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Note: Significant diseases are indicated in bold and syndromes in italics.

I. Multiple Sclerosis (MS)

1.Pathophysiology

a.etiological hypotheses

i.the autoimmune hypothesis: peripheral leukocytes become sensitized to central nervous system myelin antigens by

(1)direct exposure of leukocytes to antigens after breakdown of the blood–brain barrier during a local infection

(2)sensitizing leukocytes to viral antigens that are similar to myelin antigens {molecular mimicry}

ii.the infectious hypothesis: stems from epidemiological studies linking geographical location with disease susceptibility, although no definitive links have been made; it is thought that demyelination is a reaction to chronic viral infection, such as that from

(1)herpes 6 virus infection: evidence of viral infection is present more commonly in patients with MS, although a causative association is not established

(2)Epstein-Barr virus (EBV) infection: pediatric MS patients have twice the rate of EBV exposure than do controls, suggesting an early exposure to the virus; MS patients exhibit higher antibody levels against EBV

(3)other viruses: herpes simplex 1, simian cytomegalovirus, MSassociated retrovirus (HERV-W)

(a)patients with MS have a later mean age of infection with measles, rubella, and mumps, but not a greater overall incidence of infection

(4)Chlamydia pneumoniae—MS patients exhibit greater reactivity to Chlamydia, but equal rates of infection

b.genetics

i.associated with human leukocyte antigen (HLA) A3, -B7, -Dw2, -DQ, and -DR2 subtypes

ii.familial aggregation occurs in 15% of cases; dizygotic twin risk is 5%, similar to the risk of non-twin siblings; monozygotic twin risk is 35%

iii.risk of MS 3% with one affected parent, 30% with two affected parents

c.epidemiology

i.geography: common in northern North America, Europe, Scandinavia, New Zealand, and southern Australia (i.e., maximal distances from the equator)

ii.age: clinical onset occurs almost invariably in patients 60 years of age

(1)risk of developing MS related to geography is acquired by 12 years of age

iii.sex: for women, relative risk of the relapsing-remitting subtype 3; equal risk for men and women for the primary-progressive subtype

iv.race: relative risk 8% for Whites

2.Histology (Fig. 4–1)

a.plaques: areas of demyelination typically occurring around venules in the white matter

i.acute/active plaques: characterized by T lymphocyte and macrophage infiltration

(1)macrophages are predominant in the core of the plaque and phagocytize myelin debris; reactive astrocytes are also present in the plaque core

(2)T lymphocytes are sensitized to multiple antigens in myelin (i.e., myelin basic protein, proteolipid protein, “P-0” protein, myelinassociated glycoprotein), but the molecule that initiates the inflammatory response is unknown

ii.chronic plaques: hypercellular areas that contain mostly astrocytes, sometimes with a periphery of lipid-containing macrophages

(1)axons are demyelinated but otherwise relatively normal in appearance; loss of axons may approach 50% within the plaque

(a)axon loss is likely a reaction to demyelination and to direct injury from the inflammatory process

(2)most chronic plaques do not contain inflammatory cells, but some have ongoing myelin phagocytosis by macrophages {chronic active plaque}

iii.shadow plaques: areas of demyelination with partial remyelination

(1)oligodendroglia are reduced in the core of plaque but are increased at periphery, which accounts for the limited remyelination that occurs in chronic plaques; most of the oligodendroglia surrounding the plaque are not of a myelinating phenotype

iv.normal appearing white matter (NAWM) that does not contain plaques may show evidence of gliosis

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3.Symptoms (Box 4.1)

a.acute symptoms

i.sensory abnormalities: the most common deficit of MS

(1)subjective sensory complaints include numbness, paresthesias, band-like sensations around the chest or abdomen, saddle anesthesia, itching, and (rarely) radicular pain

(a)Lhermitte’s sign: an electric shock sensation that radiates down the spine and into the limbs upon flexion of the neck; a nonspecific finding that can be seen with many types of cervical spine lesions that involve the dorsal columns (e.g., subacute combined degeneration, tabes dorsalis)

(b)loss of proprioceptive sensation in a limb may produce significant discoordination {useless hand sign of Oppenheim}

(2)objective findings on sensory testing (in order of occurrence)

(a)loss of vibration and position sense

(b)loss of pain and light touch

(c)saddle anesthesia/associated with bowel and bladder hypotonia

ii.vision loss from optic neuritis: most commonly is a centrocecal scotoma (see p. 38), which reduces acuity; commonly is caused by lesions behind optic chiasm {retrobulbar optic neuritis}

(1)vision loss is usually gradual and associated with retroorbital or periorbital pain

(2)vision loss is often associated with a direct afferent pupillary defect {Marcus-Gunn pupil}

(3)papillitis occurs only when the head of the optic nerve is involved

iii.diplopia from ocular motor dysfunction: internuclear ophthalmoplegia impairment of CN VI CN III CN IV function

iv.weakness: acute focal weakness is fairly uncommon except in the primary progressive subtype; slow-developing, progressive weakness is more common

v.cerebellar dysfunction involving ataxia of both the trunk and extremities

vi.syndromes of spinal cord injury (see transverse myelitis below)

vii.bladder and bowel dysfunction: typically includes urinary frequency and urgency with retention, and constipation; sexual dysfunction is also common

viii.epilepsy ( 5%): any type of seizure may occur

b.chronic symptoms: spasticity, appendicular tremor; fatigue; sexual dysfunction; psychiatric disturbance, particularly depression (65%); dementia (5%)

c.paroxysmal symptoms: trigeminal neuralgia; hemifacial spasm; tonic spasms; hemiataxia; paresthesias; dysarthria

i.symptoms last only a few seconds but may recur repeatedly or occur in clusters

ii.paroxysmal symptoms are likely caused by ephaptic neural transmission between demyelinated neural systems that are in direct contact (i.e., a short circuit)

4.Subtypes based on symptomatic progression

a.relapsing-remitting MS (55% of all cases; 85% of cases at the time of presentation)—involves multiple discrete episodes of neurological injury followed by partial recovery

b.secondary progressive MS (30% of all cases)—a progressive course of neurological injury developing after several years of an apparent relapsingremitting course; likelihood of transforming into secondary progressive

subtype from relapsing-remitting subtype increases with disease duration ( 90% likelihood after 25 years of disease)

i.some patients develop progressive neurological dysfunction after a single episode of acute neurological injury (“single progressive MS”)

Box 4.1

MS symptoms are exacerbated or induced by heat, {Uthoff’s phenomenon} menses, and the post-partum period.

MS symptoms are reduced by pregnancy, particularly in the third trimester (due to reduced Th2 leukocytes).

c.primary progressive MS (10% of all cases)—neurological injury that progresses from the onset of the disease and never remits

i.progressive relapsing MS—after a minimum of 1 year of apparent primary progressive MS, the patient develops relapses in addition to the progressive course

d.clinically isolated MS

i.optic/retrobulbar neuritis—as a clinically isolated event, most patients recover to 20/40 acuity but only a third will recover completely and most will have persistent deficits in color vision and/or contrast sensitivity

(1)recurrence occurs in 30%, and often causes a greater impairment of the visual acuity than did the original episode

(2)associated with a 60% 10-year risk of developing MS if the brain magnetic resonance image scan (MRI) is abnormal; only a 10% 10-year risk if the brain MRI is normal

ii.transverse myelitis—symptoms include lower extremity weakness and sensory loss, bowel/bladder dysfunction, back pain, and occasionally spinal shock

(1)does not exhibit a familial pattern

(2)likely due to MS in cases with

(a)asymmetric symptoms (e.g., an incomplete lesion)

(b)involvement of less than two spinal segments

(c)oligoclonal bands in the cerebrospinal fluid

(d)evidence of plaque-like brain lesions on neuroimaging

iii.monophasic brainstem or cerebellar syndromes

5.Diagnostic testing: the Poser criteria for MS and the International Panel on Multiple Sclerosis diagnostic criteria (the McDonald criteria) (Table 4–1)

a.neuroimaging: cognitive and behavioral impairment correlates better with general atrophy than with lesion load

Table 4–1 Diagnostic Criteria for Multiple Sclerosis (MS)

Poser criteria for multiple sclerosis

*Supportive laboratory evidence = typical MRI lesions, asymmetric evoked potentials, abnormal urodynamic testing.

Abbreviations: CSF, cerebrospinal fluid; gad, gadolinium.

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(b)after an initial demyelinating event, glucocorticoids decrease the likelihood of developing MS over the following 2 years, but they do not reduce the long-term likelihood of developing MS

(c)high-dose oral glucocorticoids are likely to be as efficacious as IV glucocorticoids, although this has not been directly tested

(2)plasmapheresis, although it has no supportive evidence

(a)intravenous immunoglobulin (Ig) has failed to demonstrate any benefit as an adjuvant therapy for glucocorticoids

(3)methotrexate, cladribine, mitoxantrone

(4)combinations of the above therapies

ii.preventative therapy for acute attacks: all are contraindicated during pregnancy, and all have a modest effect on disability in the available short-term follow-up from clinical trials

(1)interferon 1a 30 g IM weekly (qwk.) (Avonex): reduces relapse rate by 18%

(2)interferon 1a 22–44 mg IM q.o.d (Rebif): reduces relapse rate by 30%

(3)interferon 1b 22–44 mg subcutaneously (SQ) 3 times a week (t.i.w.) (Betaseron): reduces relapse rate by 30%

(4)glatiramer acetate (Copaxone) 20 g SQ q.d., if interferons are not tolerated or antibodies against interferons develop; decreases relapse rate by 30% but inconsistent effectiveness against long-term disability

(5)mitoxantrone: used to stabilize patients with rapidly progressive disability or frequent relapses; it exhibits significant cardiotoxicity and is typically given only for a few months

iii.therapy for paroxysmal symptoms: full-dose anticonvulsants, benzodiazepines

b.therapy for progressive subtypes of MS: no therapy has yet proven effective for primary progressive MS; for second progressive MS, or for rapidly developing progressive symptoms, consider

i.interferons, as above

ii.monthly bolus of methylprednisolone

iii.monthly cyclophosphamide treatment

iv.methotrexate, cladribine, mitoxantrone

c.treatment for chronic symptoms

i.spasticity: baclofen, tizanidine, dantrolene, benzodiazepines, botulinum toxin

ii.tremor: anticonvulsants, clonazepam, propranolol, ondansetron, gabapentin; stereotactic thalamotomy in refractory cases

iii.fatigue: amantadine, pemoline, SSRIs, modafinil, 4-aminopyridine, acetylcarnitine

iv.spastic bladder: oxybutynin (Ditropan), propantheline, imipramine

(1)hypotonic bladder is rare

v.psychiatric impairment

(1)depression: SSRIs, amitriptyline, second-generation antidepressants (e.g., venlafaxine, bupropion)

(2)dementia: donepezil may be beneficial

d.treatment for paroxysmal symptoms: full-dose antiepileptics; benzodiazepines; glucocorticoids when resistant to other therapies

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II.Pediatric Multiple Sclerosis/Early-Onset Multiple Sclerosis

1.Pathophysiology

a.pediatric multiple sclerosis has a stronger association with HLA-DR than adult multiple sclerosis but has no gender preference

b.pediatricand adult-onset multiple sclerosis exhibit similar familial patterns

2.Symptoms: as per relapsing-remitting multiple sclerosis; onset 16 years of age but usually continues into adulthood as multiple sclerosis

a.episodes of optic neuritis are typically simultaneous or sequentially bilateral, not isolated unilateral episodes as in adult multiple sclerosis

i.cases with unilateral optic neuritis are more likely to develop into typical multiple sclerosis

b.Devic’s disease-like presentation is extremely rare in children

3.Diagnostic testing: neuroimaging can differentiate the disorder from acute disseminated encephalomyelitis (ADEM). However, neuroimaging and cerebrospinal fluid studies are of uncertain utility in children, therefore establishing the diagnosis of pediatric multiple sclerosis is generally made according to the Poser criteria

4.Treatment

a.acute attack treatment

i.methylprednisolone 20–30 mg/kg/d for 3–5 days, followed by PO prednisone with tapering

ii.IVIg in cases unresponsive to glucocorticoids

b.preventative therapy for acute attacks

i.interferons, adjusting the dose for weight and age

ii.cyclophosphamide

III. Multiple Sclerosis Variants

1.Devic’s disease/neuromyelitis optica

a.histology: inflammatory demyelinating lesions with complete loss of oligodendrocytes and significant leukocyte infiltration that may progress to frank necrosis and cavitation in severe cases (spinal cord optic nerves); inflammation involves gray and white matter of the spinal cord optic nerves, and does not involve much gliosis as does multiple sclerosis

i.lesions exhibit perivascular immunoglobulin and complement deposits

ii.necrotic demyelinating lesions that exhibit near complete axon loss typically occur in the optic nerves and cervical spinal cord

b.symptoms: rapid-onset of bilateral painful vision loss, and symptoms of complete spinal cord injury associated with back pain (back pain is rare for spinal multiple sclerosis); may exhibit a relapsing course, but more commonly is fulminant

i.the optic neuritis may be bilaterally simultaneous or sequential

c.diagnostic testing: different than opticospinal multiple sclerosis in that

i.neuroimaging demonstrates a normal brain in 90% of cases, and a spinal cord lesion two spinal segments in length

ii.cerebrospinal fluid analysis demonstrates oligoclonal bands only in 30% of cases and then only transiently; elevated protein and a neutrophil pleocytosis are observed

d.treatment

i.acutely treat with glucocorticoids, plasmapheresis, or IVg

ii.treat relapsing-remitting cases chronically with interferon therapy, prednisone azathioprine, or cyclophosphamide

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iii.histology: symmetric areas of myelin sheath splitting with some axon swelling that does not lead to axon loss; inflammation develops several days after injury

(1)involves a large demyelinating lesion in the center of the pons that spares a rim of the tegmentum and does not involving the tectum (Fig. 4–5); 10% also have demyelinating lesions elsewhere in the brain

b.symptoms: usually has a biphasic course that progresses over several days

i.encephalopathy and seizures caused by hyponatremia, which remit with correction to normonatremia

ii.dysarthria and dysphagia developing several days after correction to normonatremia, progressing to flaccid quadriparesis {locked-in syndrome}

(1)involvement of the tegmentum may result in pupillary and ocular motor abnormalities

c.treatment: prevention with gradual correction of hyponatremia, for example, no more than 8 mmol/L in 24 hours using 3% saline

required sodium in mmol ([Na]target [Na]actual) • (30 L) (Box 4.3) wherein 1 mL of 3% saline has 0.5 mmol Na

d.prognosis: unpredictable recovery

2.Marchiafava-Bignami disease

a.pathophysiology: classically described in chronic alcoholics who drink red wine but may occur in any alcoholic or malnourished patient; no known relation to nutritional deficiency, although associated with niacin deficiency (i.e., pellagra; see Chapter 13)

i.histology: symmetric areas of demyelination develop in the corpus callosum with histological changes similar to central pontine myelinosis but more frequently involving necrosis; demyelination may occur in any other region of white matter including the optic nerves

b.symptoms: most commonly resembles a rapid-onset frontal lobe dementia but its clinical course is highly variable and dependant upon the location of demyelination

c.treatment: vitamin supplementation

d.prognosis: often remits but may be acutely fatal

VII. Dysmyelinating Disorder (Box 4.4)

1.Pelizaeus-Merzbacher disease

a.pathophysiology: caused by abnormalities of the proteolipid protein (PLP) gene (Box 4.5); alternative splicing of this gene produces PLP (which accounts for 50% of myelin protein) and DM-20 protein (a minor myelin protein), which are necessary for myelin compaction

i.abnormalities in the PLP gene

(1)segmental aberrations: cause PLP overproduction; phenotype is of variable severity, depending upon involvement of surrounding genes

(2)point mutations that prevent PLP translation: causes dysmyelination; phenotype is mild

(3)point mutations that cause incorrect PLP folding: causes oligodendrocyte apoptosis; phenotype is severe

(4)complete gene deletion: prevents PLP production; causes dysmyelination; phenotype is mild

ii.X-linked inheritance; mosaic inactivation of the X chromosome in heterozygous females leads to

(1)no symptoms if the abnormal PLP gene causes oligodendrocyte apoptosis because the few dead oligodendrocytes are replaced by healthy oligodendrocytes

Box 4.3

30 L is estimated body volume

Box 4.4

“Dysmyelinating disease” is a misnomer— these diseases are not always characterized by abnormal myelin.

Box 4.5

PLP is also mutated in a hereditary spastic paraplegia (SPG-2)

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ii.juvenile form: onset at 3–6 years of age; symptoms are a mix between infantile and adult forms, with more signs of brainstem dysfunction but a slower progressive dementia

iii.adult form (rare): exhibits relapsing-remitting course like multiple sclerosis; symptoms include spastic paraparesis, ataxia, and palatal myoclonus

d.diagnostic testing

i.neuroimaging: decreased white matter density initially in the frontal lobes that progresses to all areas of white matter throughout the brain, often contrast enhancing in areas of active demyelination

(1)initially the subcortical white matter, diencephalon, and brainstem are spared

(2)late in the disease, generalized brain atrophy with cystic white matter degeneration develops, often with hydrocephalus

ii.brain biopsy demonstrates demyelination and Rosenthal fibers; electron microscopy demonstrates increased number of cytoplasmic projections on astrocytes

e.treatment: none specific

f.prognosis: usually death within 10 years of symptomatic onset

3.Canavan’s disease/spongy degeneration of infancy

a.pathophysiology: caused by an autosomal recessive deficiency of aspartoacylase causes accumulation of N-acetylaspartate (NAA), which acts as an osmolite producing cellular edema that leads to spongiform degeneration of white matter

b.symptoms: develop by 1 years of age

i.neonatal hypotonia that develops into spasticity

ii.progressive macrocephaly

iii.dysphagia

iv.vision loss from optic nerve atrophy

v.stimulation-induced posturing that involves extension of the lower extremity, flexion of the upper extremity, and head extension

vi.seizures

c.diagnostic testing

i.NAA levels in the urine 50-fold normal levels

ii.reduced aspartoacylase activity in fibroblasts

iii.magnetic resonance spectroscopy demonstrates an increased NAA peak

d.treatment: none specific; reduce intracranial pressure with acetazolamide

4.Vanishing white matter disease/childhood ataxia with central nervous system hypomyelination/myelopathia centralis diffusa

a.pathophysiology: caused by mutations in the gene for the EIF2B translation regulating protein on chromosome 3, which acts to downregulate protein synthesis in response to cell stressors

i.histology: leukoencephalopathy with cavitation but no evidence of myelin products in the form of inclusion bodies

b.symptoms: progressive ataxia and spasticity with relative preservation of cognition; optic atrophy and seizures develop late in the disease

i.fever or other metabolic stress can produce clinical deterioration

c.diagnostic testing

i.cerebrospinal fluid exhibits elevated glycine levels, although this is nonspecific for leukoencephalopathies or other diseases of the white matter

ii.neuroimaging

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(1)MRI demonstrates diffuse increases in T2 signal in the subcortical white matter with evidence of cystic degeneration that leaves intervening strands of relatively normal tissue

(2)magnetic resonance spectroscopy demonstrates reduced NAA, choline, and creatinine levels, and an increase in glucose and lactate levels; such changes are consistent with a replacement of tissue with cerebrospinal fluid

d.treatment: none specific

5.Megaloencephalic leukoencephalopathy with subcortical cysts/vacuolating leukoencephalopathy

a.pathophysiology: caused by autosomal recessive-inherited mutations of the MLC1 gene on chromosome 22, which has an unknown function

i.histology: oligodendrocytes exhibit abnormal compaction of the outermost layers of the myelin sheath

b.symptoms: macrocephaly with developmental delay particularly in motor function; mild mental retardation; seizures

c.diagnostic testing

i.neuroimaging: MRI demonstrates diffusely increased T2 signal in the subcortical white matter associated with cystic degeneration that is particularly pronounced in the temporal lobes

(1)cystic degeneration progresses with time; white matter signal changes are static

d.treatment: none specific

6.Aicardi-Goutieres syndrome

a.pathophysiology: caused by autosomal recessive-inheritance of the ASG1 locus, which causes an increased expression of interferonthereby causing demyelination and diffuse atrophy; appears to be associated with corticallybased infarctions as well

i.histology: areas of inflammatory demyelination involve cavitation and infiltration with gemistocytic macrophages that contain neutral fats; dystrophic calcifications in the white matter, basal ganglia, thalamus, cerebellar nuclei, and cerebral arteries also occur

(1)such abnormalities are commonly found after in utero infection with the toxoplasma, other viruses, rubella, cytomegalovirus, herpes simplex (TORCH) organisms

b.symptoms: acquired microcephaly with mental retardation and loss of developmental milestones; skin lesions (erythema, acrocyanosis)

c.diagnostic testing

i.cerebrospinal fluid demonstrates a chronic lymphocytosis and increased levels of interferon-

ii.neuroimaging demonstrates dystrophic calcifications, infarctions, and white matter loss

d.treatment: none specific

7.Adrenoleukodystrophy

(a)hyperactivity, initially appearing as attention deficit hyperactivity disorder

(b)dementia progressing to vegetative state within 2–3 years

(c)gait ataxia

(d)vision and hearing loss

(e)seizures

(2)adult-onset adrenoleukodystrophy (rare): symptoms include slowly progressive dementia, and psychosis or mood disorders

(3)adrenomyeloneuropathy: onset around 30 years of age

(a)progressive spastic paraparesis with bowel and bladder incontinence, and sexual dysfunction

(b)sensorimotor neuropathy

(c)mild dementia, mood disorders

c.diagnostic testing

i.increased VLCFA levels in blood or amniotic fluid

ii.reduced urine androgens and glucocorticoids

iii.genetic testing to confirm carriers, 10% of whom have normal VLCFA levels

iv.neuroimaging: increased white matter T2 signal, particularly in posterior regions

d.treatment

i.glucocorticoid supplementation for adrenal failure

ii.dietary fatty acid supplements (“Lorenzo’s oil”) does not reduce disease progression, but it may be beneficial if initiated in the presymptomatic state

iii.bone marrow transplantation only when neurological symptoms are mild and there is enhancement of brain lesions on the MRI

8.Metachromatic leukodystrophy

a.pathophysiology: autosomal recessive inherited mutation of arylsulfatase A (Box 4.7), which converts sulfatide to galactocerebroside in the sphingolipid metabolic pathway; alternatively, may be caused by loss of the saposin B cofactor for arylsulfatase A

i.histology: diffuse demyelination of the brain sparing U-fibers and the peripheral nerves; accumulation of sulfated lipids in neurons of the central and peripheral nervous system causes a change from blue to brown or red {metachromasia} when stained with toluidine blue or cresyl violet, respectively

b.symptoms according to subtype

i.infantile metachromatic leukodystrophy: vision loss from optic atrophy; spastic ataxia with minimal extrapyramidal features; dementia; seizures

ii.juvenile metachromatic leukodystrophy: behavioral change and mental retardation; spastic ataxia with extrapyramidal features

iii.adult metachromatic leukodystrophy: behavioral change, psychosis, and dementia

c.diagnostic testing: increased urine sulfatides, confirmed by reduced arylsulfatase activity or saposin B levels

d.treatment: bone marrow transplantation, performed before the onset of significant neurological disease

9.Krabbe’s disease/globoid cell leukodystrophy

a.pathophysiology: autosomal recessive inherited deficiency of galactosylceramidase, which converts galactosylceramide into ceramide in the sphingolipid metabolic pathway; affects both central and peripheral nervous systems

Dysmyelinating Disorder

Box 4.7

Benign deficiency of arylsulfatase A occurs in 1% of the population {aminosalicylic acid (ASA) pseudodeficiency}.

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i.histology: galactosylceramide attracts and is phagocytized by macrophages that store the indigestible PAS-positive material {globoid cells}; advanced disease exhibits extensive fibrillary astrocytosis in areas of demyelination

b.symptoms according to subtype

i.infantile Krabbe’s disease: begins with an exaggerated startle reflex, fevers, and behavioral regression, but progresses to involve atrophy and spastic weakness

ii.juvenile Krabbe’s disease: symptoms include vision loss, ataxia, behavioral regression, and spastic paraparesis

c.diagnostic testing: enzymatic assay to evaluate for deficiency of galactosylceramidase

d.treatment: bone marrow transplantation, performed before the onset of significant neurological disease

10.Giant cell neuropathy (see p. 221); phenylketonuria (see p. 279)

*Complications of glucocorticoid use: Psychosis, headache, from intracranial hypertension; peptic ulcers; hypertension from fluid retention (when using steroids with high mineralocorticoid potency); glucose intolerance and iatrogenic diabetes; opportunistic infections and poor wound healing (long-term use); cataracts, osteoporosis (long-term use); adrenal suppression: truncal obesity with muscle atrophy, hypertension, depression, hirsutism, amenorrhea, cutaneous striae.

Complications of glucocorticoid withdrawal: Nausea, weight loss; diffuse myalgias and arthralgias; fatigue; orthostatic hypotension. Abbreviations: IM, intramuscularly.