital nerve stimulation.

Paroxysmal Hemicrania minutes. Each pattern may be seen in the context of an 63 CHAPTER 6 Headache underlying continuous head pain. Characteristics that Paroxysmal hemicrania (PH) is characterized by frequent lead to a suspected diagnosis of SUNCT are the cuta- unilateral, severe, short-lasting episodes of headache. Like neous (or other) triggerability of attacks, a lack of refrac- cluster headache, the pain tends to be retroorbital but tory period to triggering between attacks, and the lack of may be experienced all over the head and is associated a response to indomethacin. Apart from trigeminal sen- with autonomic phenomena such as lacrimation and nasal sory disturbance, the neurologic examination is normal congestion. Patients with remissions are said to have in primary SUNCT. episodic PH, while those with the nonremitting form are said to have chronic PH.The essential features of PH are: The diagnosis of SUNCT is often confused with unilateral, very severe pain; short-lasting attacks (2–45 min); trigeminal neuralgia (TN) particularly in first-division very frequent attacks (usually more than five a day); marked TN (Chap. 29). Minimal or no cranial autonomic symp- autonomic features ipsilateral to the pain; rapid course toms and a clear refractory period to triggering indicate (<72 h); and excellent response to indomethacin. In con- a diagnosis of TN. trast to cluster headache, which predominantly affects males; the male:female ratio in PH is close to 1:1. Secondary (Symptomatic) SUNCT SUNCT can be seen with posterior fossa or pituitary Indomethacin (25–75 mg tid), which can completely lesions. All patients with SUNCT/SUNA should be suppress attacks of PH, is the treatment of choice. Although evaluated with pituitary function tests and a brain MRI therapy may be complicated by indomethacin-induced with pituitary views. gastrointestinal side effects, currently there are no consis- tently effective alternatives. Topiramate is helpful in some Treatment: cases. Piroxicam has been used, although it is not as effec- SUNCT/SUNA tive as indomethacin.Verapamil, an effective treatment for cluster headache, does not appear to be useful for PH. In ABORTIVE THERAPY Therapy of acute attacks is occasional patients, PH can coexist with trigeminal neural- not a useful concept in SUNCT/SUNA since the attacks gia (PH-tic syndrome); similar to cluster-tic syndrome, each are of such short duration. However, intravenous lido- component may require separate treatment. caine, which arrests the symptoms, can be used in hospi- talized patients. Secondary PH has been reported with lesions in the region of the sella turcica, including arteriovenous malfor- PREVENTIVE THERAPY Long-term prevention mation, cavernous sinus meningioma, and epidermoid to minimize disability and hospitalization is the goal of tumors. Secondary PH is more likely if the patient requires treatment. The most effective treatment for prevention is high doses (>200 mg/d) of indomethacin. In patients with lamotrigine, 200–400 mg/d. Topiramate and gabapentin apparent bilateral PH, raised CSF pressure should be sus- may also be effective. Carbamazepine, 400–500 mg/d, pected. It is important to note that indomethacin reduces has been reported by patients to offer modest benefit. CSF pressure.When a diagnosis of PH is considered, MRI is indicated to exclude a pituitary lesion. Surgical approaches such as microvascular decom- pression or destructive trigeminal procedures are sel- SUNCT/SUNA dom useful and often produce long-term complica- tions. Greater occipital nerve injection has produced SUNCT is a rare primary headache syndrome charac- limited benefit in some patients. Mixed success with terized by severe, unilateral orbital or temporal pain that occipital nerve stimulation has been observed. Com- is stabbing or throbbing in quality. Diagnosis requires at plete control with deep-brain stimulation of the poste- least 20 attacks, lasting for 5–240 s; ipsilateral conjuncti- rior hypothalamic region was reported in a single val injection and lacrimation should be present. In some patient. For intractable cases, short-term prevention patients conjunctival injection or lacrimation are miss- with intravenous lidocaine can be effective. ing, and the diagnosis of SUNA (short-lasting unilateral neuralgiform headache attacks with cranial autonomic CHRONIC DAILY HEADACHE symptoms) has been suggested. The broad diagnosis of chronic daily headache (CDH) Diagnosis can be applied when a patient experiences headache on The pain of SUNCT/SUNA is unilateral and may be 15 days or more per month. CDH is not a single entity; located anywhere in the head. Three basic patterns can it encompasses a number of different headache syn- be seen: single stabs, which are usually short-lived; groups dromes, including chronic TTH as well as headache sec- of stabs; or a longer attack comprising many stabs between ondary to trauma, inflammation, infection, medication which the pain does not completely resolve, thus giving a “saw-tooth” phenomenon with attacks lasting many

64 TABLE 6-10 (see below). Clinical trials using botulinum toxin in chronic migraine have failed to show any objective CLASSIFICATION OF CHRONIC DAILY HEADACHE benefit. PRIMARY MEDICATION-OVERUSE HEADACHE Overuse of analgesic medication for headache can aggravate >4 H DAILY <4 H DAILY SECONDARY head-ache frequency and induce a state of refractory daily or near-daily headache called medication-overuse SECTION II Clinical Manifestations of Neurologic Disease Chronic migrainea Chronic cluster Posttraumatic headache. A proportion of patients who stop taking headacheb Head injury analgesics will experience substantial improvement in Chronic tension- Iatrogenic the severity and frequency of their headache. However, type headachea Chronic Postinfectious even after cessation of analgesic use, many patients paroxysmal continue to have headache, although they may feel Hemicrania hemicrania Inflammatory, such as clinically improved in some way, especially if they have continuaa Giant cell arteritis been using codeine or barbiturates regularly.The resid- New daily SUNCT/SUNA Sarcoidosis ual symptoms probably represent the underlying persistent Behçet’s syndrome headache disorder. headachea Hypnic headache Chronic CNS Management of Medication Overuse: Out- infection Medication-overuse patients For patients who overuse medications, it headachea is essential that analgesic use be reduced and elimi- nated. One approach is to reduce the medication dose aMay be complicated by analgesic overuse. by 10% every 1–2 weeks. Immediate cessation of anal- bSome patients may have headache > 4 h per day. gesic use is possible for some patients, provided there is Note: SUNCT, short-lasting unilateral neuralgiform headache attacks no contraindication. Both approaches are facilitated by with conjunctival injection and tearing; SUNA, short-lasting unilateral the use of a medication diary maintained during the neuralgiform headache attacks with cranial autonomic symptoms. month or two before cessation; this helps to identify the scope of the problem. A small dose of an NSAID overuse, and other causes (Table 6-10). Population-based such as naproxen, 500 mg bid if tolerated, will help estimates suggest that about 4% of adults have daily or relieve residual pain as analgesic use is reduced. NSAID near-daily headache. Daily headache may be primary or overuse is not usually a problem for patients with daily secondary, an important consideration in guiding man- headache when the dose is taken once or twice daily; agement of this complaint. however, overuse problems may develop with more frequent dosing schedules. Once the patient has sub- Approach to the Patient: stantially reduced analgesic use, a preventive medica- CHRONIC DAILY HEADACHE tion should be introduced. It must be emphasized that preventives generally do not work in the presence of analgesic The first step in the management of patients with overuse. The most common cause of unresponsiveness CDH is to diagnose any underlying condition (Table to treatment is the use of a preventive when analgesics 6-10). For patients with primary headaches, diagnosis continue to be used regularly. For some patients, dis- of the headache type will guide therapy. Preventive continuing analgesics is very difficult; often the best treatments such as tricyclics, either amitriptyline or approach is to directly inform the patient that some doxepin at doses up to 1 mg/kg, are very useful in degree of pain is inevitable during this initial period. patients with CDH.Tricyclics are started in low doses (10–25 mg) daily and may be given 12 h before the Management of Medication Overuse: Inpa- expected time of awakening in order to avoid excess morning sleepiness. Anticonvulsants, such as topira- tients Some patients will require hospitalization for mate, valproate, and gabapentin, are also useful in detoxification. Such patients have typically failed efforts migraineurs. Flunarizine can also be very effective for at outpatient withdrawal or have a significant medical some patients, as can methysergide or phenelzine. condition, such as diabetes mellitus, which would com- plicate withdrawal as an outpatient. Following admis- MANAGEMENT OF MEDICALLY INTRACTABLE sion to the hospital, acute medications are withdrawn completely on the first day, in the absence of a con- DISABLING CHRONIC DAILY HEADACHE The traindication. Antiemetics and fluids are administered as management of medically intractable headache is diffi- required; clonidine is used for opiate withdrawal symp- cult.At this time, the only promising approach is occip- toms. For acute intolerable pain during the waking hours ital nerve stimulation, which appears to modulate thala- aspirin, 1 g (not approved in United States) intravenously, mic processing in migraine and has shown promise in both chronic cluster headache and hemicrania continua

TABLE 6-11 puncture (LP). Post-LP headache usually begins within 65 48 h but may be delayed for up to 12 days. Its inci- DIFFERENTIAL DIAGNOSIS OF NEW DAILY dence is between 10 and 30%. Beverages with caffeine PERSISTENT HEADACHE may provide temporary relief. Besides LP, index events may include epidural injection or a vigorous Valsalva PRIMARY SECONDARY maneuver, such as from lifting, straining, coughing, clearing the eustachian tubes in an airplane, or multiple Migrainous-type Subarachnoid hemorrhage orgasms. Spontaneous CSF leaks are well recognized, Featureless (tension-type) Low CSF volume headache and the diagnosis should be considered whenever the Raised CSF pressure headache history is typical, even when there is no headache obvious index event. As time passes from the index CHAPTER 6 Headache Posttraumatic headachea event, the postural nature may become less apparent; Chronic meningitis cases in which the index event occurred several years before the eventual diagnosis have been recognized. aIncludes postinfectious forms. Symptoms appear to result from low volume rather than low pressure: although low CSF pressures, typi- is useful. Intramuscular chlorpromazine can be helpful cally 0–50 mmH2O, are usually identified, a pressure as at night; patients must be adequately hydrated. If the high as 140 mmH2O has been noted with a docu- patient does not improve within 3–5 days, a course of mented leak. Postural orthostatic tachycardia syndrome intravenous dihydroergotamine (DHE) can be [POTS (Chap. 28)] can present with orthostatic headache employed. DHE, administered every 8 h for 3 consecu- similar to low CSF volume headache and is a diagnosis tive days, can induce a significant remission that allows that needs consideration here. a preventive treatment to be established. 5-HT3 antago- nists, such as ondansetron or granisetron, are often When imaging is indicated to identify the source of a required with DHE to prevent significant nausea. presumed leak, an MRI with gadolinium is the initial study of choice (Fig. 6-5). A striking pattern of diffuse NEW DAILY PERSISTENT HEADACHE New meningeal enhancement is so typical that in the appro- daily persistent headache (NDPH) is a clinically dis- priate clinical context the diagnosis is established. Chiari tinct syndrome; its causes are listed in Table 6-11. malformations may sometimes be noted on MRI; in Clinical Presentation The patient with NDPH FIGURE 6-5 presents with headache on most if not all days; the Magnetic resonance image showing diffuse meningeal onset is recent and clearly recalled by the patient.The enhancement after gadolinium administration in a patient headache usually begins abruptly, but onset may be with low CSF volume headache. High-resolution T1 weighted more gradual; evolution over 3 days has been pro- MRI obtained using voxel-based morphometry demonstrates posed as the upper limit for this syndrome. Patients increased gray matter activity, lateralized to the side of pain typically recall the exact day and circumstances of the in a patient with cluster headache. (From A May et al: Nat onset of headache; the new, persistent head pain does Med 5:836, 1999.) not remit. The first priority is to distinguish between a primary and a secondary cause of this syndrome. Subarachnoid hemorrhage is the most serious of the secondary causes and must be excluded either by his- tory or appropriate investigation (Chap. 22). SECONDARY NDPH Low CSF volume headache In these syndromes, head pain is positional: it begins when the patient sits or stands upright and resolves upon reclining. The pain, which is occipitofrontal, is usually a dull ache but may be throbbing. Patients with chronic low CSF volume headache typically present with a history of headache from one day to the next that is generally not present on waking but worsens during the day. Recumbency usually improves the headache within minutes, but it takes only minutes to an hour for the pain to return when the patient resumes an upright position. The most common cause of headache due to persis- tent low CSF volume is CSF leak following lumbar

SECTION II Clinical Manifestations of Neurologic Disease66 such cases surgery to decompress the posterior fossa Initial treatment is with acetazolamide (250–500 mg usually worsens the headache.The source of CSF leak- bid); the headache may improve within weeks. If age may be identified by spinal MRI, by CT myelo- ineffective, topiramate is the next treatment of choice; gram, or with 111In-DTPA CSF studies; in the absence it has many actions that may be useful in this setting, of a directly identified site of leakage, early emptying of including carbonic anhydrase inhibition, weight loss, 111In-DTPA tracer into the bladder or slow progress of and neuronal membrane stabilization, likely mediated tracer across the brain suggests a CSF leak. via effects on phosphorylation pathways. Severely dis- Initial treatment for low CSF volume headache is abled patients who do not respond to medical treat- bed rest. For patients with persistent pain, intravenous ment require intracranial pressure monitoring and may caffeine (500 mg in 500 mL saline administered over require shunting. 2 h) is often very effective. An EKG to screen for arrhythmia should be performed before administra- Post-traumatic headache A traumatic event tion. It is reasonable to administer at least two infusions can trigger a headache process that lasts for many of caffeine before embarking on additional tests to months or years after the event. The term trauma is identify the source of the CSF leak. Since intravenous used in a very broad sense: headache can develop fol- caffeine is safe and can be curative, it spares many lowing an injury to the head, but it can also develop patients the need for further investigations. If unsuc- after an infectious episode, typically viral meningitis, a cessful, an abdominal binder may be helpful. If a leak flulike illness, or a parasitic infection. Complaints of can be identified, an autologous blood patch is usually dizziness, vertigo, and impaired memory can accom- curative. A blood patch is also effective for post-LP pany the headache. Symptoms may remit after several headache; in this setting the location is empirically weeks or persist for months and even years after the determined to be the site of the LP. In patients with injury.Typically the neurologic examination is normal intractable pain, oral theophylline is a useful alternative; and CT or MRI studies are unrevealing. Chronic sub- however, its effect is less rapid than caffeine. dural hematoma may on occasion mimic this disorder. In one series, one-third of patients with NDPH Raised CSF pressure headache Raised CSF reported headache beginning after a transient flulike pressure is well recognized as a cause of headache. Brain illness characterized by fever, neck stiffness, photopho- imaging can often reveal the cause, such as a space- bia, and marked malaise. Evaluation reveals no appar- occupying lesion. NDPH due to raised CSF pressure ent cause for the headache. There is no convincing can be the presenting symptom for patients with idio- evidence that persistent Epstein-Barr infection plays a pathic intracranial hypertension (pseudotumor cerebri) role in this syndrome. A complicating factor is that without visual problems, particularly when the fundi many patients undergo LP during the acute illness; are normal. Persistently raised intracranial pressure can iatrogenic low CSF volume headache must be consid- trigger chronic migraine. These patients typically pre- ered in these cases. Post-traumatic headache may also sent with a history of generalized headache that is pre- be seen after carotid dissection and subarachnoid sent on waking and improves as the day goes on. It is hemorrhage, and following intracranial surgery. The generally worse with recumbency. Visual obscurations underlying theme appears to be that a traumatic event are frequent. The diagnosis is relatively straightforward involving the pain-producing meninges can trigger a when papilledema is present, but the possibility must be headache process that lasts for many years. considered even in patients without fundoscopic changes. Formal visual-field testing should be per- Treatment is largely empirical.Tricyclic antidepres- formed even in the absence of overt ophthalmic sants, notably amitriptyline, and anticonvulsants such involvement. Headache on rising in the morning or as topiramate, valproate, and gabapentin, have been used nocturnal headache is also characteristic of obstructive with reported benefit. The MAOI phenelzine may sleep apnea or poorly controlled hypertension. also be useful in carefully selected patients.The headache usually resolves within 3–5 years, but it can be quite Evaluation of patients suspected to have raised CSF disabling. pressure requires brain imaging. It is most efficient to obtain an MRI, including an MR venogram as the Primary NDPH Primary NDPH occurs in both initial study. If there are no contraindications, the males and females. It can be of the migrainous type, CSF pressure should be measured by LP; this should with features of migraine, or it can be featureless, be done when the patient is symptomatic so that appearing as new-onset TTH (Table 6-11). Migrain- both the pressure and the response to removal of ous features are common and include unilateral 20–30 mL of CSF can be determined. An elevated headache and throbbing pain; each feature is present opening pressure and improvement in headache fol- in about one-third of patients. Nausea, photophobia, lowing removal of CSF is diagnostic. and/or phonophobia occur in about half of patients.

Some patients have a previous history of migraine; Treatment: 67 however, the proportion of NDPH sufferers with PRIMARY STABBING HEADACHE preexisting migraine is no greater than the frequency of migraine in the general population. At 24 months, The response of primary stabbing headache to indo- ~86% of patients are headache-free. Treatment of methacin (25–50 mg two to three times daily) is usually migrainous-type primary NDPH consists of using excellent. As a general rule the symptoms wax and the preventive therapies effective in migraine (Table wane, and after a period of control on indomethacin, it is 6-7). Featureless NDPH is one of the primary appropriate to withdraw treatment and observe the headache forms most refractory to treatment. Stan- outcome. dard preventive therapies can be offered but are often ineffective. Primary Cough Headache CHAPTER 6 Headache OTHER PRIMARY HEADACHES Primary cough headache is a generalized headache that begins suddenly, lasts for several minutes, and is precipi- Hemicrania Continua tated by coughing; it is preventable by avoiding coughing or other precipitating events, which can include sneezing, The essential features of hemicrania continua are moder- straining, laughing, or stooping. In all patients with this ate and continuous unilateral pain associated with fluctu- syndrome serious etiologies must be excluded before a ations of severe pain; complete resolution of pain with diagnosis of “benign” primary cough headache can be indomethacin; and exacerbations that may be associated established. A Chiari malformation or any lesion causing with autonomic features, including conjunctival injec- obstruction of CSF pathways or displacing cerebral struc- tion, lacrimation, and photophobia on the affected side. tures can be the cause of the head pain. Other conditions The age of onset ranges from 11 to 58 years; women are that can present with cough or exertional headache as the affected twice as often as men.The cause is unknown. initial symptom include cerebral aneurysm, carotid steno- sis, and vertebrobasilar disease. Benign cough headache Treatment: can resemble benign exertional headache (below), but HEMICRANIA CONTINUA patients with the former condition are typically older. Treatment consists of indomethacin; other NSAIDs Treatment: appear to be of little or no benefit. The intramuscular PRIMARY COUGH HEADACHE injection of 100 mg indomethacin has been proposed as a diagnostic tool; administration with a placebo Indomethacin 25–50 mg two to three times daily is the injection has been recommended. Alternatively, a trial of treatment of choice. Some patients with cough headache oral indomethacin, starting with 25 mg tid, then 50 mg obtain pain relief with LP; this is a simple option when tid, and then 75 mg tid, can be given. Up to 2 weeks may compared to prolonged use of indomethacin, and it is be necessary to assess whether a dose has a useful effective in about one-third of patients. The mechanism effect. Topiramate can be helpful in some patients. of this response is unclear. Occipital nerve stimulation may have a role in patients with hemicrania continua who are unable to tolerate Primary Exertional Headache indomethacin. Primary exertional headache has features resembling Primary Stabbing Headache both cough headache and migraine. It may be precipi- tated by any form of exercise; it often has the pulsatile The essential features of primary stabbing headache are quality of migraine.The pain, which can last from 5 min stabbing pain confined to the head or, rarely, the face, last- to 24 h, is bilateral and throbbing at onset; migrainous ing from 1 to many seconds or minutes and occurring as features may develop in patients susceptible to migraine. a single stab or a series of stabs; absence of associated cra- Primary exertional headache can be prevented by avoid- nial autonomic features; absence of cutaneous triggering ing excessive exertion, particularly in hot weather or at of attacks; and a pattern of recurrence at irregular intervals high altitude. (hours to days). The pains have been variously described as “ice-pick pains” or “jabs and jolts.”They are more com- The mechanism of primary exertional headache is mon in patients with other primary headaches, such as unclear. Acute venous distension likely explains one syn- migraine, the TACs, and hemicrania continua. drome, the acute onset of headache with straining and breath holding, as in weightlifter’s headache. As exertion

68 can result in headache in a number of serious underlying advice about ceasing sexual activity if a mild, warning conditions, these must be considered in patients with exer- headache develops. Propranolol can be used to prevent tional headache. Pain from angina may be referred to the headache that recurs regularly or frequently, but the head, probably by central connections of vagal afferents, and dosage required varies from 40 to 200 mg/d. An alterna- may present as exertional headache (cardiac cephalgia).The tive is the calcium channel-blocking agent diltiazem, 60 link to exercise is the main clinical clue that headache is of mg tid. Ergotamine (1 mg) or indomethacin (25–50 mg) cardiac origin. Pheochromocytoma may occasionally cause taken about 30–45 min prior to sexual activity can also exertional headache. Intracranial lesions and stenosis of the be helpful. carotid arteries are other possible etiologies. SECTION II Clinical Manifestations of Neurologic Disease Treatment: Primary Thunderclap Headache PRIMARY EXERTIONAL HEADACHE Sudden onset of severe headache may occur in the absence Exercise regimens should begin modestly and progress of any known provocation. The differential diagnosis gradually to higher levels of intensity. Indomethacin at includes the sentinel bleed of an intracranial aneurysm, cer- daily doses from 25 to 150 mg is generally effective in vicocephalic arterial dissection, and cerebral venous throm- benign exertional headache. Indomethacin (50 mg), bosis. Headaches of explosive onset may also be caused by ergotamine (1 mg orally), dihydroergotamine (2 mg by the ingestion of sympathomimetic drugs or of tyramine- nasal spray), or methysergide (1–2 mg orally given 30–45 containing foods in a patient who is taking MAOIs, or they min before exercise) are useful prophylactic measures. may be a symptom of pheochromocytoma.Whether thun- derclap headache can be the presentation of an unruptured Primary Sex Headache cerebral aneurysm is uncertain.When neuroimaging studies and LP exclude subarachnoid hemorrhage, patients with Sex headache is precipitated by sexual excitement. The thunderclap headache usually do very well over the long pain usually begins as a dull bilateral headache which sud- term. In one study of patients whose CT scans and CSF denly becomes intense at orgasm. The headache can be findings were negative, ~15% had recurrent episodes of prevented or eased by ceasing sexual activity before orgasm. thunderclap headache, and nearly half subsequently devel- Three types of sex headache are reported: a dull ache in oped migraine or tension-type headache. the head and neck that intensifies as sexual excitement increases; a sudden, severe, explosive headache occurring at The first presentation of any sudden-onset severe orgasm; and a postural headache developing after coitus headache should be vigorously investigated with neu- that resembles the headache of low CSF pressure.The lat- roimaging (CT or, when possible, MRI with MR ter arises from vigorous sexual activity and is a form of low angiography) and CSF examination. Formal cerebral CSF pressure headache. Headaches developing at the time angiography should be reserved for those cases in which of orgasm are not always benign; 5–12% of cases of sub- no primary diagnosis is forthcoming and for clinical arachnoid hemorrhage are precipitated by sexual inter- situations that are particularly suggestive of intracranial course. Sex headache is reported by men more often than aneurysm. Reversible segmental cerebral vasoconstric- women and may occur at any time during the years of tion may be seen in primary thunderclap headache sexual activity. It may develop on several occasions in suc- without an intracranial aneurysm. In the presence of cession and then not trouble the patient again, even with- posterior leukoencephalopathy, the differential diagnosis out an obvious change in sexual activity. In patients who includes cerebral angiitis, drug toxicity (cyclosporine, stop sexual activity when headache is first noticed, the pain intrathecal methotrexate/cytarabine, pseudoephedrine, may subside within a period of 5 min to 2 h. In about half or cocaine), posttransfusion effects, and postpartum of patients, sex headache will subside within 6 months. angiopathy. Treatment with nimodipine may be helpful, About half of patients with sex headache have a history of although by definition the vasoconstriction of primary exertional headaches, but there is no excess of cough thunderclap headache resolves spontaneously. headache. Migraine is probably more common in patients with sex headache. Hypnic Headache Treatment: This headache syndrome typically begins a few hours after PRIMARY SEX HEADACHE sleep onset.The headaches last from 15 to 30 min and are typically moderately severe and generalized, although Benign sex headaches recur irregularly and infrequently. they may be unilateral and can be throbbing. Patients may Management can often be limited to reassurance and report falling back to sleep only to be awakened by a fur- ther attack a few hours later; up to three repetitions of this pattern occur through the night. Daytime naps can also precipitate head pain. Most patients are women, and

the onset is usually after age 60. Headaches are bilateral in FURTHER READINGS 69 most, but may be unilateral. Photophobia or phonopho- bia and nausea are usually absent. The major secondary CITTADINI E et al: Paroxysmal hemicrania: A prospective clinical CHAPTER 6 Headache consideration in this headache type is poorly controlled study of 31 cases. Brain 131:1142, 2008 hypertension; 24-h blood pressure monitoring is recom- mended to detect this treatable condition. COHEN AS et al:Trigeminal autonomic cephalalgias: Current and future treatments. Headache 47:969, 2007 Treatment: HYPNIC HEADACHE GOADSBY PJ: Is medication-overuse headache a distinct biological entity? Nat Clin Pract Neurol 2:401, 2006 Patients with hypnic headache generally respond to a bedtime dose of lithium carbonate (200–600 mg). For HAUGE AW et al: Effects of tonabersat on migraine with aura: a ran- those intolerant of lithium, verapamil (160 mg) or domised, double-blind, placebo-controlled crossover study. Lancet methysergide (1–4 mg at bedtime) may be alternative Neurol 8:718, 2009 strategies. One to two cups of coffee or caffeine, 60 mg orally, at bedtime may be effective in approximately HEADACHE Classification Committee of the International Headache one-third of patients. Case reports suggest that flunar- Society: The international classification of headache disorders izine, 5 mg nightly, can be effective. (second edition). Cephalalgia 24:1, 2004 LANCE JW, Goadsby PJ: Mechanism and Management of Headache. New York, Elsevier, 2005 LEVY M et al:The clinical characteristics of headache in patients with pituitary tumours. Brain 128:1921, 2005 OLESEN J et al: The Headaches. Philadelphia, Lippincott, Williams & Wilkins, 2005 SCHER AI et al: Migraine Headache in Middle Age and Late-Life Brain Infarcts. JAMA 301:2563, 2009.

CHAPTER 7 BACK AND NECK PAIN John W. Engstrom I Anatomy of the Spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Other Causes of Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 I Causes of Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 I Pain In the Neck and Shoulder . . . . . . . . . . . . . . . . . . . . . . . . 82 Congenital Anomalies of the Lumbar Spine . . . . . . . . . . . . . . . 74 Trauma to the Cervical Spine . . . . . . . . . . . . . . . . . . . . . . . . . 82 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cervical Disk Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Lumbar Disk Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cervical Spondylosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Degenerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Other Causes of Neck Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77 Thoracic Outlet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Brachial Plexus and Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Infections/Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Shoulder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Metabolic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Referred Pain from Visceral Disease . . . . . . . . . . . . . . . . . . . . 78 The importance of back and neck pain in our society is The posterior portion of the spine consists of the ver- underscored by the following: (1) the cost of back pain tebral arches and seven processes. Each arch consists of in the United States is ~$100 billion annually, including paired cylindrical pedicles anteriorly and paired laminae direct health care expenses plus costs due to loss of pro- posteriorly.The vertebral arch gives rise to two transverse ductivity; (2) back symptoms are the most common processes laterally, one spinous process posteriorly, plus cause of disability in those <45 years; (3) low back pain two superior and two inferior articular facets.The appo- is the second most common reason for visiting a physi- sition of a superior and inferior facet constitutes a facet cian in the United States; and (4) ~1% of the U.S. popu- joint. The functions of the posterior spine are to protect lation is chronically disabled because of back pain. the spinal cord and nerves within the spinal canal and to stabilize the spine by providing sites for the attachment of muscles and ligaments. The contraction of muscles ANATOMY OF THE SPINE attached to the spinous and transverse processes produces a system of pulleys and levers that results in flexion, The anterior portion of the spine consists of cylindrical extension, and lateral bending movements of the spine. vertebral bodies separated by intervertebral disks and Nerve root injury (radiculopathy) is a common cause held together by the anterior and posterior longitudinal of neck, arm, low back, and leg pain (Figs. 12-2 and 12-3). ligaments. The intervertebral disks are composed of a The nerve roots exit at a level above their respective central gelatinous nucleus pulposus surrounded by a vertebral bodies in the cervical region (the C7 nerve root tough cartilaginous ring, the annulus fibrosis; disks are exits at the C6-C7 level) and below their respective ver- responsible for 25% of spinal column length (Figs. 7-1 tebral bodies in the thoracic and lumbar regions (the T1 and 7-2).The disks are largest in the cervical and lumbar nerve root exits at the T1-T2 level). The cervical nerve regions where movements of the spine are greatest. The roots follow a short intraspinal course before exiting. By disks are elastic in youth and allow the bony vertebrae contrast, because the spinal cord ends at the vertebral L1 to move easily upon each other. Elasticity is lost with or L2 level, the lumbar nerve roots follow a long age. The function of the anterior spine is to absorb the intraspinal course and can be injured anywhere from the shock of body movements such as walking and running. upper lumbar spine to their exit at the intervertebral 70

Posterior Posterior Anterior 71 Spinous process Lamina Superior articular Superior vertebral process notch Superior articular Transverse Intervertebral process process foramen Spinous Intervertebral CHAPTER 7 Back and Neck Pain process disk Transverse Pedicle process Spinal canal Body FIGURE 7-1 Vertebral anatomy. (From A A Anterior Body Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. Inferior articular Inferior vertebral New York, McGraw-Hill, 1998; with process (facet) notch permission.) B foramen. For example, disk herniation at the L4-L5 level fibrosus of the intervertebral disk, epidural veins, and the commonly produces compression of the traversing S1 posterior longitudinal ligament. Disease of these diverse nerve root (Fig.7-3). structures may explain many cases of back pain without nerve root compression. The nucleus pulposus of the Pain-sensitive structures in the spine include the intervertebral disk is not pain-sensitive under normal periosteum of the vertebrae, dura, facet joints, annulus circumstances. Pain sensation is conveyed partially by the sinuvertebral nerve that arises from the spinal nerve at Cervical (7) 1 Cervical each spine segment and reenters the spinal canal Thoracic (12) 2 curvature through the intervertebral foramen at the same level. Lumbar (5) 3 The lumbar and cervical spine possesses the greatest 4 Lumbar potential for movement and injury. 5 curvature 6 Thoracic 7 curvature 1 2 4th Lumbar 4th Lumbar 3 pedicle vertebral body 4 5 L4 root 5th Lumbar 6 vertebral body 7 Protruded 8 L4–L5 disk 9 10 L5 Root 11 Protruded 12 L5–S1 disk 1 S1 Root 2 3 4 5 Sacrum Sacral S2 Root Coccyx curvature FIGURE 7-3 Anterior view Right lateral view Compression of L5 and S1 roots by herniated disks. (From RD Adams et al: Principles of Neurology, 8th ed. New FIGURE 7-2 York, McGraw-Hill, 2005; with permission.) Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. New York, McGraw-Hill, 1998; with permission.)

SECTION II Clinical Manifestations of Neurologic Disease72 of abdominal muscles (lifting heavy objects or strain- ing at stool) may elicit the radiating pain. The pain Approach to the Patient: may increase in postures that stretch the nerves and BACK PAIN nerve roots. Sitting stretches the sciatic nerve (L5 and S1 roots) because the nerve passes posterior to the TYPES OF BACK PAIN Understanding the type of hip. The femoral nerve (L2, L3, and L4 roots) passes pain experienced by the patient is the essential first step. anterior to the hip and is not stretched by sitting.The Attention is also focused on identification of risk factors description of the pain alone often fails to distinguish for serious underlying diseases; the majority of these are between sclerotomal pain and radiculopathy. due to radiculopathy, fracture, tumor, infection, or referred pain from visceral structures (Table 7-1). Pain associated with muscle spasm, although of obscure origin, is commonly associated with many spine disor- Local pain is caused by stretching of pain-sensitive ders. The spasms are accompanied by abnormal pos- structures that compress or irritate sensory nerve ture, taut paraspinal muscles, and dull pain. endings. The site of the pain is near the affected part of the back. Knowledge of the circumstances associated with the onset of back pain is important when weighing Pain referred to the back may arise from abdominal or possible serious underlying causes for the pain. Some pelvic viscera. The pain is usually described as pri- patients involved in accidents or work-related injuries marily abdominal or pelvic but is accompanied by may exaggerate their pain for the purpose of com- back pain and usually unaffected by posture. The pensation or for psychological reasons. patient may occasionally complain of back pain only. EXAMINATION OF THE BACK A physical Pain of spine origin may be located in the back or examination that includes the abdomen and rectum is referred to the buttocks or legs. Diseases affecting the advisable. Back pain referred from visceral organs may upper lumbar spine tend to refer pain to the lumbar be reproduced during palpation of the abdomen [pan- region, groin, or anterior thighs. Diseases affecting the creatitis, abdominal aortic aneurysm (AAA)] or per- lower lumbar spine tend to produce pain referred to cussion over the costovertebral angles (pyelonephritis). the buttocks, posterior thighs, or rarely the calves or feet. Provocative injections into pain-sensitive struc- The normal spine has cervical and lumbar lordosis, tures of the lumbar spine may produce leg pain that and a thoracic kyphosis. Exaggeration of these nor- does not follow a dermatomal distribution.This “scle- mal alignments may result in hyperkyphosis of the rotomal” pain may explain some cases of back and leg thoracic spine or hyperlordosis of the lumbar spine. pain without evidence of nerve root compression. Inspection may reveal a lateral curvature of the spine (scoliosis) or an asymmetry in the paraspinal muscles, Radicular back pain is typically sharp and radiates suggesting muscle spasm. Back pain of bony spine from the lumbar spine to the leg within the territory origin is often reproduced by palpation or percussion of a nerve root (see Lumbar Disk Disease, later in the over the spinous process of the affected vertebrae. chpater). Coughing, sneezing, or voluntary contraction Forward bending is often limited by paraspinal TABLE 7-1 muscle spasm; the latter may flatten the usual lumbar lordosis. Flexion of the hips is normal in patients with ACUTE LOW BACK PAIN: RISK FACTORS FOR AN lumbar spine disease, but flexion of the lumbar spine IMPORTANT STRUCTURAL CAUSE is limited and sometimes painful. Lateral bending to the side opposite the injured spinal element may History stretch the damaged tissues, worsen pain, and limit Pain worse at rest or at night motion. Hyperextension of the spine (with the Prior history of cancer patient prone or standing) is limited when nerve root History of chronic infection (esp. lung, urinary tract, skin) compression, facet joint pathology, or other bony History of trauma spine disease is present. Incontinence Age >50 years Pain from hip disease may mimic pain of lumbar Intravenous drug use spine disease. Hip pain can be reproduced by internal Glucocorticoid use and external rotation at the hip with the knee and History of a rapidly progressive neurologic deficit hip in flexion (Patrick sign) and by tapping the heel with the examiner’s palm while the leg is extended. Examination Unexplained fever With the patient lying flat, passive flexion of the Unexplained weight loss extended leg at the hip stretches the L5 and S1 nerve Percussion tenderness over the spine roots and the sciatic nerve. Passive dorsiflexion of Abdominal, rectal, or pelvic mass the foot during the maneuver adds to the stretch. Patrick’s sign or heel percussion sign Straight leg or reverse straight-leg raising signs Progressive focal neurologic deficit

While flexion to at least 80° is normally possible may be due to pain or a combination of pain and 73 without causing pain, tight hamstring muscles are a underlying true weakness. Breakaway weakness with- source of pain in some patients. The straight leg–raising out pain is due to lack of effort. In uncertain cases, (SLR) test is positive if the maneuver reproduces the electromyography (EMG) can determine whether or patient’s usual back or limb pain. Eliciting the SLR not true weakness is present. Findings with specific sign in the sitting position may help determine if the nerve root lesions are shown in Table 7-2 and are finding is reproducible.The patient may describe pain discussed below. in the low back, buttocks, posterior thigh, or lower leg, but the key feature is reproduction of the patient’s LABORATORY, IMAGING, AND EMG STUDIES CHAPTER 7 Back and Neck Pain usual pain. The crossed SLR sign is positive when flex- ion of one leg reproduces the pain in the opposite leg Routine laboratory studies are rarely needed for the or buttocks. The crossed SLR sign is less sensitive but initial evaluation of nonspecific acute (<3 months more specific for disk herniation than the SLR sign. duration) low back pain (ALBP). If risk factors for a The nerve or nerve root lesion is always on the side serious underlying cause are present, then laboratory of the pain.The reverse SLR sign is elicited by standing studies [complete blood count (CBC), erythrocyte the patient next to the examination table and passively sedimentation rate (ESR), urinalysis] are indicated. extending each leg with the knee fully extended.This maneuver, which stretches the L2-L4 nerve roots and CT scanning is superior to routine x-rays for the the femoral nerve, is considered positive if the patient’s detection of fractures involving posterior spine struc- usual back or limb pain is reproduced. tures, craniocervical and craniothoracic junctions, C1 and C2 vertebrae, bone fragments within the spinal The neurologic examination includes a search for canal, or malalignment; CT scans are increasingly used focal weakness or muscle atrophy, focal reflex changes, as a primary screening modality for moderate to severe diminished sensation in the legs, and signs of spinal trauma. In the absence of risk factors, these imaging cord injury.The examiner should be alert to the pos- studies are rarely helpful in nonspecific ALBP. MRI sibility of breakaway weakness, defined as fluctuating and CT-myelography are the radiologic tests of choice strength during muscle testing. Breakaway weakness for evaluation of most serious diseases involving the spine. MRI is superior for the definition of soft tissue TABLE 7-2 LUMBOSACRAL RADICULOPATHY—NEUROLOGIC FEATURES LUMBOSACRAL EXAMINATION FINDINGS PAIN NERVE ROOTS DISTRIBUTION L2a REFLEX SENSORY MOTOR Anterior thigh L3a — Anterior thigh, knee L4a — Upper anterior thigh Psoas (hip flexion) Lower anterior thigh Psoas (hip flexion) Knee, medial calf L5c Quadriceps Anterior knee Quadriceps (knee extension) Anterolateral thigh (knee) Medial calf Thigh adduction Lateral calf, dorsal foot, S1c Quadriceps (knee extension)b — Dorsal surface—foot Thigh adduction posterolateral thigh, buttocks Lateral calf Tibialis anterior (foot Gastrocnemius/ dorsiflexion) Bottom foot, posterior calf, soleus (ankle) Plantar surface—foot Peroneii (foot eversion)b posterior thigh, buttocks Lateral aspect—foot Tibialis anterior (foot dorsiflexion) Gluteus medius (hip abduction) Toe dorsiflexors Gastrocnemius/soleus (foot plantar flexion)b Abductor hallucis (toe flexors)b Gluteus maximus (hip extension) aReverse straight leg–raising sign present—see “Examination of the Back.” bThese muscles receive the majority of innervation from this root. cStraight leg–raising sign present—see “Examination of the Back.”

SECTION II Clinical Manifestations of Neurologic Disease74 structures, whereas CT-myelography provides optimal TABLE 7-3 imaging of the lateral recess of the spinal canal and bony lesions and is tolerated by claustrophobic CAUSES OF BACK AND NECK PAIN patients.While the added diagnostic value of modern neuroimaging is significant, there is concern that Congenital/developmental these studies may be overutilized in patients with Spondylolysis and spondylolisthesisa ALBP. Kyphoscoliosisa Electrodiagnostic studies can be used to assess the Spina bifida occultaa functional integrity of the peripheral nervous system Tethered spinal corda (Chap. 3). Sensory nerve conduction studies are nor- mal when focal sensory loss is due to nerve root Minor trauma damage because the nerve roots are proximal to the Strain or sprain nerve cell bodies in the dorsal root ganglia.The diag- Whiplash injuryb nostic yield of needle EMG is higher than that of nerve conduction studies for radiculopathy. Denerva- Fractures tion changes in a myotomal (segmental) distribution Traumatic—falls, motor vehicle accidents are detected by sampling multiple muscles supplied Atraumatic—osteoporosis, neoplastic infiltration, by different nerve roots and nerves; the pattern of exogenous steroids muscle involvement indicates the nerve root(s) responsible for the injury. Needle EMG provides Intervertebral disk herniation objective information about motor nerve fiber injury Degenerative when the clinical evaluation of weakness is limited by pain or poor effort. EMG and nerve conduction Disk-osteophyte complex studies will be normal when only limb pain or sen- Internal disk disruption sory nerve root injury or irritation is present. Spinal stenosis with neurogenic claudicationa Uncovertebral joint diseaseb CAUSES OF BACK PAIN (Table 7-3) Atlantoaxial joint disease (e.g., rheumatoid arthritis)a Arthritis CONGENITAL ANOMALIES OF THE Spondylosis LUMBAR SPINE Facet or sacroiliac arthropathy Autoimmune (e.g., anklyosing spondylitis, Reiter’s Spondylolysis is a bony defect in the pars interarticularis (a segment near the junction of the pedicle with the syndrome) lamina) of the vertebra; the etiology may be a stress frac- Neoplasms—metastatic, hematologic, primary bone ture in a congenitally abnormal segment. The defect (usually bilateral) is best visualized on oblique projec- tumors tions in plain x-rays, CT scan, or single photon emission Infection/inflammation CT (SPECT) bone scan and occurs in the setting of a single injury, repeated minor injuries, or growth. Vertebral osteomyelitis Although frequently asymptomatic, it is the most com- Spinal epidural abscess mon cause of persistent low back pain in adolescents Septic disk and is often activity-related. Meningitis Lumbar arachnoiditisa Spondylolisthesis is the anterior slippage of the verte- Metabolic bral body, pedicles, and superior articular facets, leaving Osteoporosis—hyperparathyroidism, immobility the posterior elements behind. Spondylolisthesis can be Osteosclerosis (e.g., Paget’s disease) associated with spondylolysis, congenital anomalies of Vascular the lumbosacral junction, infection, osteoporosis, tumor, Abdominal aortic aneurysm trauma, prior surgery, or degenerative spine disease. It Vertebral artery dissectionb occurs more frequently in women. The slippage may be Other asymptomatic or may cause low back pain and ham- Referred pain from visceral disease string tightness, nerve root injury (the L5 root most fre- Postural quently), or symptomatic spinal stenosis.Tenderness may Psychiatric, malingering, chronic pain syndromes be elicited near the segment that has “slipped” forward (most often L4 on L5 or occasionally L5 on S1).A “step” aLow back pain only. bNeck pain only. may be present on deep palpation of the posterior ele- ments of the segment above the spondylolisthetic joint. The trunk may be shortened and the abdomen protu- berant as a result of extreme forward displacement of L4 on L5; in severe cases cauda equina syndrome (CES) may occur (see later). Surgery is considered for symp- toms persisting for >1 year that do not respond to con- servative measures (e.g., rest, physical therapy). Surgery is usually indicated for cases with progressive neurologic deficit, abnormal gait or postural deformity, slippage >50%, or scoliosis.

Spina bifida occulta is a failure of closure of one or sev- 75 eral vertebral arches posteriorly; the meninges and spinal cord are normal. A dimple or small lipoma may overlie CHAPTER 7 Back and Neck Pain the defect. Most cases are asymptomatic and discovered incidentally during evaluation for back pain. Tethered cord syndrome usually presents as a progressive cauda equina disorder (see later), although myelopathy may also be the initial manifestation.The patient is often a young adult who complains of perineal or perianal pain, sometimes following minor trauma. Neuroimaging studies reveal a low-lying conus (below L1-L2) and a short and thickened filum terminale. TRAUMA FIGURE 7-4 MRI of lumbar herniated disk; left S1 radiculopathy. Sagit- A patient with a complaint of back pain and inability to tal T1-weighted image on the left with arrows outlining disk move the legs may have a spinal fracture or dislocation, margins. Sagittal T2 image on the right reveals a protruding and, with fractures above L1, spinal cord compression. disk at the L5–S1 level (arrows), which displaces the central Care must be taken to avoid further damage to the thecal sac. spinal cord or nerve roots by immobilizing the back pending results of x-rays. individuals. Disk herniation is unusual prior to age 20 and is rare in the fibrotic disks of the elderly. Degenera- Sprains and Strains tion of the nucleus pulposus and the annulus fibrosus increases with age and may be asymptomatic or painful. The terms low back sprain, strain, or mechanically induced Genetic factors may play a role in predisposing some muscle spasm refer to minor, self-limited injuries associ- patients to disk degeneration. The pain may be located ated with lifting a heavy object, a fall, or a sudden decel- in the low back only or referred to the leg, buttock, or eration such as in an automobile accident. These terms hip. A sneeze, cough, or trivial movement may cause the are used loosely and do not clearly describe a specific nucleus pulposus to prolapse, pushing the frayed and anatomic lesion. The pain is usually confined to the weakened annulus posteriorly. With severe disk disease, lower back, and there is no radiation to the buttocks or the nucleus may protrude through the annulus (hernia- legs. Patients with paraspinal muscle spasm often assume tion) or become extruded to lie as a free fragment in the unusual postures. spinal canal. Traumatic Vertebral Fractures The mechanism by which intervertebral disk injury causes back pain is controversial. The inner annulus Most traumatic fractures of the lumbar vertebral bodies fibrosus and nucleus pulposus are normally devoid of result from injuries producing anterior wedging or innervation. Inflammation and production of proinflam- compression.With severe trauma, the patient may sustain matory cytokines within the protruding or ruptured a fracture-dislocation or a “burst” fracture involving the disk may trigger or perpetuate back pain. Ingrowth of vertebral body and posterior elements. Traumatic verte- nociceptive (pain) nerve fibers into inner portions of a bral fractures are caused by falls from a height (a pars diseased disk may be responsible for chronic “disko- interarticularis fracture of the L5 vertebra is common), genic” pain. Nerve root injury (radiculopathy) from disk sudden deceleration in an automobile accident, or direct herniation may be due to compression, inflammation, or injury. Neurologic impairment is common, and early both; pathologically, demyelination and axonal loss are surgical treatment is indicated. In victims of blunt usually present. trauma, CT scans of the chest, abdomen, or pelvis can be reformatted to detect associated vertebral fractures. Symptoms of a ruptured disk include back pain, abnormal posture, limitation of spine motion (particu- LUMBAR DISK DISEASE larly flexion), or radicular pain. A dermatomal pattern of sensory loss or a reduced or absent deep tendon reflex is This is a common cause of chronic or recurrent low more suggestive of a specific root lesion than is the pat- back and leg pain (Figs. 7-3 and 7-4). Disk disease is tern of pain. Motor findings (focal weakness, muscle most likely to occur at the L4-L5 and L5-S1 levels, but upper lumbar levels are involved occasionally. The cause is often unknown; the risk is increased in overweight

SECTION II Clinical Manifestations of Neurologic Disease76 atrophy, or fasciculations) occur less frequently than treatment should also be considered if steady pain focal sensory or reflex changes. Symptoms and signs are and/or neurologic findings do not substantially improve usually unilateral, but bilateral involvement does occur over 4–12 weeks. with large central disk herniations that compress multi- ple descending nerve roots within the spinal canal. Clin- The usual surgical procedure is a partial hemil- ical manifestations of specific nerve root lesions are aminectomy with excision of the prolapsed disk. Fusion summarized in Table 7-2. There is suggestive evidence of the involved lumbar segments should be considered that lumbar disk herniation with a nonprogressive nerve only if significant spinal instability is present (i.e., degen- root deficit can be managed nonsurgically. The size of erative spondylolisthesis or isthmic spondylolysis). Over the disk protrusion may naturally decrease over time. a recent 5-year period, the number of lumbar fusion The differential diagnosis covers a variety of serious procedures performed in the United States more than and treatable conditions, including epidural abscess, doubled, for uncertain reasons. There are no large hematoma, or tumor. Fever, constant pain uninfluenced prospective, randomized trials comparing fusion to other by position, sphincter abnormalities, or signs of spinal types of surgical intervention. In one study, patients with cord disease suggests an etiology other than lumbar disk persistent low back pain despite an initial diskectomy disease. Bilateral absence of ankle reflexes can be a nor- fared no better with spine fusion than with a conserva- mal finding in old age or a sign of bilateral S1 radicu- tive regimen of cognitive intervention and exercise. lopathy. An absent deep tendon reflex or focal sensory loss may indicate injury to a nerve root, but other sites Cauda equina syndrome (CES) signifies an injury of of injury along the nerve must also be considered. For multiple lumbosacral nerve roots within the spinal canal. example, an absent knee reflex may be due to a femoral Low back pain, weakness and areflexia in the legs, saddle neuropathy or an L4 nerve root injury. A loss of sensa- anesthesia, and loss of bladder function may occur. The tion over the foot and lateral lower calf may result from problem must be distinguished from disorders of the lower a peroneal or lateral sciatic neuropathy or an L5 nerve spinal cord (conus medullaris syndrome), acute transverse root injury. Focal muscle atrophy may reflect a nerve myelitis (Chap. 30), and Guillain-Barré syndrome (Chap. 41). root or peripheral nerve injury, an anterior horn cell Combined involvement of the conus medullaris and disease, or disuse. cauda equina can occur. CES is commonly due to a An MRI scan or CT-myelogram is necessary to estab- ruptured lumbosacral intervertebral disk, lumbosacral lish the location and type of pathology. Spinal MRI yields spine fracture, hematoma within the spinal canal (e.g., exquisite views of intraspinal and adjacent soft tissue following lumbar puncture in patients with coagulopa- anatomy. Bony lesions of the lateral recess or interverte- thy), compressive tumor, or other mass lesion.Treatment bral foramen are optimally visualized by CT-myelography. options include surgical decompression, sometimes The correlation of neuroradiologic findings to symptoms, urgently in an attempt to restore or preserve motor or particularly pain, is not simple. Contrast-enhancing tears sphincter function, or radiotherapy for metastatic tumors in the annulus fibrosus or disk protrusions are widely (Chap. 32). accepted as common sources of back pain; however, many studies have found that most asymptomatic adults DEGENERATIVE CONDITIONS have similar findings. Asymptomatic disk protrusions are also common and may enhance with contrast. Further- Lumbar spinal stenosis describes a narrowed lumbar spinal more, in patients with known disk herniation treated canal. Neurogenic claudication is the usual symptom, con- either medically or surgically, persistence of the hernia- sisting of back and buttock or leg pain induced by walk- tion 10 years later had no relationship to the clinical ing or standing and relieved by sitting. Symptoms in the outcome. In summary, MRI findings of disk protrusion, legs are usually bilateral. Lumbar stenosis, by itself, is fre- tears in the annulus fibrosus, or contrast enhancement quently asymptomatic, and the correlation between the are common incidental findings that, by themselves, severity of symptoms and degree of stenosis of the spinal should not dictate management decisions for patients canal is poor. Unlike vascular claudication, symptoms are with back pain. often provoked by standing without walking. Unlike lum- There are four indications for intervertebral disk bar disk disease, symptoms are usually relieved by sitting. surgery: (1) progressive motor weakness from nerve root Focal weakness, sensory loss, or reflex changes may occur injury demonstrated on clinical examination or EMG, when spinal stenosis is associated with radiculopathy. (2) bowel or bladder disturbance or other signs of spinal Severe neurologic deficits, including paralysis and uri- cord compression, (3) incapacitating nerve root pain nary incontinence, occur rarely. Spinal stenosis can be despite conservative treatment for 4 weeks at a mini- acquired (75%), congenital, or due to a combination of mum, and (4) recurrent incapacitating pain despite con- these factors. Congenital forms (achondroplasia, idio- servative treatment.The latter two criteria are more sub- pathic) are characterized by short, thick pedicles that pro- jective and less well established than the others. Surgical duce both spinal canal and lateral recess stenosis.Acquired factors that contribute to spinal stenosis include degenera- tive diseases (spondylosis, spondylolisthesis, scoliosis), trauma,

AB with stiffness. The relationship between clinical symp- 77 CHAPTER 7 Back and Neck Pain toms and radiologic findings is usually not straightfor- FIGURE 7-5 ward. Pain may be prominent when x-ray, CT, or MRI Spinal stenosis. Sagittal T2 fast spin echo magnetic reso- findings are minimal, and large osteophytes can be seen nance imaging of a normal (A) and stenotic (B) lumbar spine, in asymptomatic patients. Radiculopathy occurs when revealing multifocal narrowing (arrows) of the cerebrospinal hypertrophied facets and osteophytes compress nerve fluid spaces surrounding the nerve roots within the thecal sac. roots in the lateral recess or intervertebral foramen. Osteophytes arising from the vertebral body may cause spine surgery, metabolic or endocrine disorders (epidural or contribute to central spinal canal stenosis. Disc lipomatosis, osteoporosis, acromegaly, renal osteodystro- degeneration may also play a role in reducing the cross- phy, hypoparathyroidism), and Paget’s disease. MRI sectional area of the intervertebral foramen; the provides the best definition of the abnormal anatomy descending pedicle may compress the exiting nerve (Fig. 7-5). root. Rarely, osteoarthritic changes in the lumbar spine are sufficient to compress the cauda equina. Conservative treatment of symptomatic spinal steno- sis includes nonsteroidal anti-inflammatory drugs Ankylosing Spondylitis (NSAIDs), exercise programs, and symptomatic treat- ment of acute pain episodes. Surgical therapy is consid- This distinctive arthritic spine disease typically presents ered when medical therapy does not relieve symptoms with the insidious onset of low back and buttock pain. sufficiently to allow for activities of daily living or when Patients are often males below age 40. Associated fea- significant focal neurologic signs are present. Most tures include morning back stiffness, nocturnal pain, patients with neurogenic claudication treated surgically pain unrelieved by rest, an elevated ESR, and the histo- experience at least 75% relief of back and leg pain. Up compatibility antigen HLA-B27. Onset at a young age to 25% develop recurrent stenosis at the same spinal and back pain improving with exercise are characteristic. level or an adjacent level 5 years after the initial surgery; Loss of the normal lumbar lordosis and exaggeration of recurrent symptoms usually respond to a second surgical thoracic kyphosis develop as the disease progresses. decompression. Inflammation and erosion of the outer fibers of the annulus fibrosus at the point of contact with the verte- Facet joint hypertrophy can produce unilateral radicular bral body are followed by ossification and bony growth symptoms or signs due to bony compression; symptoms that bridges adjacent vertebral bodies and reduces spine are often indistinguishable from disk-related radiculopa- mobility in all planes. Radiologic hallmarks are periar- thy. Stretch signs, focal motor weakness, hyporeflexia, or ticular destructive changes, sclerosis of the sacroiliac dermatomal sensory loss may be present. Hypertrophic joints, and bridging of vertebral bodies to produce the superior or inferior facets can be visualized by x-rays, fused “bamboo spine.” CT, or MRI. Surgical foraminotomy results in long- term relief of leg and back pain in 80–90% of these Stress fractures through the spontaneously ankylosed patients. The usefulness of therapeutic facet joint blocks posterior bony elements of the rigid, osteoporotic spine for pain has not been rigorously studied. may produce focal pain, spinal instability, spinal cord compression, or CES. Atlantoaxial subluxation with ARTHRITIS spinal cord compression occasionally occurs. Ankylosis of the ribs to the spine and a decrease in the height of Spondylosis, or osteoarthritic spine disease, typically the thoracic spine may compromise respiratory func- occurs in later life and primarily involves the cervical tion. For many patients, therapy with anti-tumor necro- and lumbosacral spine. Patients often complain of back sis factor agents is effective in reducing disease activity. pain that is increased with movement and associated Similar to ankylosing spondylitis, restricted movements may accompany Reiter’s syndrome, psoriatic arthritis, and chronic inflammatory bowel disease. NEOPLASMS (See Chap. 32) Back pain is the most common neuro- logic symptom in patients with systemic cancer and may be the presenting symptom. The cause is usually vertebral metastases. Metastatic carcinoma (breast, lung, prostate, thyroid, kidney, gastrointestinal tract), multiple myeloma, and non-Hodgkin’s and Hodgkin’s lymphomas frequently involve the spine. Cancer-related back pain

SECTION II Clinical Manifestations of Neurologic Disease78 tends to be constant, dull, unrelieved by rest, and worse METABOLIC CAUSES at night. By contrast, mechanical low back pain usually improves with rest. Plain x-rays may or may not show Osteoporosis and Osteosclerosis destructive lesions in one or several vertebral bodies without disk space involvement. MRI, CT, and CT- Immobilization or underlying conditions such as osteo- myelography are the studies of choice when spinal malacia, hyperparathyroidism, hyperthyroidism, multiple metastasis is suspected. MRI is preferred, but the most myeloma, metastatic carcinoma, or glucocorticoid use may rapidly available procedure is best because the patient’s accelerate osteoporosis and weaken the vertebral body, lead- condition may worsen quickly. Less than 5% of patients ing to compression fractures and pain. The most common who are nonambulatory at the time of diagnosis ever causes of nontraumatic vertebral body fractures are post- regain the ability to walk, thus early diagnosis is crucial. menopausal (type 1) or senile (type 2) osteoporosis. Com- pression fractures occur in up to half of patients with severe INFECTIONS/INFLAMMATION osteoporosis, and those who sustain a fracture have a 4.5- fold increased risk for recurrence.The sole manifestation of Vertebral osteomyelitis is usually caused by staphylococci, a compression fracture may be localized back pain or radic- but other bacteria or tuberculosis (Pott’s disease) may be ular pain exacerbated by movement and often reproduced responsible. The primary source of infection is usually by palpation over the spinous process of the affected verte- the urinary tract, skin, or lungs. Intravenous drug use is a bra.The clinical context, neurologic signs, and x-ray appear- well-recognized risk factor. Whenever pyogenic ance of the spine establish the diagnosis. Antiresorptive osteomyelitis is found, the possibility of bacterial endo- drugs including bisphosphonates (e.g., alendronate), trans- carditis should be considered. Back pain exacerbated by dermal estrogen, and tamoxifen have been shown to reduce motion and unrelieved by rest, spine tenderness over the the risk of osteoporotic fractures. Fewer than one-third of involved spine segment, and an elevated ESR are the patients with prior compression fractures are adequately most common findings in vertebral osteomyelitis. Fever treated for osteoporosis despite the increased risk for future or an elevated white blood cell count is found in a fractures; rates of primary prevention among individuals at minority of patients. Plain radiographs may show a nar- risk, but without a history of fracture, are even less. Com- rowed disk space with erosion of adjacent vertebrae; pression fractures above the midthoracic region suggest however, these diagnostic changes may take weeks or malignancy; if tumor is suspected, a bone biopsy or diagnos- months to appear. MRI and CT are sensitive and spe- tic search for a primary tumor is indicated. cific for osteomyelitis; CT may be more readily available in emergency settings and better tolerated by some Interventions [percutaneous vertebroplasty (PVP), patients with severe back pain. kyphoplasty] exist for osteoporotic compression fractures associated with debilitating pain. Candidates for PVP have Spinal epidural abscess (Chap. 30) presents with back midline back pain, palpation tenderness over the spinous pain (aggravated by movement or palpation) and fever. process of the affected vertebral body, <80% loss of ver- Signs of nerve root injury or spinal cord compression tebral body height, and onset of symptoms within the may be present. The abscess may track over multiple prior 4 months.The PVP technique consists of injection spinal levels and is best delineated by spine MRI. of polymethylmethacrylate, under fluoroscopic guidance, into the affected vertebral body. Kyphoplasty adds the Lumbar adhesive arachnoiditis with radiculopathy is due inflation of a balloon in the vertebral body prior to to fibrosis following inflammation within the subarach- the injection of cement. Rare complications can include noid space. The fibrosis results in nerve root adhesions, extravasation of cement into the epidural space (resulting and presents as back and leg pain associated with motor, in myelopathy) or fatal pulmonary embolism from migra- sensory, or reflex changes. Causes of arachnoiditis include tion of cement into paraspinal veins.Approximately three- multiple lumbar operations, chronic spinal infections, quarters of patients who meet selection criteria have spinal cord injury, intrathecal hemorrhage, myelography reported enhanced quality of life. Relief of pain follow- (rare), intrathecal injection of glucocorticoids or anes- ing PVP has also been reported in patients with vertebral thetics, and foreign bodies. The MRI shows clumped metastases, myeloma, or hemangiomas. nerve roots located centrally or adherent to the dura peripherally, or loculations of cerebrospinal fluid within Osteosclerosis, an abnormally increased bone density the thecal sac. Clumped nerve roots may also occur with often due to Paget’s disease, is readily identifiable on demyelinating polyneuropathy or neoplastic infiltration. routine x-ray studies and may or may not produce back Treatment is usually unsatisfactory. Microsurgical lysis of pain. Spinal cord or nerve root compression may result adhesions, dorsal rhizotomy, and dorsal root ganglionec- from bony encroachment. tomy have been tried, but outcomes have been poor. Dorsal column stimulation for pain relief has produced REFERRED PAIN FROM VISCERAL DISEASE varying results. Epidural injections of glucocorticoids have been of limited value. Diseases of the thorax, abdomen, or pelvis may refer pain to the posterior portion of the spinal segment that innervates

the diseased organ. Occasionally, back pain may be the first The pain is referred to the sacral region. Endometriosis 79CHAPTER 7 Back and Neck Pain and only manifestation. Upper abdominal diseases gener- or uterine cancers may invade the uterosacral ligaments. ally refer pain to the lower thoracic or upper lumbar region Pain associated with endometriosis is typically premen- (eighth thoracic to the first and second lumbar vertebrae), strual and often continues until it merges with men- lower abdominal diseases to the mid-lumbar region (sec- strual pain. Uterine malposition may cause uterosacral ond to fourth lumbar vertebrae), and pelvic diseases to ligament traction (retroversion, descensus, and prolapse) the sacral region. Local signs (pain with spine palpation, or produce sacral pain after prolonged standing. paraspinal muscle spasm) are absent, and little or no pain accompanies routine movements of the spine. Menstrual pain may be felt in the sacral region. The poorly localized, cramping pain can radiate down the Low Thoracic or Lumbar Pain with legs. Pain due to neoplastic infiltration of nerves is typi- Abdominal Disease cally continuous, progressive in severity, and unrelieved by rest at night. Less commonly, radiation therapy of Peptic ulcers or tumors of the posterior wall of the pelvic tumors may produce sacral pain from late radia- stomach or duodenum typically produce epigastric pain, tion necrosis of tissue or nerves. Low back pain that but midline back or paraspinal pain may occur if radiates into one or both thighs is common in the last retroperitoneal extension is present. Fatty foods are weeks of pregnancy. more likely to induce back pain associated with biliary disease. Diseases of the pancreas produce back pain to Urologic sources of lumbosacral back pain include the right of the spine (head of the pancreas involved) or chronic prostatitis, prostate cancer with spinal metastasis to the left (body or tail involved). Pathology in retroperi- (Chap. 32), and diseases of the kidney and ureter. Lesions toneal structures (hemorrhage, tumors, pyelonephritis) of the bladder and testes do not usually produce back produces paraspinal pain that radiates to the lower pain. Infectious, inflammatory, or neoplastic renal dis- abdomen, groin, or anterior thighs. A mass in the iliop- eases may produce ipsilateral lumbosacral pain, as can soas region often produces unilateral lumbar pain with renal artery or vein thrombosis. Paraspinal lumbar pain radiation toward the groin, labia, or testicles.The sudden may be a symptom of ureteral obstruction due to appearance of lumbar pain in a patient receiving antico- nephrolithiasis. agulants suggests retroperitoneal hemorrhage. OTHER CAUSES OF BACK PAIN Isolated low back pain occurs in 15–20% of patients with a contained rupture of an AAA. The classic clinical Postural Back Pain triad of abdominal pain, shock, and back pain occurs in <20% of patients.Two of these three features are present There is a group of patients with nonspecific chronic in two-thirds of patients, and hypotension is present in low back pain (CLBP) in whom no anatomic lesion can half. The typical patient is an elderly male smoker with be found despite exhaustive investigation.These individ- back pain. Frequently, the diagnosis is initially missed uals complain of vague, diffuse back pain with pro- because the symptoms and signs can be nonspecific. longed sitting or standing that is relieved by rest. The Common misdiagnoses include nonspecific back pain, physical examination is unrevealing except for “poor diverticulitis, renal colic, sepsis, and myocardial infarction. posture.” Imaging studies and laboratory evaluations do A careful abdominal examination revealing a pulsatile not identify a specific cause. Exercises to strengthen the mass (present in 50–75% of patients) is an important paraspinal and abdominal muscles are sometimes helpful. physical finding. Patients with suspected AAA should be evaluated with abdominal ultrasound, CT, or MRI. Psychiatric Disease Inflammatory bowel disorders (colitis, diverticulitis) or CLBP may be encountered in patients who seek finan- cancers of the colon may produce lower abdominal pain, cial compensation; in malingerers; or in those with con- midlumbar back pain, or both.The pain may have a belt- current substance abuse, chronic anxiety states, or line distribution around the body. A lesion in the trans- depression. Many patients with CLBP have a history of verse or proximal descending colon may refer pain to the psychiatric illness (depression, anxiety, substance abuse) mid or left back at the L2-L3 level. Lesions of the sigmoid or childhood trauma (physical or sexual abuse) that colon may refer pain to the upper sacral or midline supra- antedates the onset of back pain. Preoperative psycho- pubic regions or left lower quadrant of the abdomen. logical assessment has been used to exclude patients with marked psychological impairments that predict a Sacral Pain with Gynecologic poor surgical outcome. and Urologic Disease Unidentified Pelvic organs rarely cause low back pain, except for gyne- cologic disorders involving the uterosacral ligaments. The cause of low back pain occasionally remains unclear. Some patients have had multiple operations for disk

SECTION II Clinical Manifestations of Neurologic Disease80 disease but have persistent pain and disability.The origi- collars can be modestly helpful by limiting spontaneous nal indications for surgery may have been questionable, and reflex neck movements that exacerbate pain. Evi- with back pain only, no definite neurologic signs, or a dence regarding the efficacy of ice is lacking; heat may minor disk bulge noted on CT or MRI. Scoring sys- provide a short-term reduction in pain and disability. tems based upon neurologic signs, psychological factors, These interventions are optional given the lack of nega- physiologic studies, and imaging studies have been devised tive evidence, low cost, and low risk. Biofeedback has to minimize the likelihood of unsuccessful surgery. not been studied rigorously. Facet joint, trigger point, and ligament injections are not recommended for acute Treatment: treatment. BACK PAIN A role for modification of posture has not been vali- ACUTE LOW BACK PAIN (ALBP) ALBP is dated by rigorous clinical studies. As a practical matter, defined as pain of <3 months’ duration. Full recovery can temporary suspension of activity known to increase be expected in 85% of adults with ALBP without leg mechanical stress on the spine (heavy lifting, prolonged pain. Most have purely “mechanical” symptoms (i.e., pain sitting, bending or twisting, straining at stool) may be that is aggravated by motion and relieved by rest). helpful. Observational studies have been used to justify a Education is an important part of treatment. Satisfac- minimalist approach to this problem. These studies tion and the likelihood of follow-up increase when share a number of limitations: (1) a true placebo control patients are educated about prognosis, treatment group is often lacking; (2) patients who consult different methods, activity modifications, and strategies to pre- provider groups (generalists, orthopedists, neurologists) vent future exacerbations. In one study, patients who are assumed to have similar etiologies for their back felt they did not receive an adequate explanation for pain; (3) no information is provided about the details of their symptoms wanted further diagnostic tests. Evi- treatment; and (4) no attempt to tabulate structural dence for the efficacy of structured education programs causes of ALBP is made. (“back school”) is inconclusive; there is modest evidence for a short-term benefit, but evidence for a long-term The algorithms for the treatment of back pain benefit is lacking. Randomized studies of back school (Fig. 7-6) draw from published clinical practice guide- for primary prevention of low back injury and pain have lines (CPGs). However, since CPGs are based on incom- failed to demonstrate any benefit. plete evidence, guidelines should not substitute for clin- ical judgment. NSAIDs and acetaminophen (Table 5-1) are effective over-the-counter agents for ALBP. Muscle relaxants The initial assessment excludes serious causes of (cyclobenzaprine, 10 mg PO qhs as initial dose, up to spine pathology that require urgent intervention, includ- 10 mg PO tid) provide short-term (4–7 days) benefit, ing infection, cancer, and trauma. Risk factors for a seri- particularly at night if sleep is affected, but drowsiness ous cause of ALBP are shown in Table 7-1. Laboratory limits daytime use. Opioid analgesics are no more effec- studies are unnecessary if risk factors are absent. Plain tive than NSAIDs or acetaminophen for initial treatment spine films or CT are rarely indicated in the first month of of ALBP, nor do they increase the likelihood of return to symptoms unless a spine fracture is suspected. work. Short-term use of opioids may be necessary in patients unresponsive to or intolerant of acetaminophen Clinical trials have shown no benefit of >2 days of or NSAIDs. There is no evidence to support the use of bed rest for uncomplicated ALBP. There is evidence that oral glucocorticoids or tricyclic antidepressants for bed rest is also ineffective for patients with sciatica or ALBP. for acute back pain with signs of nerve root injury. Simi- larly, traction is not effective for ALBP. Possible advan- Epidural glucocorticoids may occasionally produce tages of early ambulation for ALBP include maintenance short-term pain relief in ALBP with radiculopathy, but of cardiovascular conditioning, improved disk and carti- proof is lacking for pain relief beyond 1 month. Epidural lage nutrition, improved bone and muscle strength, and glucocorticoids, anesthetics, or opioids are not indicated increased endorphin levels. One trial of early vigorous in the initial treatment of ALBP without radiculopathy. exercise was negative, but the value of less vigorous Diagnostic nerve root blocks have been advocated to exercise or other exercise programs are unknown. Early determine if pain originates from a specific nerve root. resumption of normal physical activity (without heavy However, improvement may result even when the nerve manual labor) is likely to be beneficial. root is not responsible for the pain; this may occur as a placebo effect, from a pain-generating lesion located Proof is lacking to support the treatment of acute distally along the peripheral nerve, or from anesthesia back and neck pain with acupuncture, transcutaneous of the sinuvertebral nerve. Therapeutic nerve root electrical nerve stimulation, massage, ultrasound, blocks with injection of glucocorticoids and a local diathermy, magnets, or electrical stimulation. Cervical anesthetic should be considered only after conservative

Acute low back pain — Not improving over Ͼ4 weeks 81 Leg symptoms? Acute low back +/– leg symptoms Yes No Medical history and examination Consult specialist; EMG/NCV Risk factors for Risk factors for serious etiology? neurologic examination No Clear nerve root signs? Yes No Radiculopathy? serious etiology? Table 7-1 and 7-3 No diagnostic tests Yes Yes No No Present Reassurance No Patient education Imaging study (MRI, or Specialist Evaluate CHAPTER 7 Back and Neck Pain Pain relief necessary? CT-myelography) No follow-up; nerve and treat Yes Are imaging and neurologic root, plexus, evaluations concordant? or CNS problem? Follow-up at 2 weeks Yes Yes Absent Return to normal activity? No Consult spine surgeon Appropriate Algorithm C intervention Symptomatic treatment options Encourage early return to usual activity, excluding 1 heavy manual labor Activity alterations to minimize symptoms Reconsider symptomatic treatment options Exercise program optional Yes Acetaminophen or NSAIDs Symptoms improving? Short duration muscle relaxants or opioids optional Bed rest optional — no more than 2 days No Yes Spinal manipulation optional Physical therapy optional Resume normal activity By 12 weeks: Address psychosocial issues Resume normal Consider long-term management options activity Consider re-evaluation B Follow-up at 2 weeks Back and leg pain managed > 4 weeks Return to activity tolerance? Focal neurologic deficit by examination or EMG Focal pathology by spine imaging study No Yes Patient symptoms worse or not improving Will patient consider surgery? Review response to initial treatment Resume normal activity Review risk factors Yes No Modify symptomatic treatment Spine surgery consultation to discuss: No Algorithm B at 1 Surgical procedure Follow-up 2 weeks later Yes Risks/benefits Return to normal activity? Short-term and long-term outcomes Availability of second opinion No Does the patient choose surgery? Yes Algorithm B Enter Algorithm B at 1 postoperatively C A blood count; ESR, erythrocyte sedimentation rate; UA, urinal- FIGURE 7-6 ysis; EMG, electromyography; NCV, nerve conduction velocity Algorithms for management of acute low back pain, age studies; MRI, magnetic resonance imaging; CT, computed ≥18 years. A. Symptoms <3 months, first 4 weeks. B. Man- tomography; CNS, central nervous system.) agement weeks 4–12. 1 , entry point from Algorithm C post- operatively or if patient declines surgery. C. Surgical options. (NSAIDs, nonsteroidal anti-inflammatory drugs; CBC, complete measures fail, particularly when temporary relief of pain adequate placebo control. Specific PT or chiropractic is necessary. protocols that may provide benefit have not been fully defined. A short course of lumbar spinal manipulation or physical therapy (PT) for symptomatic relief of uncom- CHRONIC LOW BACK PAIN CLBP, defined as plicated ALBP is a reasonable option. Prospective, ran- pain lasting >12 weeks, accounts for 50% of total back domized studies are difficult to perform in part because pain costs. Risk factors include obesity, female gender, there is no consensus about what constitutes an