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Multiple Sclerosis depleters valbenazine, deutetrabenazine, and tetrabenazine. Other options are amantadine, clonazepam, and, in refractory disease, DBS. Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is an acute life-threatening disorder caused by an idiosyncratic reaction to therapeutic doses of dopamine-blocking agents. Affected patients pre- sent with fever, rhabdomyolysis, altered mental status, rigidity, and dystonia. The creatine kinase level often is remarkably elevated. The most effective treatment is removal of the offending agent and supportive management. Treatment options include dopamine agonists and the mus- cle relaxant dantrolene, although there is only weak evidence supporting their effectiveness. Mortality may be as high as FIGURE 24. Optic nerve papillitis is characterized by hyperemia and swelling 10%. Patients who have dementia with Lewy bodies are par- of the disk, blurring of disk margins, and distended veins. Papillitis is seen in one- ticularly susceptible to neuroleptic malignant syndrome. A third of patients with optic neuritis.

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is an acute life-threatening disorder caused by an idiosyncratic reaction to therapeutic doses of dopamine-blocking agents. Affected patients pre- sent with fever, rhabdomyolysis, altered mental status, rigidity, and dystonia. The creatine kinase level often is remarkably elevated. The most effective treatment is removal of the offending agent and supportive management. Treatment options include dopamine agonists and the mus- cle relaxant dantrolene, although there is only weak evidence supporting their effectiveness. Mortality may be as high as FIGURE 24. Optic nerve papillitis is characterized by hyperemia and swelling 10%. Patients who have dementia with Lewy bodies are par- of the disk, blurring of disk margins, and distended veins. Papillitis is seen in one- ticularly susceptible to neuroleptic malignant syndrome. A third of patients with optic neuritis. similar condition, parkinsonism-hyperpyrexia syndrome, can be triggered by rapid withdrawal of dopaminergic medica- deficits in one eye that are occasionally associated with pain tion in patients with Parkinson disease, including when with eye movement and/or flashing lights (photopsia). Formal medications are stopped in the hospital before surgery. See ophthalmologic examination shows a reduction in visual acu- MKSAP 19 Pulmonary and Critical Care Medicine for more ity, a scotoma or visual field deficit, difficulty with color dis- information about neuroleptic malignant syndrome. crimination, and an afferent pupillary defect. Papillitis (flared appearance of the optic disc caused by inflammatory changes) (Figure 24) can sometimes be seen, although this finding only e Tardive dyskinesia is an extrapyramidal complication of occurs with involvement of the head of the nerve. Optic disc dopamine receptor-blocking medications characterized pallor (Figure 25) is usually seen as a late consequence of optic by choreiform and dystonic craniofacial movements; neuritis and is secondary to atrophy of the optic nerve. symptoms can take months to resolve or become per- Spinal cord involvement or myelitis results in sensory manent. and/or motor symptoms below the affected spinal level. Unlike e Neuroleptic malignant syndrome is an acute life-threat- other spinal cord processes, MS generally causes a partial ening disorder caused by exposure to therapeutic doses of myelitis, and symptoms of full-cord transection are rare; dopamine-blocking agents; it presents with fever, rhab- crossed sensory-motor symptoms may also occur (as in partial domyolysis, altered mental status, rigidity, and dystonia. Brown-Séquard syndrome). Neurologic examination generally reveals focal weakness and/or reduced sensation below a spe- cific spinal dermatome. Muscle tone can be reduced acutely, whereas spasticity and hyperreflexia often are delayed find- Multiple Sclerosis ings. During acute inflammation, some patients will also

similar condition, parkinsonism-hyperpyrexia syndrome, can be triggered by rapid withdrawal of dopaminergic medica- deficits in one eye that are occasionally associated with pain tion in patients with Parkinson disease, including when with eye movement and/or flashing lights (photopsia). Formal medications are stopped in the hospital before surgery. See ophthalmologic examination shows a reduction in visual acu- MKSAP 19 Pulmonary and Critical Care Medicine for more ity, a scotoma or visual field deficit, difficulty with color dis- information about neuroleptic malignant syndrome. crimination, and an afferent pupillary defect. Papillitis (flared appearance of the optic disc caused by inflammatory changes) (Figure 24) can sometimes be seen, although this finding only e Tardive dyskinesia is an extrapyramidal complication of occurs with involvement of the head of the nerve. Optic disc dopamine receptor-blocking medications characterized pallor (Figure 25) is usually seen as a late consequence of optic by choreiform and dystonic craniofacial movements; neuritis and is secondary to atrophy of the optic nerve. symptoms can take months to resolve or become per- Spinal cord involvement or myelitis results in sensory manent. and/or motor symptoms below the affected spinal level. Unlike e Neuroleptic malignant syndrome is an acute life-threat- other spinal cord processes, MS generally causes a partial ening disorder caused by exposure to therapeutic doses of myelitis, and symptoms of full-cord transection are rare; dopamine-blocking agents; it presents with fever, rhab- crossed sensory-motor symptoms may also occur (as in partial domyolysis, altered mental status, rigidity, and dystonia. Brown-Séquard syndrome). Neurologic examination generally reveals focal weakness and/or reduced sensation below a spe- cific spinal dermatome. Muscle tone can be reduced acutely, whereas spasticity and hyperreflexia often are delayed find- Multiple Sclerosis ings. During acute inflammation, some patients will also Presenting Signs and Symptoms Multiple sclerosis (MS) is an autoimmune disorder of the cen- tral nervous system (CNS) that causes inflammatory damage to the brain, spinal cord, and optic nerve. Most of the overt clini- cal symptoms of MS occur as a direct consequence of func- tional interruption of critical axonal pathways by inflamma- tory lesions. Relapses or flares involve development of neurologic symptoms over the course of hours to days and often peak in severity over the course of days to weeks. This is typically followed by a period of remission lasting weeks to months. Remyelination and recruitment of other brain regions to functionally substitute for the damaged area may result in clinical improvement during times of remission. The most common clinical manifestations of MS are optic neuritis, myelitis, and brainstem/cerebellar syndromes. Patients with optic neuritis typically have subacute visual FIGURE 25. Apale, flat optic disk characteristic of optic nerve atrophy.

Presenting Signs and Symptoms Multiple sclerosis (MS) is an autoimmune disorder of the cen- tral nervous system (CNS) that causes inflammatory damage to the brain, spinal cord, and optic nerve. Most of the overt clini- cal symptoms of MS occur as a direct consequence of func- tional interruption of critical axonal pathways by inflamma- tory lesions. Relapses or flares involve development of neurologic symptoms over the course of hours to days and often peak in severity over the course of days to weeks. This is typically followed by a period of remission lasting weeks to months. Remyelination and recruitment of other brain regions to functionally substitute for the damaged area may result in clinical improvement during times of remission. The most common clinical manifestations of MS are optic neuritis, myelitis, and brainstem/cerebellar syndromes. Patients with optic neuritis typically have subacute visual FIGURE 25. Apale, flat optic disk characteristic of optic nerve atrophy. 62

Multiple Sclerosis experience a tight, band-like sensation around the body involving the affected spinal level (“MS hug”). Lhermitte sign, ¢ Most of the overt clinical symptoms of multiple sclerosis which also can occur with upper cervical cord lesions from (MS) occur as a direct consequence of functional interrup- other causes, manifests as a shock-like sensation radiating tion of critical axonal pathways by inflammatory lesions; down the spine or limbs with flexion of the neck. Urinary the most common clinical manifestations of MS are optic frequency, urgency, hesitancy, or retention also may be seen. neuritis, myelitis, and brainstem/cerebellar syndromes. Brainstem syndromes often involve pathways for eye e Any patient with a suspected relapse of multiple sclerosis HVC movement and result in diplopia or oscillopsia (a sensation of should be screened for causes of Uhthoff phenomenon jerking of the visual field). Examination may reveal dysconju- (transient worsening of neurologic symptoms associated gate eye movements, nystagmus, and/or internuclear ophthal- with increased body temperature) masquerading as a moplegia (inability to adduct one eye and nystagmus in the relapse (or “pseudorelapse”) to avoid unnecessary treatment. abducting eye). Disruption of vestibular or cerebellar path- ways may result in ataxia and/or vertigo. Neurologic examina- tion will reveal appendicular or truncal ataxia, dysmetria on finger-to-nose testing, difficulty with rapid alternating move- Diagnosis of Multiple Sclerosis ments, and impairment of tandem gait. Diagnostic Criteria and Testing Most patients with MS also develop subtle, chronic symp- Because no specific genetic or serologic diagnostic biomarker toms that occur as a result of more widespread cortical demy- is available for diagnosing MS, the diagnosis is made through elination and nonlesional axonal pathology. At least 50% of rigorous application of diagnostic criteria that integrate clini- patients with MS experience cognitive deficits, typically in cal and radiologic findings. The McDonald criteria require domains of short-term memory, visuospatial function, and symptoms of CNS demyelination separated in space and time processing speed. Many patients with MS also report fatigue, froma series of clinical relapses or progression, signs on physi- which can manifest as a feeling of exhaustion despite adequate cal examination, distribution of lesions on MRI, and (if neces- sleep, a feeling of brain fog, and easy physical fatigability. sary) the presence of cerebrospinal fluid (CSF)-unique oligo- Many patients with MS also experience Uhthoff phenom- clonal bands. Proper application of the diagnostic criteria can enon, a transient worsening of baseline neurologic symptoms prevent unnecessary neurologic testing, referrals, and misdi- in the setting of hot weather, immersion in a hot bath, physical agnoses. A standardized MRI brain protocol should be used for exertion, or fever. This worsening occurs because of a tempo- all diagnostic evaluations of potential MS. Spinal cord imaging rary reduction in neuronal electrical conductance at higher also should be performed in patients with symptoms of myeli- temperatures, which causes magnification of symptoms from tis, patients with insufficient features on a brain MRI to sup- previously demyelinated pathways. Any patient with a sus- port the diagnosis, and patients older than 40 years with pected relapse should be screened for causes of Uhthoff phe- nonspecific brain MRI findings. Strict adherence to the nomenon masquerading as a relapse (or “pseudorelapse”) to McDonald criteria for MS-specific lesions is critical because avoid unnecessary treatment. Patients often need reassurance many other disorders (migraine, head trauma, and cerebrovas- and counseling that such events are not indicative of new cular disease) also can cause brain (but not spinal) lesions inflammatory damage. on MRI. Figure 26 shows examples of periventricular,

experience a tight, band-like sensation around the body involving the affected spinal level (“MS hug”). Lhermitte sign, ¢ Most of the overt clinical symptoms of multiple sclerosis which also can occur with upper cervical cord lesions from (MS) occur as a direct consequence of functional interrup- other causes, manifests as a shock-like sensation radiating tion of critical axonal pathways by inflammatory lesions; down the spine or limbs with flexion of the neck. Urinary the most common clinical manifestations of MS are optic frequency, urgency, hesitancy, or retention also may be seen. neuritis, myelitis, and brainstem/cerebellar syndromes. Brainstem syndromes often involve pathways for eye e Any patient with a suspected relapse of multiple sclerosis HVC movement and result in diplopia or oscillopsia (a sensation of should be screened for causes of Uhthoff phenomenon jerking of the visual field). Examination may reveal dysconju- (transient worsening of neurologic symptoms associated gate eye movements, nystagmus, and/or internuclear ophthal- with increased body temperature) masquerading as a moplegia (inability to adduct one eye and nystagmus in the relapse (or “pseudorelapse”) to avoid unnecessary treatment. abducting eye). Disruption of vestibular or cerebellar path- ways may result in ataxia and/or vertigo. Neurologic examina- tion will reveal appendicular or truncal ataxia, dysmetria on finger-to-nose testing, difficulty with rapid alternating move- Diagnosis of Multiple Sclerosis ments, and impairment of tandem gait. Diagnostic Criteria and Testing Most patients with MS also develop subtle, chronic symp- Because no specific genetic or serologic diagnostic biomarker toms that occur as a result of more widespread cortical demy- is available for diagnosing MS, the diagnosis is made through elination and nonlesional axonal pathology. At least 50% of rigorous application of diagnostic criteria that integrate clini- patients with MS experience cognitive deficits, typically in cal and radiologic findings. The McDonald criteria require domains of short-term memory, visuospatial function, and symptoms of CNS demyelination separated in space and time processing speed. Many patients with MS also report fatigue, froma series of clinical relapses or progression, signs on physi- which can manifest as a feeling of exhaustion despite adequate cal examination, distribution of lesions on MRI, and (if neces- sleep, a feeling of brain fog, and easy physical fatigability. sary) the presence of cerebrospinal fluid (CSF)-unique oligo- Many patients with MS also experience Uhthoff phenom- clonal bands. Proper application of the diagnostic criteria can enon, a transient worsening of baseline neurologic symptoms prevent unnecessary neurologic testing, referrals, and misdi- in the setting of hot weather, immersion in a hot bath, physical agnoses. A standardized MRI brain protocol should be used for exertion, or fever. This worsening occurs because of a tempo- all diagnostic evaluations of potential MS. Spinal cord imaging rary reduction in neuronal electrical conductance at higher also should be performed in patients with symptoms of myeli- temperatures, which causes magnification of symptoms from tis, patients with insufficient features on a brain MRI to sup- previously demyelinated pathways. Any patient with a sus- port the diagnosis, and patients older than 40 years with pected relapse should be screened for causes of Uhthoff phe- nonspecific brain MRI findings. Strict adherence to the nomenon masquerading as a relapse (or “pseudorelapse”) to McDonald criteria for MS-specific lesions is critical because avoid unnecessary treatment. Patients often need reassurance many other disorders (migraine, head trauma, and cerebrovas- and counseling that such events are not indicative of new cular disease) also can cause brain (but not spinal) lesions inflammatory damage. on MRI. Figure 26 shows examples of periventricular, FIGURE 26. Left, fluid-attenuated inversion recovery brain MRI that shows periventricular (red arrow), juxtacortical (yellow arrow), and infratentorial (green arrow) lesions specific to multiple sclerosis (MS); if visible, lesions in the cortex can substitute for juxtacortical lesions, according to official diagnostic criteria. Middle, coronal T1-weighted postcontrast MRI of the brain showing a contrast-enhancing MS lesion (blue arrow). Right, sagittal 12-weighted MRI of the spinal cord showing an MS lesion (gold arrow).

FIGURE 26. Left, fluid-attenuated inversion recovery brain MRI that shows periventricular (red arrow), juxtacortical (yellow arrow), and infratentorial (green arrow) lesions specific to multiple sclerosis (MS); if visible, lesions in the cortex can substitute for juxtacortical lesions, according to official diagnostic criteria. Middle, coronal T1-weighted postcontrast MRI of the brain showing a contrast-enhancing MS lesion (blue arrow). Right, sagittal 12-weighted MRI of the spinal cord showing an MS lesion (gold arrow). 63

Multiple Sclerosis juxtacortical, and infratentorial lesions that are specific to MS An elevated IgG blood-to-CSF index and an elevated IgG syn- and satisfy the McDonald criteria; if visible, lesions in the cor- thesis rate also are possible. Nonspecific mild elevations in the tex may substitute for juxtacortical lesions, according to the CSF leukocyte count or protein level are sometimes seen. official diagnostic criteria. Ancillary testing can show objective clinical evidence of a demyelinating lesion. Demyelinating e The McDonald criteria for diagnosing multiple sclerosis lesions of the optic nerve can be electrophysiologically con- require symptoms of central nervous system demyelina- firmed with visual evoked potentials. Optic coherence tomog- tion separated in space and time froma series of clinical raphy, which uses near-infrared light to quantify the thickness relapses or progression, signs on physical examination, of the retinal nerve fiber layer and macula, also can confirm optic nerve damage in acute or previous optic neuritis. distribution of lesions on MRI, and (if necessary) the presence of CSF-unique oligoclonal bands. Conductance delay in brainstem auditory evoked potentials and somatosensory evoked potentials can act as surrogate e Proper application of diagnostic criteria can prevent HVC markers of demyelination in brainstem and spinal cord path- unnecessary neurologic testing, referrals, and misdiag-

juxtacortical, and infratentorial lesions that are specific to MS An elevated IgG blood-to-CSF index and an elevated IgG syn- and satisfy the McDonald criteria; if visible, lesions in the cor- thesis rate also are possible. Nonspecific mild elevations in the tex may substitute for juxtacortical lesions, according to the CSF leukocyte count or protein level are sometimes seen. official diagnostic criteria. Ancillary testing can show objective clinical evidence of a demyelinating lesion. Demyelinating e The McDonald criteria for diagnosing multiple sclerosis lesions of the optic nerve can be electrophysiologically con- require symptoms of central nervous system demyelina- firmed with visual evoked potentials. Optic coherence tomog- tion separated in space and time froma series of clinical raphy, which uses near-infrared light to quantify the thickness relapses or progression, signs on physical examination, of the retinal nerve fiber layer and macula, also can confirm optic nerve damage in acute or previous optic neuritis. distribution of lesions on MRI, and (if necessary) the presence of CSF-unique oligoclonal bands. Conductance delay in brainstem auditory evoked potentials and somatosensory evoked potentials can act as surrogate e Proper application of diagnostic criteria can prevent HVC markers of demyelination in brainstem and spinal cord path- unnecessary neurologic testing, referrals, and misdiag- ways. Despite the usefulness of such testing for determining noses in patients suspected of having multiple sclerosis. anatomic localization, however, MRI is the only objective measure that fulfills the diagnostic criteria. Differential Diagnosis of Multiple Sclerosis CSF testing is not required for a diagnosis of MS if the Knowledge of the various rheumatologic, inflammatory, infec- McDonald criteria are otherwise met. However, CSF findings tious, and metabolic disorders with the potential to mimic the can be used to support the diagnosis when the MRI criteria are clinical signs/symptoms and radiologic changes of MS is not fully met. The normally functioning blood-brain barrier important when considering the diagnosis (Table 42). excludes immunoglobulins from the CSF in healthy persons, which results in a blood to CSF IgG ratio of 500:1 or greater. Clinical Course of Multiple Sclerosis Oligoclonal bands indicate elevations in oligoclonal immuno- Approximately 85% of patients with MS experience an initial globulin concentrations in the CSF and may result from dis- relapsing-remitting course. Those with a first demyelinating ruption of the blood-brain barrier or intrathecal production of event that does not meet the definition of clinically definite IgG. The presence of oligoclonal bands in the CSF that are MS are said to have a clinically isolated syndrome. Any absent in the serum occurs in 85% to 90% of persons with MS. future disease activity, defined as a clinical relapse or a new

ways. Despite the usefulness of such testing for determining noses in patients suspected of having multiple sclerosis. anatomic localization, however, MRI is the only objective measure that fulfills the diagnostic criteria. Differential Diagnosis of Multiple Sclerosis CSF testing is not required for a diagnosis of MS if the Knowledge of the various rheumatologic, inflammatory, infec- McDonald criteria are otherwise met. However, CSF findings tious, and metabolic disorders with the potential to mimic the can be used to support the diagnosis when the MRI criteria are clinical signs/symptoms and radiologic changes of MS is not fully met. The normally functioning blood-brain barrier important when considering the diagnosis (Table 42). excludes immunoglobulins from the CSF in healthy persons, which results in a blood to CSF IgG ratio of 500:1 or greater. Clinical Course of Multiple Sclerosis Oligoclonal bands indicate elevations in oligoclonal immuno- Approximately 85% of patients with MS experience an initial globulin concentrations in the CSF and may result from dis- relapsing-remitting course. Those with a first demyelinating ruption of the blood-brain barrier or intrathecal production of event that does not meet the definition of clinically definite IgG. The presence of oligoclonal bands in the CSF that are MS are said to have a clinically isolated syndrome. Any absent in the serum occurs in 85% to 90% of persons with MS. future disease activity, defined as a clinical relapse or a new TABLE 42. Differential Diagnosis of Multiple Sclerosis Disorder Notes Other demyelinating diseases ADEM Monophasic, often postinfectious syndrome causing large, diffuse areas of inflammatory CNS demyelination Characterized by fevers and encephalopathy, typically with focal neurologic symptoms, which differentiate ADEM from MS Rare in adults

ADEM Monophasic, often postinfectious syndrome causing large, diffuse areas of inflammatory CNS demyelination Characterized by fevers and encephalopathy, typically with focal neurologic symptoms, which differentiate ADEM from MS Rare in adults Neuromyelitis optica spectrum Antibody-mediated inflammation directed at aquaporin-4 antibody channels in the CNS or, disorder less commonly, myelin oligodendrocyte glycoprotein (MOG) that results in inflammatory | demyelination in the optic nerves and spinal cord. Can be differentiated from MS by NMO IgG (anti-aquaporin-4) or anti-MOG antibody testing and by its lack of significant brain involvement, large and longitudinally extensive spinal cord lesions, and profound cerebrospinal fluid leukocytosis Idiopathic transverse myelitis Monophasic, often postinfectious syndrome causing spinal cord inflammation Differentiated from MS by the presence of symptoms and findings unique to the underlying systemic disorder in addition to any neurologic symptoms? Systemic inflammatory diseases SLE White-matter changes on MRI and encephalopathy sometimes present Sjdgren syndrome Can cause an NMO-like disorder (with optic neuritis and myelitis), multiple cranial neuropathies, and a small-fiber neuropathy Sarcoidosis Causes granulomatous inflammation in the parenchyma and meninges of the brain and spinal cord = Occasionally associated with myelopathy | (Continued on the next page) 64

Multiple Sclerosis TABLE 42. Differential Diagnosis of Multiple Sclerosis (Continued) | Disorder Notes | Metabolic disorders | | Adult-onset leukodystrophies (such Rare | as adrenoleukodystrophy and May cause white-matter changes and progressive neurologic symptoms metachromatic leukodystrophy) Family history typically present Vitamin By deficiency Can cause optic neuropathy, cognitive changes, and subacute combined degeneration of the spinal cord (spasticity, weakness, and vibratory and proprioceptive sensory loss) Copper deficiency Can cause a myelopathy identical to that of vitamin B,2 deficiency; associated with bariatric gastric surgery, malabsorption syndromes, and excessive zinc ingestion Infections HIV infection, Lyme disease, and Can cause encephalopathy and myelopathy syphilis Can be diagnosed with appropriate serologic and spinal fluid analysis HTLV Causes a slowly progressive myelopathy with thoracic cord atrophy Sometimes termed tropical spastic paraparesis because more common in patients in | | Vascular disorders equatorial latitudes

HIV infection, Lyme disease, and Can cause encephalopathy and myelopathy syphilis Can be diagnosed with appropriate serologic and spinal fluid analysis HTLV Causes a slowly progressive myelopathy with thoracic cord atrophy Sometimes termed tropical spastic paraparesis because more common in patients in | | Vascular disorders equatorial latitudes Sporadic and genetic stroke Microvascular ischemic diseases potentially causing nonspecific white-matter changes on syndromes (hypercoagulability MRI that are often confused with MS | and viscosity disorders, such as Distinguished from MS by age, other vascular risk factors, and findings on neurologic exam polycythemia and myeloma) CNS vasculitis Primary type diagnosed by catheter angiography or tissue biopsy Can present with both stroke-like changes and meningeal contrast enhancement on MRI Susac syndrome Causes small-vessel arteriopathy that causes dysfunction of the retina and cochlear and corpus callosum lesions seen on MRI Subacute clinical progression, without remission or relapse Migraine Subcortical white-matter lesions sometimes present and often confused with MS lesions CADASIL a possible diagnosis in patients with a familial syndrome of migraine, subcortical strokes, mood disorders, and early dementia Primary CNS neoplasm (gliomas or Neoplasms with progressively worsening symptoms and neuroimaging findings lymphomas) or metastatic disease Brain biopsy indicated when imaging cannot differentiate neoplasms from demyelinating disease

Primary CNS neoplasm (gliomas or Neoplasms with progressively worsening symptoms and neuroimaging findings lymphomas) or metastatic disease Brain biopsy indicated when imaging cannot differentiate neoplasms from demyelinating disease Paraneoplastic syndromes May cause progressive cerebellar ataxia or myeloneuropathy (neuropathy affecting the spinal cord and peripheral nerves) Personality and mental status changes in addition to seizures and movement disorders possible with paraneoplastic limbic encephalitis Diagnosis often made on the basis of cancer screening and antibody testing Somatoform disorders Psychiatric disorders presenting with neurologic-like symptoms that are due to somatization, conversion, and similar conditions Neurologic evaluation findings entirely normal, or inconsistency or incongruency of neurologic findings. ADEM = acute disseminated encephalomyelitis; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS = central nervous — system; HTLV = human T-lymphotropic virus; MS = multiple sclerosis, NMO = neuromyelitis optica; SLE = systemic lupus erythematosus. For more information on idiopathic transverse myelitis, see Disorders of the Spinal Cord.

ADEM = acute disseminated encephalomyelitis; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS = central nervous — system; HTLV = human T-lymphotropic virus; MS = multiple sclerosis, NMO = neuromyelitis optica; SLE = systemic lupus erythematosus. For more information on idiopathic transverse myelitis, see Disorders of the Spinal Cord. or contrast-enhancing lesion on MRI, results in conversion relapsing-remitting MS of approximately 90%, whereas to a diagnosis of clinically definite relapsing-remitting MS patients without brain lesions have a much lower risk (Figure 27). Because disease-modifying therapies reduce the (10%-20%). risk of conversion from a clinically isolated syndrome to Determination of activity status may also inform treat- relapsing-remitting MS by approximately 50%, stratifica- ment decisions in relapsing-remitting MS (see Figure 27). In tion of risk for conversion can inform treatment decisions. the first few years that a patient has this type of MS, significant Patients with brain lesions on MRI at the time of their clini- or complete recovery from relapse is common. Eventually, cally isolated syndrome have a 10-year risk of conversion to postrelapse recovery generally diminishes and permanent 65

Multiple Sclerosis Clinical onset of symptoms Relapsing-remitting symptoms | Progressive symptoms Active |_______, A Progression Active, with Progression > -——————_> progression < > 1 i) \ <x 1 RRMS +> No No 1 Se progression Active, without progression 2 = 1 $ progression < = 3 x Vv Y Z 3 SPMS PPMS

A Progression Active, with Progression > -——————_> progression < > 1 i) \ <x 1 RRMS +> No No 1 Se progression Active, without progression 2 = 1 $ progression < = 3 x Vv Y Z 3 SPMS PPMS cls > Vv P= > Progression Progression > Not active = Not active, with — < > % J progression < a ° % 2 ° 2 No No

cls > Vv P= > Progression Progression > Not active = Not active, with — < > % J progression < a ° % 2 ° 2 No No Vv progression progression » Not active, without < cls 1 progression

Vv progression progression » Not active, without < cls 1 progression FIGURE 27. Atclinical onset, multiple sclerosis (MS) can be either relapsing or progressive in nature. An initial, isolated demyelinating event results in a preliminary diagnosis of a clinically isolated syndrome (CIS). Any further activity (defined as a clinical relapse, new or enlarging T2-weighted lesion on MRI, or gadolinium-enhancing lesion on MRI) results in a diagnosis of relapsing-remitting MS (RRMS). Over time, RRMS can either be classified as active (if evidence of activity exists) or not active. Some patients with RRMS can later exhibit signs of progression (defined as slowly progressive accumulation of disability), and their condition can be reclassified as secondary progressive MS (SPMS). An initial clinical onset of progressive, nonrelapsing symptoms is diagnosed as primary progressive MS (PPMS). Any patients with progressive MS (PPMS or SPMS) can later exhibit signs of activity and/or progression, which allows for further stratification into four categories based on the presence or absence of these qualities. CIS = clinically isolated syndrome; MS = multiple sclerosis; PPMS = primary progressive MS; RRMS = relapsing-remitting MS; SPMS = secondary progressive MS.

FIGURE 27. Atclinical onset, multiple sclerosis (MS) can be either relapsing or progressive in nature. An initial, isolated demyelinating event results in a preliminary diagnosis of a clinically isolated syndrome (CIS). Any further activity (defined as a clinical relapse, new or enlarging T2-weighted lesion on MRI, or gadolinium-enhancing lesion on MRI) results in a diagnosis of relapsing-remitting MS (RRMS). Over time, RRMS can either be classified as active (if evidence of activity exists) or not active. Some patients with RRMS can later exhibit signs of progression (defined as slowly progressive accumulation of disability), and their condition can be reclassified as secondary progressive MS (SPMS). An initial clinical onset of progressive, nonrelapsing symptoms is diagnosed as primary progressive MS (PPMS). Any patients with progressive MS (PPMS or SPMS) can later exhibit signs of activity and/or progression, which allows for further stratification into four categories based on the presence or absence of these qualities. CIS = clinically isolated syndrome; MS = multiple sclerosis; PPMS = primary progressive MS; RRMS = relapsing-remitting MS; SPMS = secondary progressive MS. disability accumulates. Without treatment, half of patients radiologically isolated syndrome are at high risk for later conver- with relapsing-remitting MS develop secondary progressive sion to clinically definite MS and should be monitored closely. MS after a median of 10 to 15 years. In secondary progressive MS, relapses become infrequent or cease completely, but e Approximately 85% of patients with multiple sclerosis slowly progressive neurologic disability continues to accrue in multiple domains. Data now suggest that use of disease- (MS) experience an initial relapsing-remitting course; modifying therapies can decrease the chance of conversion to 15% have primary progressive MS at presentation.

disability accumulates. Without treatment, half of patients radiologically isolated syndrome are at high risk for later conver- with relapsing-remitting MS develop secondary progressive sion to clinically definite MS and should be monitored closely. MS after a median of 10 to 15 years. In secondary progressive MS, relapses become infrequent or cease completely, but e Approximately 85% of patients with multiple sclerosis slowly progressive neurologic disability continues to accrue in multiple domains. Data now suggest that use of disease- (MS) experience an initial relapsing-remitting course; modifying therapies can decrease the chance of conversion to 15% have primary progressive MS at presentation. secondary progressive MS. e Disease-modifying therapies reduce the risk of conver-

modifying therapies can decrease the chance of conversion to 15% have primary progressive MS at presentation. secondary progressive MS. e Disease-modifying therapies reduce the risk of conver- Approximately 15% of patients with MS have primary pro- sion froma clinically isolated syndrome to relapsing- gressive MS at presentation. This subtype often develops later remitting multiple sclerosis by approximately 50%. in life (in the fifth or sixth decade) compared with the younger e Without treatment, half the patients with relapsing- age of onset (third or fourth decade of life) in typical relapsing- remitting multiple sclerosis (MS) develop secondary remitting MS. Because patients with both primary and second- progressive MS after a median of 10 to 15 years; the pro- ary progressive MS can have periods of disability progression or portion of patients converting to secondary progressive stability (with some even having permanent halting of progres- MS has decreased since the introduction of disease- sion), adding the modifiers “with progression” and “without modifying therapies. progression” to these diagnostic terms has been suggested

Approximately 15% of patients with MS have primary pro- sion froma clinically isolated syndrome to relapsing- gressive MS at presentation. This subtype often develops later remitting multiple sclerosis by approximately 50%. in life (in the fifth or sixth decade) compared with the younger e Without treatment, half the patients with relapsing- age of onset (third or fourth decade of life) in typical relapsing- remitting multiple sclerosis (MS) develop secondary remitting MS. Because patients with both primary and second- progressive MS after a median of 10 to 15 years; the pro- ary progressive MS can have periods of disability progression or portion of patients converting to secondary progressive stability (with some even having permanent halting of progres- MS has decreased since the introduction of disease- sion), adding the modifiers “with progression” and “without modifying therapies. progression” to these diagnostic terms has been suggested (Figure 27). Occasionally, patients with these types of MS may meet criteria for relapsing activity (clinical relapses, new or Treatment of Multiple Sclerosis contrast-enhancing lesions on MRI) and thus can be further Lifestyle Modifications and General Health Care stratified into “active” and “not active” categories. Although some patients with MS may avoid physical activity Patients with a radiologically isolated syndrome have no because of disability, fatigue, and the Uhthoff phenomenon, clinical symptoms of MS but are found incidentally to have MRI repeated studies have shown multiple benefits from both findings that meet the radiologic criteria for MS. Although an MS strengthening and aerobic exercise programs. Patients with diagnosis cannot be made in the absence of demyelinating signs significant Uhthoff phenomenon induced by exercise should and symptoms, it has been shown that patients with a be reassured that neurologic injury will not result from

(Figure 27). Occasionally, patients with these types of MS may meet criteria for relapsing activity (clinical relapses, new or Treatment of Multiple Sclerosis contrast-enhancing lesions on MRI) and thus can be further Lifestyle Modifications and General Health Care stratified into “active” and “not active” categories. Although some patients with MS may avoid physical activity Patients with a radiologically isolated syndrome have no because of disability, fatigue, and the Uhthoff phenomenon, clinical symptoms of MS but are found incidentally to have MRI repeated studies have shown multiple benefits from both findings that meet the radiologic criteria for MS. Although an MS strengthening and aerobic exercise programs. Patients with diagnosis cannot be made in the absence of demyelinating signs significant Uhthoff phenomenon induced by exercise should and symptoms, it has been shown that patients with a be reassured that neurologic injury will not result from 66

Multiple Sclerosis exercise; they also can be counseled on strategies to minimize Treatment of Acute Exacerbations discomfort, such as heat avoidance or external cooling (cold An MS relapse is defined as new or worsening neurologic water, fans, body-cooling devices) during exercise. symptoms lasting more than 24 hours. Symptoms lasting only Exercise also can help preserve bone health. Patients with minutes to hours should not be considered or treated as a MS have a three- to sixfold increased risk of reduced bone relapse. The possibility of a pseudorelapse should always be mineral density, most likely from a combination of reduced considered before initiating treatment; suspicion of this condi physical activity, repeated use of glucocorticoids, and vitamin tion should trigger clinical investigation for an underlying D deficiency. Vitamin D deficiency is common in MS patients, cause. The subsequent treatment of any infection or metabolic and reduced serum levels of vitamin D are predictive of MS disturbance often results in improvement in neurologic development and future accumulation of lesions on MRI. The symptoms. role of vitamin D supplementation is controversial. Some stud- The standard treatment for MS relapses is high-dose glu- ies have showna benefit of this vitamin in reducing symptoms cocorticoids, typically intravenous methylprednisolone (1 g/d of fatigue and MRI activity compared with placebo. However, for 3 to 5 days). Multiple trials have shown that bioequivalent reductions in relapses or disability progression have not been doses of oral glucocorticoids (such as prednisone, 1250 mg/d) shown. Cochrane meta-analyses of all available trials suggest are equally effective and well tolerated, with reduced cost. that current evidence is insufficient to suggest a protective role Adverse effects of high-dose glucocorticoids include insom- for vitamin D supplementation in MS. nia, hyperglycemia, metallic taste, gastritis, fluid retention, Measures to prevent infection are needed for patients receiv- irritability, and (rarely) psychosis. These effects are typically ing more aggressive, immunosuppressive MS treatments, espe- short lived, given the brief duration of treatment. Frequent or cially given the increased risk of MS relapse at the time of systemic prolonged glucocorticoid treatment should be avoided to min- infection. Current MS treatment guidelines recommend annual imize the risks of osteopenia and early cataracts. vaccination against influenza (with inactivated vaccine) and main- MS relapses also can be treated with administration of a tenance of standard immunizations. Immunizations should be short course of intramuscular adrenocorticotropin hormone withheld during MS relapses. All live vaccines are contraindicated gel. This approach has a more favorable adverse-effect profile in patients receiving immunosuppressant or immunomodulating compared with external glucocorticoid administration. Use of therapies. Patients with MS-related bladder dysfunction are at this gel is limited by prohibitive pricing. higher risk of recurrent urinary tract infection, and thus strategies Patients not responding to glucocorticoid treatment may to reduce the frequency of bladder infections are necessary. respond to plasmapheresis, administered as five consecutive Smoking cessation is advised for all patients with MS exchanges. because of the threefold risk of conversion from relapsing- remitting MS to secondary progressive MS and faster rates of disability accumulation in cigarette smokers. e The standard treatment for MS relapses is high-dose

exercise; they also can be counseled on strategies to minimize Treatment of Acute Exacerbations discomfort, such as heat avoidance or external cooling (cold An MS relapse is defined as new or worsening neurologic water, fans, body-cooling devices) during exercise. symptoms lasting more than 24 hours. Symptoms lasting only Exercise also can help preserve bone health. Patients with minutes to hours should not be considered or treated as a MS have a three- to sixfold increased risk of reduced bone relapse. The possibility of a pseudorelapse should always be mineral density, most likely from a combination of reduced considered before initiating treatment; suspicion of this condi physical activity, repeated use of glucocorticoids, and vitamin tion should trigger clinical investigation for an underlying D deficiency. Vitamin D deficiency is common in MS patients, cause. The subsequent treatment of any infection or metabolic and reduced serum levels of vitamin D are predictive of MS disturbance often results in improvement in neurologic development and future accumulation of lesions on MRI. The symptoms. role of vitamin D supplementation is controversial. Some stud- The standard treatment for MS relapses is high-dose glu- ies have showna benefit of this vitamin in reducing symptoms cocorticoids, typically intravenous methylprednisolone (1 g/d of fatigue and MRI activity compared with placebo. However, for 3 to 5 days). Multiple trials have shown that bioequivalent reductions in relapses or disability progression have not been doses of oral glucocorticoids (such as prednisone, 1250 mg/d) shown. Cochrane meta-analyses of all available trials suggest are equally effective and well tolerated, with reduced cost. that current evidence is insufficient to suggest a protective role Adverse effects of high-dose glucocorticoids include insom- for vitamin D supplementation in MS. nia, hyperglycemia, metallic taste, gastritis, fluid retention, Measures to prevent infection are needed for patients receiv- irritability, and (rarely) psychosis. These effects are typically ing more aggressive, immunosuppressive MS treatments, espe- short lived, given the brief duration of treatment. Frequent or cially given the increased risk of MS relapse at the time of systemic prolonged glucocorticoid treatment should be avoided to min- infection. Current MS treatment guidelines recommend annual imize the risks of osteopenia and early cataracts. vaccination against influenza (with inactivated vaccine) and main- MS relapses also can be treated with administration of a tenance of standard immunizations. Immunizations should be short course of intramuscular adrenocorticotropin hormone withheld during MS relapses. All live vaccines are contraindicated gel. This approach has a more favorable adverse-effect profile in patients receiving immunosuppressant or immunomodulating compared with external glucocorticoid administration. Use of therapies. Patients with MS-related bladder dysfunction are at this gel is limited by prohibitive pricing. higher risk of recurrent urinary tract infection, and thus strategies Patients not responding to glucocorticoid treatment may to reduce the frequency of bladder infections are necessary. respond to plasmapheresis, administered as five consecutive Smoking cessation is advised for all patients with MS exchanges. because of the threefold risk of conversion from relapsing- remitting MS to secondary progressive MS and faster rates of disability accumulation in cigarette smokers. e The standard treatment for MS relapses is high-dose Many patients with MS are women in their childbearing glucocorticoids, typically intravenous methylpredniso-

exercise; they also can be counseled on strategies to minimize Treatment of Acute Exacerbations discomfort, such as heat avoidance or external cooling (cold An MS relapse is defined as new or worsening neurologic water, fans, body-cooling devices) during exercise. symptoms lasting more than 24 hours. Symptoms lasting only Exercise also can help preserve bone health. Patients with minutes to hours should not be considered or treated as a MS have a three- to sixfold increased risk of reduced bone relapse. The possibility of a pseudorelapse should always be mineral density, most likely from a combination of reduced considered before initiating treatment; suspicion of this condi physical activity, repeated use of glucocorticoids, and vitamin tion should trigger clinical investigation for an underlying D deficiency. Vitamin D deficiency is common in MS patients, cause. The subsequent treatment of any infection or metabolic and reduced serum levels of vitamin D are predictive of MS disturbance often results in improvement in neurologic development and future accumulation of lesions on MRI. The symptoms. role of vitamin D supplementation is controversial. Some stud- The standard treatment for MS relapses is high-dose glu- ies have showna benefit of this vitamin in reducing symptoms cocorticoids, typically intravenous methylprednisolone (1 g/d of fatigue and MRI activity compared with placebo. However, for 3 to 5 days). Multiple trials have shown that bioequivalent reductions in relapses or disability progression have not been doses of oral glucocorticoids (such as prednisone, 1250 mg/d) shown. Cochrane meta-analyses of all available trials suggest are equally effective and well tolerated, with reduced cost. that current evidence is insufficient to suggest a protective role Adverse effects of high-dose glucocorticoids include insom- for vitamin D supplementation in MS. nia, hyperglycemia, metallic taste, gastritis, fluid retention, Measures to prevent infection are needed for patients receiv- irritability, and (rarely) psychosis. These effects are typically ing more aggressive, immunosuppressive MS treatments, espe- short lived, given the brief duration of treatment. Frequent or cially given the increased risk of MS relapse at the time of systemic prolonged glucocorticoid treatment should be avoided to min- infection. Current MS treatment guidelines recommend annual imize the risks of osteopenia and early cataracts. vaccination against influenza (with inactivated vaccine) and main- MS relapses also can be treated with administration of a tenance of standard immunizations. Immunizations should be short course of intramuscular adrenocorticotropin hormone withheld during MS relapses. All live vaccines are contraindicated gel. This approach has a more favorable adverse-effect profile in patients receiving immunosuppressant or immunomodulating compared with external glucocorticoid administration. Use of therapies. Patients with MS-related bladder dysfunction are at this gel is limited by prohibitive pricing. higher risk of recurrent urinary tract infection, and thus strategies Patients not responding to glucocorticoid treatment may to reduce the frequency of bladder infections are necessary. respond to plasmapheresis, administered as five consecutive Smoking cessation is advised for all patients with MS exchanges. because of the threefold risk of conversion from relapsing- remitting MS to secondary progressive MS and faster rates of disability accumulation in cigarette smokers. e The standard treatment for MS relapses is high-dose Many patients with MS are women in their childbearing glucocorticoids, typically intravenous methylpredniso- years. The estrogenic state of pregnancy has an immunomod- lone; frequent or prolonged glucocorticoid treatment

exercise; they also can be counseled on strategies to minimize Treatment of Acute Exacerbations discomfort, such as heat avoidance or external cooling (cold An MS relapse is defined as new or worsening neurologic water, fans, body-cooling devices) during exercise. symptoms lasting more than 24 hours. Symptoms lasting only Exercise also can help preserve bone health. Patients with minutes to hours should not be considered or treated as a MS have a three- to sixfold increased risk of reduced bone relapse. The possibility of a pseudorelapse should always be mineral density, most likely from a combination of reduced considered before initiating treatment; suspicion of this condi physical activity, repeated use of glucocorticoids, and vitamin tion should trigger clinical investigation for an underlying D deficiency. Vitamin D deficiency is common in MS patients, cause. The subsequent treatment of any infection or metabolic and reduced serum levels of vitamin D are predictive of MS disturbance often results in improvement in neurologic development and future accumulation of lesions on MRI. The symptoms. role of vitamin D supplementation is controversial. Some stud- The standard treatment for MS relapses is high-dose glu- ies have showna benefit of this vitamin in reducing symptoms cocorticoids, typically intravenous methylprednisolone (1 g/d of fatigue and MRI activity compared with placebo. However, for 3 to 5 days). Multiple trials have shown that bioequivalent reductions in relapses or disability progression have not been doses of oral glucocorticoids (such as prednisone, 1250 mg/d) shown. Cochrane meta-analyses of all available trials suggest are equally effective and well tolerated, with reduced cost. that current evidence is insufficient to suggest a protective role Adverse effects of high-dose glucocorticoids include insom- for vitamin D supplementation in MS. nia, hyperglycemia, metallic taste, gastritis, fluid retention, Measures to prevent infection are needed for patients receiv- irritability, and (rarely) psychosis. These effects are typically ing more aggressive, immunosuppressive MS treatments, espe- short lived, given the brief duration of treatment. Frequent or cially given the increased risk of MS relapse at the time of systemic prolonged glucocorticoid treatment should be avoided to min- infection. Current MS treatment guidelines recommend annual imize the risks of osteopenia and early cataracts. vaccination against influenza (with inactivated vaccine) and main- MS relapses also can be treated with administration of a tenance of standard immunizations. Immunizations should be short course of intramuscular adrenocorticotropin hormone withheld during MS relapses. All live vaccines are contraindicated gel. This approach has a more favorable adverse-effect profile in patients receiving immunosuppressant or immunomodulating compared with external glucocorticoid administration. Use of therapies. Patients with MS-related bladder dysfunction are at this gel is limited by prohibitive pricing. higher risk of recurrent urinary tract infection, and thus strategies Patients not responding to glucocorticoid treatment may to reduce the frequency of bladder infections are necessary. respond to plasmapheresis, administered as five consecutive Smoking cessation is advised for all patients with MS exchanges. because of the threefold risk of conversion from relapsing- remitting MS to secondary progressive MS and faster rates of disability accumulation in cigarette smokers. e The standard treatment for MS relapses is high-dose Many patients with MS are women in their childbearing glucocorticoids, typically intravenous methylpredniso- years. The estrogenic state of pregnancy has an immunomod- lone; frequent or prolonged glucocorticoid treatment ulatory effect that tends to reduce MS disease activity during should be avoided to minimize the risks associated with pregnancy, often precluding the need for treatment during this long-term glucocorticoid use.

years. The estrogenic state of pregnancy has an immunomod- lone; frequent or prolonged glucocorticoid treatment ulatory effect that tends to reduce MS disease activity during should be avoided to minimize the risks associated with pregnancy, often precluding the need for treatment during this long-term glucocorticoid use. period. Although the risk of relapse is increased slightly in the first 3 months of pregnancy, this does not seem to contribute Disease-Modifying Therapies negatively to prognosis; multiple studies have shown that Prevention of MS relapse is vital. Various immunomodulatory pregnancy does not result in additional permanent disability or immunosuppressive medications have been shown to and that multiparous women have better long-term MS out- reduce the risk of relapse, disability progression, and new MRI comes than nulliparous or uniparous women. Data on the lesion formation. Evidence suggests that disease-modifying effect of breastfeeding on MS relapse risk are inconclusive. therapies also may reduce mortality and prevent conversion to secondary progressive MS. Many choices of disease-modifying therapy for patients HVC e Studies have shown multiple benefits from both with relapsing-remitting MS exist (Table 43), each differing strengthening and aerobic exercise programs in patients in its route of administration, mechanism of action, and

comes than nulliparous or uniparous women. Data on the lesion formation. Evidence suggests that disease-modifying effect of breastfeeding on MS relapse risk are inconclusive. therapies also may reduce mortality and prevent conversion to secondary progressive MS. Many choices of disease-modifying therapy for patients HVC e Studies have shown multiple benefits from both with relapsing-remitting MS exist (Table 43), each differing strengthening and aerobic exercise programs in patients in its route of administration, mechanism of action, and with multiple sclerosis. potential adverse effects. Interferon beta preparations, glati- ramer acetate, and teriflunomide have additional utility in HVC e Current multiple sclerosis (MS) treatment guidelines clinically isolated syndrome for prevention of conversion to recommend vaccination against influenza and mainte- clinically definite MS. Despite many options for those with nance of standard immunizations; smoking is associ- relapsing disease, the options for patients with progressive ated with a threefold risk of conversion from relapsing- forms of MS are limited. Mitoxantrone, siponimod, and clad- remitting MS to secondary progressive MS and faster ribine are currently the only FDA-approved therapies for rates of disability accumulation. patients with secondary progressive MS with activity (see 67

Multiple Sclerosis TABLE 43. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis _ Medication Route of Potential Adverse Effects Recommended Monitoring Pregnancy | Administration Category? | Interferon beta-1a Intramuscular or Flu-like symptoms, fatigue, CBC and liver enzymes every Cc | (three formulations) — subcutaneous depression, increased 3-6 months | | andinterferon beta- — injection spasticity, transaminitis, rare | | 1b (two formulations) autoimmune hepatitis, and | | injection-site reactions |

TABLE 43. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis _ Medication Route of Potential Adverse Effects Recommended Monitoring Pregnancy | Administration Category? | Interferon beta-1a Intramuscular or Flu-like symptoms, fatigue, CBC and liver enzymes every Cc | (three formulations) — subcutaneous depression, increased 3-6 months | | andinterferon beta- — injection spasticity, transaminitis, rare | | 1b (two formulations) autoimmune hepatitis, and | | injection-site reactions | | Glatiramer acetate Subcutaneous Injection-site reactions, None B | (three formulations) —_ injection lipoatrophy of skin at injection | sites, and rare systemic panic attack-like syndrome | | Sphingosine-1- Oral Transaminitis, lymphopenia, Pretreatment cardiac screening Fingolimod=C phosphate increased risk of serious (all), cardiac monitoring (for Siponimod and | treatments herpesvirus infection, bradycardia) after administration ozanimod =no | | (fingolimod, hypertension, bradycardia of first dose (fingolimod only), assigned | | siponimod, (usually only with the first ophthalmologic screening (for category; no dose), macular edema, basal macular edema), liver enzymes, adequate data in | | ozanimod) cell carcinoma, PML, disability CBC monitoring (for excessive humans, but | worsening after discontinuation lymphopenia), yearly skin teratogenicity | examination (for basal cell seen inlaboratory | carcinoma). CYP2C9 genotype animal testing. | screening for siponimod dosing. i}

| Glatiramer acetate Subcutaneous Injection-site reactions, None B | (three formulations) —_ injection lipoatrophy of skin at injection | sites, and rare systemic panic attack-like syndrome | | Sphingosine-1- Oral Transaminitis, lymphopenia, Pretreatment cardiac screening Fingolimod=C phosphate increased risk of serious (all), cardiac monitoring (for Siponimod and | treatments herpesvirus infection, bradycardia) after administration ozanimod =no | | (fingolimod, hypertension, bradycardia of first dose (fingolimod only), assigned | | siponimod, (usually only with the first ophthalmologic screening (for category; no dose), macular edema, basal macular edema), liver enzymes, adequate data in | | ozanimod) cell carcinoma, PML, disability CBC monitoring (for excessive humans, but | worsening after discontinuation lymphopenia), yearly skin teratogenicity | examination (for basal cell seen inlaboratory | carcinoma). CYP2C9 genotype animal testing. | screening for siponimod dosing. i} Fumaric acid esters Oral Diarrhea, nausea, abdominal Frequent monitoring of CBC in first (dimethyl fumarate, cramping, flushing, 6 months after administration and diroximel fumarate, lymphopenia, PML then every 6 months thereafter monomethy| | fumarate)

Fumaric acid esters Oral Diarrhea, nausea, abdominal Frequent monitoring of CBC in first (dimethyl fumarate, cramping, flushing, 6 months after administration and diroximel fumarate, lymphopenia, PML then every 6 months thereafter monomethy| | fumarate) | Teriflunomide Oral Alopecia, gastrointestinal Monitoring of CBC for distress, respiratory infections, lymphopenia, liver enzymes, and transaminitis, lymphopenia, blood pressure frequently in the | hypertension, and peripheral first 6 months, every 6 months neuropathy thereafter

| Teriflunomide Oral Alopecia, gastrointestinal Monitoring of CBC for distress, respiratory infections, lymphopenia, liver enzymes, and transaminitis, lymphopenia, blood pressure frequently in the | hypertension, and peripheral first 6 months, every 6 months neuropathy thereafter | Cladribine Oral Black-box warnings for Cancer screening, CBC, exclusion No assigned malignancies and of infections, administration of category; teratogenicity, lymphopenia, vaccinations and herpes contraindicated in infections, hematologic prophylaxis when necessary females and toxicity, graft-versus-host males not disease with blood transfusion, planning to use hepatotoxicity contraception because of embryo-lethality and teratogenicity | seen in laboratory animals

| Cladribine Oral Black-box warnings for Cancer screening, CBC, exclusion No assigned malignancies and of infections, administration of category; teratogenicity, lymphopenia, vaccinations and herpes contraindicated in infections, hematologic prophylaxis when necessary females and toxicity, graft-versus-host males not disease with blood transfusion, planning to use hepatotoxicity contraception because of embryo-lethality and teratogenicity | seen in laboratory animals Natalizumab Intravenous Black-box warning of Rigorous, regimented, industry- € increased risk of PML, sponsored monitoring (TOUCH common adverse effects of program) and JC virus antibody headache and chest testing (both screening and discomfort, and rare intermittent monitoring) hepatotoxicity, infusion reactions, and anaphylactic reactions

Natalizumab Intravenous Black-box warning of Rigorous, regimented, industry- € increased risk of PML, sponsored monitoring (TOUCH common adverse effects of program) and JC virus antibody headache and chest testing (both screening and discomfort, and rare intermittent monitoring) hepatotoxicity, infusion reactions, and anaphylactic reactions Alemtuzumab Intravenous Infusion reactions (including Rigorous, regimented, industry- anaphylaxis), infections sponsored monitoring program (especially herpes virus and (Lemtrada REMS); monthly CBC, fungal), autoimmune serum creatinine measurement, thyroiditis, ITP, glomerular and urinalysis; quarterly thyroid nephropathy, increased risk of function for 48 months after first dermatologic malignancy infusion; yearly skin examination (Continued on the next page) 68

Multiple Sclerosis TABLE 43. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis (Continued) Medication Route of Potential Adverse Effects Recommended Monitoring Pregnancy Administration Category? Ocrelizumab Intravenous Allergic infusion reactions Preinfusion screening with CBC No assigned (such as urticaria, pruritus, and hepatitis B serologies; category, with anaphylaxis), infections consider preinfusion vaccinations some risk seen in (especially herpesvirus or (against, for example, herpes animal studies; hepatitis B virus reactivations); zoster, streptococcal pneumonia, contraception possible increased risks for hepatitis B) suggested for PML and cancer 6 months after each infusion

Medication Route of Potential Adverse Effects Recommended Monitoring Pregnancy Administration Category? Ocrelizumab Intravenous Allergic infusion reactions Preinfusion screening with CBC No assigned (such as urticaria, pruritus, and hepatitis B serologies; category, with anaphylaxis), infections consider preinfusion vaccinations some risk seen in (especially herpesvirus or (against, for example, herpes animal studies; hepatitis B virus reactivations); zoster, streptococcal pneumonia, contraception possible increased risks for hepatitis B) suggested for PML and cancer 6 months after each infusion Ofatumumab Subcutaneous Injection site reactions, Screen for hepatitis B; consider No assigned infections, reduced vaccinations (against, forexample, category, with immunoglobulin levels herpes zoster, streptococcal some risk seen in pneumonia, hepatitis B) before animal studies; initiation contraception | | suggested and | warnings for potential fetal harm

Ofatumumab Subcutaneous Injection site reactions, Screen for hepatitis B; consider No assigned infections, reduced vaccinations (against, forexample, category, with immunoglobulin levels herpes zoster, streptococcal some risk seen in pneumonia, hepatitis B) before animal studies; initiation contraception | | suggested and | warnings for potential fetal harm Mitoxantrone Intravenous Black-box warnings for Required monitoring of cardiac D cardiotoxicity and acute function by echocardiography or myelogenous leukemia; other — multigated radionucleotide adverse effects of infection, angiography before each infusion nausea, oral sores, alopecia, and regular CBC menstrual irregularities, and blue discoloration of urine

Mitoxantrone Intravenous Black-box warnings for Required monitoring of cardiac D cardiotoxicity and acute function by echocardiography or myelogenous leukemia; other — multigated radionucleotide adverse effects of infection, angiography before each infusion nausea, oral sores, alopecia, and regular CBC menstrual irregularities, and blue discoloration of urine CBC = complete blood count; ITP = immune thrombocytopenic purpura; PML = progressive multifocal leukoencephalopathy; REMS = risk evaluation and migraine strategy. | ®Pregnancy categories: A, no disclosed fetal effects; B, animal studies failed to demonstrate fetal risk; C, animal studies suggest adverse fetal effects; D, evidence of human fetal | risk; X= documented fetal abnormalities. The FDA is no longer using these letter categories for newly approved drugs; for prescription drugs that were previously approved, | these changes will be phased in gradually. | ee|

| ®Pregnancy categories: A, no disclosed fetal effects; B, animal studies failed to demonstrate fetal risk; C, animal studies suggest adverse fetal effects; D, evidence of human fetal | risk; X= documented fetal abnormalities. The FDA is no longer using these letter categories for newly approved drugs; for prescription drugs that were previously approved, | these changes will be phased in gradually. | ee| Figure 27 for activity definitions). No medications have Once patients begin to take a disease-modifying therapy, proven efficacy in those with secondary progressive MS monitoring for treatment breakthrough (relapses, disability without activity. Ocrelizumab is the only FDA-approved ther- progression, MRI activity) and adverse effects should continue apy for primary progressive MS. Clinical trials of interferon intermittently, and a change in treatment should be consid- beta, glatiramer acetate, fingolimod, and natalizumab in pro- ered if any such events occur. gressive forms of MS have failed to show benefit, and thus Interferon beta (available as interferon beta-1a and inter- prescribing these medications in progressive MS not only feron beta-1b) is an immunomodulatory cytokine treatment increases cost but burdens patients with unnecessary adverse that shifts immune responses away from autoimmunity and

Figure 27 for activity definitions). No medications have Once patients begin to take a disease-modifying therapy, proven efficacy in those with secondary progressive MS monitoring for treatment breakthrough (relapses, disability without activity. Ocrelizumab is the only FDA-approved ther- progression, MRI activity) and adverse effects should continue apy for primary progressive MS. Clinical trials of interferon intermittently, and a change in treatment should be consid- beta, glatiramer acetate, fingolimod, and natalizumab in pro- ered if any such events occur. gressive forms of MS have failed to show benefit, and thus Interferon beta (available as interferon beta-1a and inter- prescribing these medications in progressive MS not only feron beta-1b) is an immunomodulatory cytokine treatment increases cost but burdens patients with unnecessary adverse that shifts immune responses away from autoimmunity and effects. For this reason, guidelines suggest cessation of dis- increase the integrity of the blood-brain barrier. Interferons ease-modifying therapy in those with secondary progressive beta-1a and beta-1b are available in multiple formulations and MS who have had no disease activity and have been nonam- are administered via subcutaneous or intramuscular injection bulatory for 2 consecutive years. on schedules varying from every other day to twice monthly. Guidelines suggest consideration of comorbidities, patient They reduce relapse rates by approximately one-third com- tolerability, risk stratification, and disease activity when decid- pared with placebo and have positive effects on disability ing on a disease-modifying therapy. There is no clear consen- progression and MRI findings. Head-to-head studies show sus about how to select the appropriate therapy, what defines general equivalence of the formulations, although those treatment failure, or how to decide in what order medications requiring frequent injections have slightly higher efficacy in should be introduced. The self-injection medications (inter- some studies. Interferon beta may exacerbate depression, and feron betas or glatiramer acetate) have traditionally been used care should be taken when administering it to patients with a as first-line agents, given their favorable risk profiles. However, history of psychiatric disease. recent evidence suggests that use of higher efficacy treatments Glatiramer acetate exerts its immunomodulatory effect (such as fingolimod, natalizumab, or alemtuzumab) as first- through modification of the nonbinding sites of major histo- line agents significantly reduces the risk of disability and con- compatibility complex molecules. Structurally similar to version to secondary progressive MS compared with the myelin basic protein, it also may work through molecular interferon betas or glatiramer acetate. For this reason, guide- mimicry. Glatiramer acetate is available for daily or three lines suggest use of higher efficacy agents for all patients with times weekly subcutaneous injection. Reduction in relapse highly active MS. rates is similar to that of the interferon beta formulations.

effects. For this reason, guidelines suggest cessation of dis- increase the integrity of the blood-brain barrier. Interferons ease-modifying therapy in those with secondary progressive beta-1a and beta-1b are available in multiple formulations and MS who have had no disease activity and have been nonam- are administered via subcutaneous or intramuscular injection bulatory for 2 consecutive years. on schedules varying from every other day to twice monthly. Guidelines suggest consideration of comorbidities, patient They reduce relapse rates by approximately one-third com- tolerability, risk stratification, and disease activity when decid- pared with placebo and have positive effects on disability ing on a disease-modifying therapy. There is no clear consen- progression and MRI findings. Head-to-head studies show sus about how to select the appropriate therapy, what defines general equivalence of the formulations, although those treatment failure, or how to decide in what order medications requiring frequent injections have slightly higher efficacy in should be introduced. The self-injection medications (inter- some studies. Interferon beta may exacerbate depression, and feron betas or glatiramer acetate) have traditionally been used care should be taken when administering it to patients with a as first-line agents, given their favorable risk profiles. However, history of psychiatric disease. recent evidence suggests that use of higher efficacy treatments Glatiramer acetate exerts its immunomodulatory effect (such as fingolimod, natalizumab, or alemtuzumab) as first- through modification of the nonbinding sites of major histo- line agents significantly reduces the risk of disability and con- compatibility complex molecules. Structurally similar to version to secondary progressive MS compared with the myelin basic protein, it also may work through molecular interferon betas or glatiramer acetate. For this reason, guide- mimicry. Glatiramer acetate is available for daily or three lines suggest use of higher efficacy agents for all patients with times weekly subcutaneous injection. Reduction in relapse highly active MS. rates is similar to that of the interferon beta formulations. 69

Multiple Sclerosis Combining glatiramer acetate with interferon beta provides It is administered as an intravenous infusion with an initial no added benefit. course of once daily for 5 days, followed by 3 consecutive days The sphingosine-1-phosphate medications (fingolimod, 1 year later. Alemtuzumab reduces relapse rates and disability ozanimod, and siponimod) are oral agents that result in progression by approximately half and reduces new lesions and sequestration of activated lymphocytes within lymph nodes. brain atrophy on MRI compared with interferon beta. Despite Both drugs are effective treatments for relapsing-remitting MS high efficacy, use of this drug also is limited due to significant by reducing relapse rates, the risk of disability progression, safety concerns (see Table 43), all of which require intensive and the development of new MRI lesions. Whereas fingolimod safety monitoring and potential prophylaxis. showed no benefit in a trial for primary progressive MS, Ocrelizumab and ofatumumab are monoclonal antibod- siponimod also is approved for use in patients with secondary ies against the CD20 antigen that cause lysis of circulating B progressive MS with activity. Intensive screening and monitor- cells. Ocrelizumab is administered through intravenous infu- ing are necessary with both medications because of rare sion and ofatumumab is given by subcutaneous injection. adverse effects, including infection and heart block. Ocrelizumab is the first medication to show benefit for patients The fumaric acid esters (dimethyl fumarate, diroximel with both relapsing-remitting MS (reductions in relapse rates, fumarate, and monomethyl fumarate) are oral agents that acti- MRI disease burden, and disability accumulation) and pri- vate the nuclear factor-like 2 transcriptional pathway and mary progressive MS (reduced chance of disability progres-

The fumaric acid esters (dimethyl fumarate, diroximel with both relapsing-remitting MS (reductions in relapse rates, fumarate, and monomethyl fumarate) are oral agents that acti- MRI disease burden, and disability accumulation) and pri- vate the nuclear factor-like 2 transcriptional pathway and mary progressive MS (reduced chance of disability progres- result in immunomodulation. Dimethyl fumarate reduces sion). Safety concerns include allergic infusion reactions (for ocrelizumab), injection-related reactions (for ofatumumab), relapse rates by slightly less than half and reduces the risk of and increased risk for treatment-related infections. disability progression and MRI lesion development. Diroximel Mitoxantrone is an anthracenedione chemotherapeutic fumarate, a prodrug that is rapidly converted into dimethyl agent that exerts an immunosuppressive effect by reducing fumarate, is an alternative, as is monomethyl fumarate. lymphocyte proliferation. Although mitoxantrone is highly Infectious risks of correlate with prolonged lymphopenia, and effective for relapsing-remitting MS and is one of few drugs frequent blood-count monitoring is required. approved for use in secondary progressive MS, guidelines sug- Teriflunomide is an oral medication that inhibits a gest its use only in exceptional situations, given its significant mitochondrial enzyme involved in pyrimidine synthesis in risks of cardiac toxicity and treatment-related leukemia. rapidly dividing cells. This drug reduces relapse rates by a third compared with placebo and reduces the risk of disabil- ity progression and new MRI lesion development. Dual- ¢ The use of disease-modifying therapy in relapsing- method contraception is recommended with teriflunomide remitting multiple sclerosis (MS) results in prevention because of its known teratogenic effects. of relapses and disability progression, may reduce mor- Cladribine is an oral purine antimetabolite with a unique tality, and may prevent of conversion to secondary pro- dosing strategy (administered in two brief courses over 2 years) gressive MS. that markedly reduces relapse rates and disability progression ¢ Ocrelizumab is the only available therapy for primary HVC in patients with relapsing-remitting MS and secondary pro- progressive multiple sclerosis (MS), and mitoxantrone, gressive MS with activity. Because of safety concerns (such as siponimod, and cladribine are the only FDA-approved malignancy, infection, and hepatotoxicity) it is generally rec- therapies for secondary progressive MS with activity. ommended for patients who have had inadequate response to, ¢ Natalizumab is a highly effective treatment in multiple or are unable to tolerate, alternate treatments. sclerosis (MS); it is typically limited to use as a second- Natalizumab is a monoclonal antibody targeting a cellular line agent because of the risk of progressive multifocal adhesion molecule on activated T-cells required for transmigra- leukoencephalopathy but can be considered as first-line tion into the CNS. Administered intravenously once monthly, therapy in patients with highly active MS. natalizumab is a highly effective treatment, resulting in a two- thirds reduction in relapse rates, slowing of disability progres- sion by approximately 40%, and a reduction in MRI activity of Symptomatic Management approximately 90% compared with placebo. Despite this high Despite the use of disease-modifying therapies, many patients efficacy, natalizumab is typically limited to use as a second-line still experience both chronic and intermittent neurologic agent because of the risk of progressive multifocal leukoen- symptoms. Proper management of these symptoms with phar- cephalopathy (PML), a CNS demyelinating infection caused by macologic and nonpharmacologic approaches can increase reactivation of the JC virus. Duration of treatment, seropositiv- quality of life for patients with MS. ity for the JC virus, and previous exposure to chemotherapy or MS spasticity is due to corticospinal tract damage, result- immunosuppressants increase PML risk. PML is uncommon in ing in increased muscle tone, painful muscle cramps, spasms, time-limited treatment in patients without other risk factors. and contractures. The use of muscle relaxants, such as Alemtuzumab is an anti-CD52 monoclonal antibody that baclofen, tizanidine, cyclobenzaprine, and the benzodiaz- causes complement-mediated lysis of circulating lymphocytes. epines may be helpful. Gabapentin, medical marijuana,

result in immunomodulation. Dimethyl fumarate reduces sion). Safety concerns include allergic infusion reactions (for ocrelizumab), injection-related reactions (for ofatumumab), relapse rates by slightly less than half and reduces the risk of and increased risk for treatment-related infections. disability progression and MRI lesion development. Diroximel Mitoxantrone is an anthracenedione chemotherapeutic fumarate, a prodrug that is rapidly converted into dimethyl agent that exerts an immunosuppressive effect by reducing fumarate, is an alternative, as is monomethyl fumarate. lymphocyte proliferation. Although mitoxantrone is highly Infectious risks of correlate with prolonged lymphopenia, and effective for relapsing-remitting MS and is one of few drugs frequent blood-count monitoring is required. approved for use in secondary progressive MS, guidelines sug- Teriflunomide is an oral medication that inhibits a gest its use only in exceptional situations, given its significant mitochondrial enzyme involved in pyrimidine synthesis in risks of cardiac toxicity and treatment-related leukemia. rapidly dividing cells. This drug reduces relapse rates by a third compared with placebo and reduces the risk of disabil- ity progression and new MRI lesion development. Dual- ¢ The use of disease-modifying therapy in relapsing- method contraception is recommended with teriflunomide remitting multiple sclerosis (MS) results in prevention because of its known teratogenic effects. of relapses and disability progression, may reduce mor- Cladribine is an oral purine antimetabolite with a unique tality, and may prevent of conversion to secondary pro- dosing strategy (administered in two brief courses over 2 years) gressive MS. that markedly reduces relapse rates and disability progression ¢ Ocrelizumab is the only available therapy for primary HVC in patients with relapsing-remitting MS and secondary pro- progressive multiple sclerosis (MS), and mitoxantrone, gressive MS with activity. Because of safety concerns (such as siponimod, and cladribine are the only FDA-approved malignancy, infection, and hepatotoxicity) it is generally rec- therapies for secondary progressive MS with activity. ommended for patients who have had inadequate response to, ¢ Natalizumab is a highly effective treatment in multiple or are unable to tolerate, alternate treatments. sclerosis (MS); it is typically limited to use as a second- Natalizumab is a monoclonal antibody targeting a cellular line agent because of the risk of progressive multifocal adhesion molecule on activated T-cells required for transmigra- leukoencephalopathy but can be considered as first-line tion into the CNS. Administered intravenously once monthly, therapy in patients with highly active MS. natalizumab is a highly effective treatment, resulting in a two- thirds reduction in relapse rates, slowing of disability progres- sion by approximately 40%, and a reduction in MRI activity of Symptomatic Management approximately 90% compared with placebo. Despite this high Despite the use of disease-modifying therapies, many patients efficacy, natalizumab is typically limited to use as a second-line still experience both chronic and intermittent neurologic agent because of the risk of progressive multifocal leukoen- symptoms. Proper management of these symptoms with phar- cephalopathy (PML), a CNS demyelinating infection caused by macologic and nonpharmacologic approaches can increase reactivation of the JC virus. Duration of treatment, seropositiv- quality of life for patients with MS. ity for the JC virus, and previous exposure to chemotherapy or MS spasticity is due to corticospinal tract damage, result- immunosuppressants increase PML risk. PML is uncommon in ing in increased muscle tone, painful muscle cramps, spasms, time-limited treatment in patients without other risk factors. and contractures. The use of muscle relaxants, such as Alemtuzumab is an anti-CD52 monoclonal antibody that baclofen, tizanidine, cyclobenzaprine, and the benzodiaz- causes complement-mediated lysis of circulating lymphocytes. epines may be helpful. Gabapentin, medical marijuana, 70

Disorders of the Spinal Cord synthetic tetrahydrocannabinol compounds, and cannabis rare risk of seizures and should not be used in patients with extract are beneficial in reducing painful spasms. Strategic use known epilepsy or with kidney impairment. of botulinum toxin and intrathecal baclofen pumps may help Bladder dysfunction occurs in many patients with MS. in patients whose disease is refractory to oral therapies. Urinary frequency and urgency can be ameliorated with absti- Physical therapy, stretching, and massage therapy can be used nence from caffeine, bladder training and timed voids, and as nonpharmacologic alternatives or additions to therapy. anticholinergic medications (solifenacin, oxybutynin, toltero- Neuropathic pain is a common MS-related symptom and dine). Patients with urinary hesitancy or retention can be can be addressed with many of the same pharmacologic agents more difficult to treat. Anticholinergic agents can worsen

as nonpharmacologic alternatives or additions to therapy. anticholinergic medications (solifenacin, oxybutynin, toltero- Neuropathic pain is a common MS-related symptom and dine). Patients with urinary hesitancy or retention can be can be addressed with many of the same pharmacologic agents more difficult to treat. Anticholinergic agents can worsen used to treat painful diabetic neuropathy (see MKSAP 19 retention and increase the risk of urinary tract infection. Patients with a mixed pattern of bladder symptoms should be Endocrinology and Metabolism). Nonpharmacologic approaches, evaluated by a urologist; intermittent catheterization or an such as transcutaneous electrical nerve stimulation, also can be indwelling catheter may be necessary. integrated into the management plan. Limb tremor can occur in patients with MS and is often Chronic fatigue is a common and life-impairing symptom difficult to treat. Occupational therapy and botulinum toxin in MS. Although fatigue is sometimes related to concurrent may be helpful. depression, insomnia, or other comorbid conditions, patients Pseudobulbar affect is a rare complication of MS that can with MS without any of these issues also can experience disa- be a significant impediment to social interaction for affected bling fatigue. Cognitive behavioral therapy, regular exercise, patients. This symptom manifests as uncontrolled fits of and treatment of underlying depression can be beneficial. The laughter or crying that occur without distinct or appropriate stimulant medications modafinil, armodafinil, amantadine, triggers. Dextromethorphan-quinidine can help reduce this and amphetamines may be helpful. Complementary and alter- symptom. native medicine approaches, such as magnetic therapy and ginkgo biloba, also have shown efficacy in some studies. Depression is far more common in MS patients than in e Muscle relaxants, such as baclofen, tizanidine,

used to treat painful diabetic neuropathy (see MKSAP 19 retention and increase the risk of urinary tract infection. Patients with a mixed pattern of bladder symptoms should be Endocrinology and Metabolism). Nonpharmacologic approaches, evaluated by a urologist; intermittent catheterization or an such as transcutaneous electrical nerve stimulation, also can be indwelling catheter may be necessary. integrated into the management plan. Limb tremor can occur in patients with MS and is often Chronic fatigue is a common and life-impairing symptom difficult to treat. Occupational therapy and botulinum toxin in MS. Although fatigue is sometimes related to concurrent may be helpful. depression, insomnia, or other comorbid conditions, patients Pseudobulbar affect is a rare complication of MS that can with MS without any of these issues also can experience disa- be a significant impediment to social interaction for affected bling fatigue. Cognitive behavioral therapy, regular exercise, patients. This symptom manifests as uncontrolled fits of and treatment of underlying depression can be beneficial. The laughter or crying that occur without distinct or appropriate stimulant medications modafinil, armodafinil, amantadine, triggers. Dextromethorphan-quinidine can help reduce this and amphetamines may be helpful. Complementary and alter- symptom. native medicine approaches, such as magnetic therapy and ginkgo biloba, also have shown efficacy in some studies. Depression is far more common in MS patients than in e Muscle relaxants, such as baclofen, tizanidine, those without the disorder. Furthermore, the suicide rate for cyclobenzaprine, and the benzodiazepines, can help

used to treat painful diabetic neuropathy (see MKSAP 19 retention and increase the risk of urinary tract infection. Patients with a mixed pattern of bladder symptoms should be Endocrinology and Metabolism). Nonpharmacologic approaches, evaluated by a urologist; intermittent catheterization or an such as transcutaneous electrical nerve stimulation, also can be indwelling catheter may be necessary. integrated into the management plan. Limb tremor can occur in patients with MS and is often Chronic fatigue is a common and life-impairing symptom difficult to treat. Occupational therapy and botulinum toxin in MS. Although fatigue is sometimes related to concurrent may be helpful. depression, insomnia, or other comorbid conditions, patients Pseudobulbar affect is a rare complication of MS that can with MS without any of these issues also can experience disa- be a significant impediment to social interaction for affected bling fatigue. Cognitive behavioral therapy, regular exercise, patients. This symptom manifests as uncontrolled fits of and treatment of underlying depression can be beneficial. The laughter or crying that occur without distinct or appropriate stimulant medications modafinil, armodafinil, amantadine, triggers. Dextromethorphan-quinidine can help reduce this and amphetamines may be helpful. Complementary and alter- symptom. native medicine approaches, such as magnetic therapy and ginkgo biloba, also have shown efficacy in some studies. Depression is far more common in MS patients than in e Muscle relaxants, such as baclofen, tizanidine, those without the disorder. Furthermore, the suicide rate for cyclobenzaprine, and the benzodiazepines, can help patients with MS and depression is elevated compared with treat multiple sclerosis—associated spasticity.

used to treat painful diabetic neuropathy (see MKSAP 19 retention and increase the risk of urinary tract infection. Patients with a mixed pattern of bladder symptoms should be Endocrinology and Metabolism). Nonpharmacologic approaches, evaluated by a urologist; intermittent catheterization or an such as transcutaneous electrical nerve stimulation, also can be indwelling catheter may be necessary. integrated into the management plan. Limb tremor can occur in patients with MS and is often Chronic fatigue is a common and life-impairing symptom difficult to treat. Occupational therapy and botulinum toxin in MS. Although fatigue is sometimes related to concurrent may be helpful. depression, insomnia, or other comorbid conditions, patients Pseudobulbar affect is a rare complication of MS that can with MS without any of these issues also can experience disa- be a significant impediment to social interaction for affected bling fatigue. Cognitive behavioral therapy, regular exercise, patients. This symptom manifests as uncontrolled fits of and treatment of underlying depression can be beneficial. The laughter or crying that occur without distinct or appropriate stimulant medications modafinil, armodafinil, amantadine, triggers. Dextromethorphan-quinidine can help reduce this and amphetamines may be helpful. Complementary and alter- symptom. native medicine approaches, such as magnetic therapy and ginkgo biloba, also have shown efficacy in some studies. Depression is far more common in MS patients than in e Muscle relaxants, such as baclofen, tizanidine, those without the disorder. Furthermore, the suicide rate for cyclobenzaprine, and the benzodiazepines, can help patients with MS and depression is elevated compared with treat multiple sclerosis—associated spasticity. that of patients with depression only. MS-related depression is e Clinicians should be vigilant for the signs of depression likely multifactorial, involving the emotional response to deal- in patients with multiple sclerosis; if present, they ing with a chronic disease, the consequence of demyelinating should screen for suicidality and have a low threshold lesions and inflammatory cytokines on neurotransmitter for offering therapy and referrals to psychiatry. function, and the adverse effects of treatments (such as inter- ¢ Dalfampridine, a voltage-gated potassium channel antag- feron beta). Clinicians should be vigilant for the signs of onist, can improve walking speed, leg strength, and gait depression, screen for suicidality if present, and have a low in patients with MS and baseline gait impairment. threshold for initiating antidepressants and offering referrals to psychiatry or psychology for counseling. Cognitive dysfunction occurs in at least half of patients

that of patients with depression only. MS-related depression is e Clinicians should be vigilant for the signs of depression likely multifactorial, involving the emotional response to deal- in patients with multiple sclerosis; if present, they ing with a chronic disease, the consequence of demyelinating should screen for suicidality and have a low threshold lesions and inflammatory cytokines on neurotransmitter for offering therapy and referrals to psychiatry. function, and the adverse effects of treatments (such as inter- ¢ Dalfampridine, a voltage-gated potassium channel antag- feron beta). Clinicians should be vigilant for the signs of onist, can improve walking speed, leg strength, and gait depression, screen for suicidality if present, and have a low in patients with MS and baseline gait impairment. threshold for initiating antidepressants and offering referrals to psychiatry or psychology for counseling. Cognitive dysfunction occurs in at least half of patients with MS, affecting employability and quality of life. Typical Disorders of the findings include deficits in short-term memory and process- Spinal Cord ing speed, although almost any domain can be impaired. Trials

that of patients with depression only. MS-related depression is e Clinicians should be vigilant for the signs of depression likely multifactorial, involving the emotional response to deal- in patients with multiple sclerosis; if present, they ing with a chronic disease, the consequence of demyelinating should screen for suicidality and have a low threshold lesions and inflammatory cytokines on neurotransmitter for offering therapy and referrals to psychiatry. function, and the adverse effects of treatments (such as inter- ¢ Dalfampridine, a voltage-gated potassium channel antag- feron beta). Clinicians should be vigilant for the signs of onist, can improve walking speed, leg strength, and gait depression, screen for suicidality if present, and have a low in patients with MS and baseline gait impairment. threshold for initiating antidepressants and offering referrals to psychiatry or psychology for counseling. Cognitive dysfunction occurs in at least half of patients with MS, affecting employability and quality of life. Typical Disorders of the findings include deficits in short-term memory and process- Spinal Cord ing speed, although almost any domain can be impaired. Trials of pharmacologic therapy, such as memantine, donepezil, and Presenting Symptoms and methylphenidate, have not shown efficacy. Exercise, formal Signs of Myelopathy neuropsychological testing, and cognitive rehabilitative and Myelopathy (disease of the spinal cord) arises from extrinsic accommodative strategies (such as creating checklists to over- (external compression) and intrinsic (intramedullary) patho- come memory deficits) are sometimes beneficial. logic causes. Recognition and treatment of spinal cord injury Maintenance of mobility in MS patients is essential to in a timely manner is crucial, given the vital anatomy con- maintaining quality of life. An active healthy lifestyle is neces- tained within this small-diameter structure. sary to help stave off future disability. Physical and occupa- Determining the location and mechanism of injury is tional therapy can provide gait safety training and improve crucial for rapidly deciding on the accurate site and type of balance and endurance. Assistive devices, such as braces, neuroimaging required and the kind of specialty consultation canes, walkers, and electrostimulatory walk-assist devices, (such as neurosurgical) needed. Spinal cord injury often pre- can provide additional benefit. Pharmacologic therapy with sents with symptoms and signs at or below the site of a lesion. dalfampridine, a voltage-gated potassium channel antagonist, Corticospinal tract injury results in spastic paresis or paralysis, can improve walking speed, leg strength, and gait in patients with weakness, hyperreflexia, muscle spasticity, and extensor with MS and baseline gait impairment. Dalfampridine has a plantar responses. There is often loss of sensation at or below

of pharmacologic therapy, such as memantine, donepezil, and Presenting Symptoms and methylphenidate, have not shown efficacy. Exercise, formal Signs of Myelopathy neuropsychological testing, and cognitive rehabilitative and Myelopathy (disease of the spinal cord) arises from extrinsic accommodative strategies (such as creating checklists to over- (external compression) and intrinsic (intramedullary) patho- come memory deficits) are sometimes beneficial. logic causes. Recognition and treatment of spinal cord injury Maintenance of mobility in MS patients is essential to in a timely manner is crucial, given the vital anatomy con- maintaining quality of life. An active healthy lifestyle is neces- tained within this small-diameter structure. sary to help stave off future disability. Physical and occupa- Determining the location and mechanism of injury is tional therapy can provide gait safety training and improve crucial for rapidly deciding on the accurate site and type of balance and endurance. Assistive devices, such as braces, neuroimaging required and the kind of specialty consultation canes, walkers, and electrostimulatory walk-assist devices, (such as neurosurgical) needed. Spinal cord injury often pre- can provide additional benefit. Pharmacologic therapy with sents with symptoms and signs at or below the site of a lesion. dalfampridine, a voltage-gated potassium channel antagonist, Corticospinal tract injury results in spastic paresis or paralysis, can improve walking speed, leg strength, and gait in patients with weakness, hyperreflexia, muscle spasticity, and extensor with MS and baseline gait impairment. Dalfampridine has a plantar responses. There is often loss of sensation at or below 71