Lesions in the white-matter tracts of the CNS cause various symptoms during the course of a patient’s illness (Fig. 15-1, bottom). Moreover, simultaneous involvement of two separate CNS areas often produces combinations of disparate symptoms. For example, plaques may simultaneously develop in the cerebellum and thoracic spinal cord, which would cause ataxia and paraparesis.

Cerebellar Signs

As some of their earliest manifestations, MS patients often develop ataxia, intention tremor, and other signs of cerebellar and cerebellar outflow tract injury. When the cerebellum is involved, patients typically develop an ataxic gait (see Fig. 2-13); however, with minimal involvement, patients’ gait impairment may consist only of difficulty walking in a heel-to-toe (tandem gait) pattern. Cerebellar involvement also typically causes scanning speech, a variety of dysarthria analogous to a “speech ataxia,” characterized by irregular cadence and uneven emphasis on words. For example, when asked to repeat a pair of short syllables, such as “ba…ga…ba…ga…,” a patient might place unequal stress on different syllables, blur them together, or pause excessively. Other manifestations of cerebellar involvement include intention tremor (see Fig. 2-11), dysdiadochokinesia, and an irregular, conspicuous, head tremor (titubation).

Neurologists usually attribute visual acuity impairment in MS to inflammation in the retrobulbar portion of the optic nerve, retrobulbar neuritis (optic neuritis) (see Fig. 12-6). Optic neuritis typically causes an irregular area of visual loss in one eye, a scotoma, that often includes the center of vision (Fig. 15-2). It also leads to color desaturation, in which colors, especially red, lose their intensity.

FIGURE 15-2 Optic or retrobulbar neuritis impairs vision in a large, irregular area (scotoma) of the affected eye.

In addition to reducing vision, optic neuritis characteristically causes pain in the affected eye. Probably because ocular movement puts traction on an inflamed optic nerve, eye pain increases when patients look from side to side.

Optic neuritis, as well as other lesions of the optic nerve, causes a readily identifiable, surprising pupillary light reaction (see Fig. 4-2). Swinging a flashlight from the normal eye to the one with optic neuritis will lead to dilation, rather than continued constriction, of both pupils. This paradoxical, unilateral reaction results from less light entering the pupillary reflex arc compared to when the light was shone into the normal eye. Sometimes called the “swinging flashing test,” this abnormality in the afferent limb of the light reflex results in an afferent pupillary defect or “Marcus Gunn” pupil, which neurologists interpret as a sign of optic nerve pathology.

Unless the optic disk is swollen, routine ophthalmoscopic examination usually reveals no abnormality. This discrepancy between visual loss and the normal appearance of the disk has given rise to the saying, “The patient sees nothing and the physician sees nothing.” As an optic neuritis attack subsides, most vision returns and pain subsides. However, with repeated attacks, progressive visual loss ensues and the disk becomes atrophic.

Statistics vary on the relationship of optic neuritis to MS. They indicate that approximately 25% of MS patients present with optic neuritis as their initial symptom and 50% of MS patients suffer an attack during their illness. A single attack of optic neuritis with no other neurologic symptoms and an MRI showing no lesions means that the individual has only about a 25% likelihood of developing MS in the following 10 years; however, when one or more MRI lesions accompany optic neuritis, the individual’s likelihood increases to about 70% during the same period.

Ocular Motility Abnormalities

MS also causes ocular motility abnormalities, including nystagmus and the characteristic internuclear ophthalmoplegia (INO), which is also known as the medial longitudinal fasciculus (MLF) syndrome. Either brainstem or cerebellar involvement can cause nystagmus. Although it is clinically indistinguishable from nystagmus induced by other conditions (see Chapter 12), MS-induced nystagmus typically occurs in combination with dysarthria and tremor (Charcot’s triad).

In MS-induced INO, MLF demyelination interrupts nerve impulse transmission from the pontine conjugate gaze centers to the oculomotor nuclei (Figs 15-3 and 15-4). The primary symptom of INO is diplopia on lateral gaze because of paresis of the adducting eye. INO is strong evidence of MS; however, systemic lupus erythematosus (SLE or lupus [see later]) and small basilar artery strokes may also cause it. In addition, Wernicke–Korsakoff syndrome, myasthenia gravis, and botulism can produce patterns of ocular muscle weakness that mimic INO. From a physiologic viewpoint, INO is analogous to a disconnection syndrome, such as conduction aphasia, in which communicating links are severed but each neurologic center remains intact (see Chapter 8).

FIGURE 15-3 Under normal conditions, when looking laterally, the pontine conjugate gaze center stimulates the adjacent abducens (sixth) nerve nucleus and, through the medial longitudinal fasciculus (MLF), the contralateral oculomotor (third) nerve nucleus. For example, when looking to the right, as in this illustration, the right pontine gaze center stimulates the right abducens and the left oculomotor nuclei (see Fig. 12-12).

FIGURE 15-4 In internuclear ophthalmoplegia (INO), also known as the MLF syndrome, an interruption of the medial longitudinal fasciculus (MLF) prevents impulses from reaching the oculomotor (third) nuclei. Because those nuclei themselves remain intact, the pupils and eyelids are normal in both eyes. However, when looking to the right, because the left oculomotor nucleus is not stimulated, the left eye fails to adduct. The right eye abducts, but nystagmus develops. With bilateral INO, which is characteristic of multiple sclerosis (MS), neither eye adducts and abducting eyes have nystagmus.

Spinal Cord Symptoms and Signs

Patients with spinal cord involvement, typically the primary and sometimes the only source of disability in primary progressive MS, have paraparesis with hyperactive deep tendon reflexes and Babinski signs. They usually have three troublesome, common symptoms (the three Is) – incontinence, impotence, and impairment of gait. Another troublesome, often incapacitating feature of spinal cord involvement consists of spasticity of the legs. Even in the absence of paraparesis, spasticity impairs patients’ gait and causes painful leg spasms. Patients with cervical spinal cord involvement often describe electrical sensations, elicited by neck flexion, that extend from the neck down the spine (Lhermitte’s sign).

Spinal cord involvement also typically leads to urinary incontinence from a combination of spasticity, paresis, and incoordination (dyssynergia) of the bladder sphincter muscles (Fig. 15-5). MS patients initially often have incontinence during sleep and sexual intercourse. As the disease progresses, patients develop intermittent urinary retention and then complete loss of control. They often require intermittent or continuous catheterization, which leads to frequent, chronic, or recurrent urinary tract infections.

FIGURE 15-5 The urinary outflow of the bladder has two sphincters: an internal sphincter controlled by the autonomic nervous system (ANS), and an external one under voluntary control. Normal urinary bladder emptying (urination) occurs when the detrusor (wall) muscle contracts and both sphincter muscles relax. Purposefully urinating requires voluntary action (to relax the external sphincter) and reflex parasympathetic (ANS) activity (to contract the detrusor and relax the internal sphincter). Urinary retention occurs with either anticholinergic medication or excessive sympathetic activity because both inhibit detrusor contraction and internal sphincter muscle relaxation. Urinary retention also occurs with spinal cord injury because the external sphincter is unable to relax because it is spastic and paretic (dyssynergic).

Erectile dysfunction, decreased desire, and other forms of sexual impairment plague the majority of MS patients (see Chapter 16). About 40% of women with MS do not engage in sexual intercourse. Even before developing erectile dysfunction, men often experience premature or retrograde ejaculation. Sexual dysfunction, with or without urinary incontinence, is attributable to MS involving the spinal cord. With spinal cord damage severe enough to cause paraplegia, men have lowered and abnormal sperm production, but women can conceive and bear children.

Fatigue and Other Important Symptoms

An inexplicable generalized, daily sense of fatigue, which neurologists sometimes call “lassitude” (weariness of body or mind), affects about 50–80% of MS patients. This symptom, which is entirely subjective, does not correlate with patients’ age or degree of paresis. It reduces MS patients’ compliance with medical regimens, quality of life, ability to work, and compliance with medical regimens. In addition, it intensifies other MS symptoms, including depression and cognitive impairment.

MS-induced fatigue represents a physiologic cause of the chronic fatigue syndrome (see Chapter 6). Although many, but not all, studies found that depression is comorbid, antidepressants do not alleviate MS-induced fatigue.

Various pain syndromes also commonly occur in MS. For example, approximately 2% of MS patients suffer from trigeminal neuralgia (see Chapter 9) and 10% Lhermitte’s sign. Many MS patients have pain in their limbs or trunk. These pains probably arise from MS plaques irritating CNS pain-transmitting fibers in, respectively, the brainstem and cervical spinal cord. As with other forms of neuropathic pain (see Chapter 14), antiepileptic drugs, such as gabapentin and carbamazepine, provide some relief.

Because MS, in general, spares CNS structures that contain little or no myelin, symptoms that originate in gray-matter injury rarely complicate the illness. For example, MS patients seldom develop signs of focal cerebral cortical dysfunction, such as seizures or aphasia. Similarly, because the basal ganglia, like the cerebral cortex, are devoid of myelin, MS patients almost never develop involuntary movement disorders (see Chapter 18).

Pregnancy

Women with MS remain fertile. Oral contraceptives do not influence MS. If women conceive, they do not have an increased rate of miscarriages, obstetric complications, or fetal malformations. Throughout pregnancy, the rates of both first MS attacks and MS exacerbations significantly fall. In fact, during the third trimester, the exacerbation rate falls to 70% of its baseline. If MS exacerbations occur, they do not affect the pregnancy. After delivery, women who breastfeed extend the protection associated with pregnancy.

As for delivery, MS patients require cesarean sections for only the usual indications. Epidural anesthesia also has no effect on the course of MS.

Although the pregnancy and delivery pose little or no threat, during the first 3 postpartum months, mothers with MS have a 20–30% incidence of exacerbation. Postpartum exacerbations are more incapacitating than ones that strike before conception. In the long run, neither pregnancy nor parity worsens the course of MS.

Psychiatric Comorbidity in MS

Depression

Depression is the most common psychiatric comorbidity of MS. It develops more frequently in patients with MS than in patients with most other chronic, equally debilitating nonneurologic illnesses, such as rheumatoid arthritis. Depressive symptoms arise frequently at the onset of the illness, during exacerbations, and late in its course. They also correlate with cognitive and physical impairment, loss of bodily function, inability to work, and lack of family and social support. A history of depression and “trait anxiety” predisposes MS patients to depression. Depressive symptoms occur more when MS involves the cerebrum rather than only the spinal cord, and when MRIs show cerebral atrophy and a great total MS lesion area or volume (lesion load or burden).

Unlike depressive illness that occurs in families without MS, genetic influence in MS-induced depression is negligible. For example, the rate of depression in first-degree relatives of depressed MS patients is considerably lower than the rate of depression in first-degree relatives of depressed individuals who do not have MS. Also, MS-induced depression equally affects men and women.

Even when depressive symptoms do not reach the severity and duration of a major depression, which occurs in 25–50% of MS patients during their lifetime, they interfere with MS patients following their arduous regimen of self-injecting medicines, self-catheterization, and participating in rigorous physical therapy programs.

Largely reflecting the high incidence of depression, the suicide rate of patients in MS clinics is as high as seven times greater than that of comparably aged individuals. Compared to all MS patients, those who have attempted or completed suicide have been younger than 30 years and symptomatic for less than 1 year. In addition, their history includes depression in themselves or their family, alcohol abuse, and limited psychosocial support. However, MS-induced cognitive impairment is not a risk factor for suicide.

Well-controlled studies failed to prove that antidepressants improve MS patients’ mood. Moreover, antidepressants with anticholinergic side effects may precipitate urinary retention and SSRIs may increase spasticity. Nevertheless, neurologists prescribe antidepressants for patients with MS in the same regimen as for patients with other neurologic illnesses. Electroconvulsive therapy (ECT) may be effective and can be administered with only the usual precautions. In other words, MS cerebral lesions are not a counterindication to ECT. Whichever treatment physicians and their patients choose, adding psychotherapy, social services, occupational counseling, or physical therapy would benefit them.

Although bipolar disorder occurs at twice the rate in MS patients than in the general population, mania rarely develops. If it occurs, consultants must look for excessive steroid treatment of MS (see later).

Consultants may also encounter “MS-induced euphoria” – an elevation of mood clearly inappropriate to these patients’ disability. This euphoria is associated with physical deterioration, chronicity of the illness, and at least subtle intellectual impairment, as well as steroid treatment. Some euphoric patients are masking depression or protecting themselves with denial. Others simply sense relief as an MS attack subsides. Whether or not psychologic factors seem to explain the euphoria, extensive cerebral involvement usually underlies it. In particular, pseudobulbar palsy may explain pathological laughter (see Chapter 4).

Psychosis

The prevalence of psychosis, unlike the prevalence of depression, is not significantly greater in MS patients than unaffected individuals. In fact, the prevalence of psychosis in MS is less than in most other neurologic illnesses, including Alzheimer disease, head trauma, and epilepsy. Except for cases in scattered reports, MS does not present with psychosis.

Nevertheless, severely disordered thinking occurs in MS patients. On a practical level, psychiatrists should begin by assuming that, in MS patients, it reflects adverse effects of medications or concomitant physical illness, such as a urinary tract infection, i.e., delirium superimposed on cognitive impairment.

Cognitive Impairment

Almost all MS patients in the initial phase of their illness have normal cognitive capacity. They satisfactorily complete their day-to-day functions, routine mental status evaluation, and Mini-Mental State Examination (MMSE) (see Fig. 7-1). However, more demanding measures, such as the Wechsler Adult Intelligence Scale (WAIS), Selective Reminding Test, and Halstead Category Test, reveal at least clinically silent deficits in 45–65% of MS patients.

With greater duration of the illness and, to a lesser extent, physical disability, cognitive function unequivocally declines. Cognitive impairment correlates with fatigue and depression. Memory deterioration occurs first and, throughout the course, most prominently. Language function, in contrast, is comparatively spared. Late in the course of the illness, all cognitive domains deteriorate to the point of dementia.

MS-induced cognitive impairment can hamper activities of daily living, prevent full compliance with medical regimens, and burden caregivers (see later). Moreover, it can precipitate thought and mood disorders.

Certain MRI abnormalities frequently occur: enlarged cerebral ventricles, corpus callosum atrophy, periventricular white-matter demyelination, and overall lesion load. Of all of them, cognitive impairment correlates most closely with the periventricular region lesion load.

Cognitive impairment in MS differs from that in Alzheimer disease in several respects. In MS, carrying an apolipoprotein E4 allele does not pose a significant risk for cognitive impairment. MS produces a subcortical rather than cortical dementia. Also, cognitive impairment typically appears late in the course of MS and long after physical disability has developed, but in Alzheimer disease, it long precedes the onset of physical disability. Also, by way of contrast, in vascular dementia, intellectual and physical deficits appear and worsen together.

Physicians attempting to reduce cognitive deficits in MS might institute cognitive rehabilitation, enhanced structure, occupational therapy, and psychotherapy. Immunomodulators possibly delay the onset or slow the progression of cognitive as well as physical disabilities (see later), but donepezil (Aricept) does not help.

Pediatric MS

Approximately 4% of cases develop in children and adolescents. Pediatric MS patients present with the same neurologic symptoms and signs and are subject to similar neuropsychiatric comorbidities as their adult counterparts. However, their course is almost always relapsing-remitting at its onset and evolves into a secondary progressive pattern only after decades.

Cognitive impairments, which typically interfere with their schoolwork, develop in 30% of pediatric MS patients. Only about 6% of pediatric MS patients develop major depression, but up to 75% develop fatigue. Despite widespread cerebral disease, they are not prone to develop attention deficit hyperactivity, autism symptoms, or specific learning disabilities.

Caregiver Stress

Distress and reduced quality of life can overwhelm caregivers of MS patients. Characteristics of both MS patients and their caregivers determine the nature and severity of the stress. Patients’ characteristics associated with high stress levels include not only their physical disabilities, but also their overall poor quality of life, presence of depression and anxiety, and degree of cognitive impairment. Caregivers’ characteristics associated with high stress levels include a change in their life’s role and the onset or exacerbation of a pre-existing, subclinical depression. To reduce the stress, the patient and caregiver require assistance from family, friends, and perhaps a support group; social and financial services; and current, valid information about all aspects of the illness.

Laboratory Tests

When patients’ clinical evaluation is equivocal, several tests are required to diagnose MS and exclude other illnesses. None is diagnostic and all yield false-negative and false-positive results.

Imaging Studies

Computed tomography (CT) can show atrophy, reveal large areas of demyelination, and exclude large mass lesions that can masquerade as MS. However, it is too insensitive and too nonspecific to be useful in diagnosing MS.

MRI – certainly the most valuable test – can readily reveal demyelinated areas indicative of MS plaques. The revised McDonald criteria call for combinations of one gadolinium-enhanced lesion or nine T2-weighted hyperintense MRI lesions located in various regions of the brain, particularly in the periventricular area (Figs 15-6 and 20-25), or spinal cord (Fig. 15-7). Although not pathognomonic, these hyperintensities are detectable in more than 90% of MS patients.

FIGURE 15-6 Left, This axial T2-weighted magnetic resonance imaging (MRI) scan through the cerebrum of a patient with multiple sclerosis (MS) shows multiple plaques (*) concentrated around the ventricles (V), particularly in the posterior regions. The MS plaques are characteristically white (hyperintense), sharply demarcated, and located in the periventricular region. Center, This axial T2-weighted, fluid-attenuated inversion recovery (FLAIR) image of the same study also shows hyperintense lesions (*) surrounding the ventricles (V). FLAIR images, in which cerebrospinal fluid remains black, highlight demyelinated areas. Right, The sagittal T2 FLAIR image of the same study shows the periventricular hyperintensities surrounding the lateral ventricle (V).

FIGURE 15-7 This magnetic resonance imaging scan of a patient with multiple sclerosis reveals a plaque – the hyperintense lesion – in the high cervical spinal cord.

MRI readily detects lesions in large, heavily myelinated tracts of the CNS, such as the corpus callosum, periventricular area, MLF and other brainstem tracts, cerebellum, optic nerves, and spinal cord. It can show asymptomatic as well as symptomatic lesions.

Because gadolinium enhances MS lesions during the first month after they arise, gadolinium-enhanced MRI can distinguish between new and old lesions. Neurologists accept the appearance of new MRI lesions, even in the absence of acute symptoms, as a marker of active disease.

In addition to showing lesions, the MRI may reveal atrophy of the corpus callosum and cerebrum. Communicating hydrocephalus or hydrocephalus ex vacuo, which occurs commonly, reflects cerebral atrophy and compensatory enlarged ventricles. The cerebral and corpus callosum atrophy correlates with chronicity and cognitive impairment; however, as previously noted, overall lesion load and, more so, periventricular white-matter demyelination correlate more closely with cognitive impairment.

Despite its reliability, MRI may be misleading. Small T2-weighted hyperintensities, “unidentified bright objects” (UBOs), appear in numerous conditions besides MS, including migraine, hypertensive cerebrovascular disease, and normal, benign age-related changes. When accompanied by neurologic symptoms, MRI UBOs may lead to a misdiagnosis. As another pitfall, the MRI reveals demyelination – although usually not multiple, large, periventricular plaques – in neurologic diseases other than MS, such as the leukodystrophies (see later).

Cerebrospinal Fluid

Routine CSF analysis during an MS attack will usually contain protein concentrations that are either normal (40 mg/100 mL) or only slightly elevated, and a mild, nonspecific gamma globulin elevation (9% or greater), but no increase in white blood cells (WBCs). One suggestive feature is that the CSF of 90% of MS patients contains CSF oligoclonal bands that consist of discrete IgG antibodies (Fig. 15-8). However, oligoclonal bands are also present in other inflammatory diseases involving the CNS, such as lupus, chronic meningitis, sarcoidosis, neurosyphilis, Lyme disease, acquired immunodeficiency syndrome (AIDS), and paraneoplastic limbic encephalitis.

FIGURE 15-8 Electrophoresis of cerebrospinal fluid (CSF) of a patient with multiple sclerosis (left), compared to the CSF of one with no central nervous system inflammatory disease (right), shows three distinct, horizontal oligoclonal bands.

CSF myelin basic protein, another protein not normally present, is essentially a myelin breakdown product. As with oligoclonal bands, myelin basic protein occurs in many inflammatory CNS diseases. In diagnosing MS, CSF myelin basic protein carries even less weight than CSF oligoclonal bands.

Evoked Responses

Although routine electroencephalograms (EEGs) do not help in the diagnosis, related electrophysiologic testing, evoked response or evoked potential tests, can reveal characteristic interruptions in the visual, auditory, or sensory pathways. Evoked potential testing is based on repetitive stimulation of these pathways, which are heavily myelinated, and then detecting the responses with scalp electrodes similar to those used for EEGs. Normal responses are so small that they are lost in normal cerebral electrical activity and background noise. In evoked testing, hundreds of responses are computer-averaged. After canceling out normal electrical activity, computer averaging displays an otherwise undetectable composite wave pattern. MS injury slows and distorts electrophysiologic conduction. Any injury lengthens the interval between the stimulus and composite response, which is reflected in an abnormally increased latency, and distortion of the final composite wave pattern.

Evoked response tests are particularly useful in demonstrating lesions that are undetectable on neurologic examination. For example, if a patient has deficits referable only to the spinal cord, but evoked response tests reveal a subclinical optic nerve injury, the physician would know that at least two CNS areas were injured and that the illness was disseminated in space.

Visual-evoked responses (VERs) reveal visual pathway lesions. The patient stares at a rapidly flashing pattern on a television screen and a computer averages responses detected over the occipital cortex. Optic neuritis increases the latency or distorts the waveform. Because VERs can indicate the site of an interruption in the visual pathway, they are helpful in distinguishing ocular, cortical, and psychogenic blindness (see Chapter 12).

Brainstem auditory-evoked responses (BAERs) reveal auditory pathway lesions. By measuring responses to a series of clicks in each ear, BAERs may indicate MS brainstem involvement. They are also useful in characterizing hearing impairments, diagnosing acoustic neuromas, and evaluating hearing in people unable to cooperate, such as infants and those with autism.

Somatosensory-evoked responses reveal lesions in the sensory system that extends from the limbs to the cerebral cortex. This test involves stimulating the limbs and detecting the resulting cerebral potentials. MS and other disorders of the spinal cord and even nerve injuries in the limbs interfere with neurophysiologic transmission and produce evoked response abnormalities.

Therapy

For attacks of MS or optic neuritis, with or without other signs of MS, neurologists generally administer high doses of intravenous steroids, such as methylprednisolone, that shorten attacks and possibly reduce residual disability. Physicians must cautiously administer steroid treatment because it potentially leads to steroid psychosis (see later) or other serious complications (Fig. 15-9).

FIGURE 15-9 Left, A 38-year-old woman who had had multiple sclerosis for 9 years developed left-sided paresthesias and left homonymous hemianopsia. Her magnetic resonance imaging (MRI) scan showed a large region of high signal (hyperintensity) in the white matter of her right parietal-occipital cerebrum. Right, Six months after a course of steroids for the exacerbation, her deficits resolved and the MRI lesion almost completely resolved, but new, small lesions appeared.

Acknowledging that no cure is available, neurologists prescribe “disease-modifying therapies.” This strategy, which relies on immunomodulators, attempts to reduce the frequency, severity, and residual disability of relapses. It does reduce the lesion load and disease activity as determined by the MRI.

Immunomodulator treatment, in general, aims to reduce the numbers of T-cell lymphocytes or impair their ability to penetrate the blood–brain barrier. Some treatments require that patients inject themselves with recombinant human interferon preparations, such as intramuscular beta-interferon-1a (Avonex), subcutaneous beta-interferon-1a (Rebif), beta-interferon-1b (Betaseron), or a preparation of four amino acids similar to myelin basic protein (glatiramer acetate [Copaxone]).

Natalizumab (Tysabri), a unique immunomodulator that neurologists administer intravenously, consists of humanized monoclonal antibodies directed against molecules on the cell surface of leukocytes. It reduces entry of inflammatory cells into the CNS, which reduces their destructive potential. Fingolimod (Gilenya), the first oral medicine approved for MS, sequesters lymphocytes within lymph nodes.

Immunomodulators not only fail to arrest MS, they have many drawbacks. Compared to a placebo, they may not even prevent disability at 5 years. Their efficacy varies widely between patients. Furthermore, they are apt to cause various side effects, particularly several hours of fatigue and flulike symptoms following each injection.

Immunomodulators are also expensive (see Appendix 2). For example, one population-based study that examined their cost-effectiveness showed that each quality-adjusted year cost $800 000. Immunomodulators are counterindicated in pregnant women. Neoplasms, especially leukemias and lymphomas, on rare occasions complicate long-term immunosuppression in MS patients.

While natalizumab blunts lymphocytes’ destructive effects in the CNS, it similarly impairs lymphocytes’ protective effects. Probably as a result of natalizumab reducing their immunologic capability, one person for every 1000 MS patients treated for 1.5 years with natalizumab for MS initially developed progressive multifocal leukoencephalopathy (PML) (see later). Subsequent studies found that the MS patients who developed PML had anti-JC virus antibodies before their natalizumab treatment, which suggests that they harbored a quiescent infection. Neurologists now exclude patients with those antibodies from natalizumab treatment.

Although ultimately unsubstantiated, initial reports indicated that interferons caused or exacerbated pre-existing depression in MS patients. Nevertheless, many neurologists still avoid prescribing interferons to patients with a history of depression. (Alpha-interferon, when used as a treatment for hepatitis, may lead to depression.)

Neurologists treat many individual symptoms. For example, depending on the nature of a patient’s bladder dysfunction, either cholinergic medications, such as bethanechol (Urecholine), or anticholinergic ones, such as oxybutynin (Ditropan), might alleviate incontinence; however, patients with advanced disease may require self-catheterization or sphincter bypass. Although paresis cannot be improved, the accompanying spasticity, which is just as much of an impediment, usually responds to baclofen, diazepam, muscle relaxants, or injections of botulinum toxin (see Chapter 18). Formal exercise programs reduce disability and promote social contacts. Although inhaled cannabis purportedly reduces bladder dysfunction, spasticity, and pain, it impairs stamina and cognition.

Steroid Psychosis

Steroid treatment of MS – as with steroid treatment of lupus, organ transplant rejection, and acute asthma – can induce anxiety, euphoria, mania, depressive symptoms, and psychosis. Likewise, Cushing syndrome and other conditions that generate excessive steroid production can produce these symptoms. Even athletes surreptitiously using steroids for bodybuilding and energy can develop personality and behavioral changes. Steroids often produce insomnia, ravenous appetite, and tremor (see Chapter 18), any of which constitutes the first sign of steroid treatment. The influence of pre-existing psychiatric illness as a risk factor remains controversial.

Glucocorticoid steroids, such as prednisone, are more apt than mineralocorticoid steroids, such as dexamethasone, to induce a steroid psychosis. The incidence of steroid psychosis, which usually begins 1–4 days after starting treatment, increases from 4% of patients receiving less than 40 mg of prednisone daily to 20% of patients receiving more than 80 mg daily. When physicians discontinue steroid treatment, its adverse symptoms recede within 6 weeks in 90% of patients.

Psychosis in a patient with lupus or other systemic inflammatory disease receiving high-dose steroids poses a clinical dilemma. Because these diseases can directly affect the CNS, abruptly decreasing the steroids might intensify the cerebral involvement of the illness. In addition, at a time when the body is under stress and consequently requires an increased dose of steroids, suddenly stopping them may precipitate adrenal insufficiency. As a general rule, in patients with a systemic inflammatory disease, physicians should maintain or increase the steroid dose at least until the evaluation is complete. On the other hand, because steroids are not life-saving in MS, physicians should reduce or discontinue them as soon as possible. In the interim, first- or second-generation antipsychotics may suppress psychosis, but antidepressants may exacerbate it. According to a few reports, if the situation requires continued steroid treatment, prophylactic use of lithium may prevent steroid psychosis.

Conditions That Mimic MS

Physicians may reasonably confuse MS with a conversion disorder and other psychiatric illness when patients present with symptoms of clumsiness, sexual impairments, nonspecific sensory loss, or fatigue. Perhaps some young paraplegic patients described in the original psychoanalytic literature, who improved after a course of psychoanalysis, may actually have enjoyed the spontaneous resolution of an MS episode.

Common symptoms and signs that should point to a disease other than MS – “red flags” – include the onset of symptoms before the age of 20 years or after 50 years, multiple family members with the same symptoms, lack of eye signs, a single manifestation, presence of systemic symptoms, and normal results on MRI, evoked potential, and CSF testing.

Demyelinating Diseases That May Mimic MS

Guillain–Barré Syndrome

Most neurologic disorders that mimic MS are peripheral nervous system (PNS) or CNS demyelinating illnesses. Even though it is a demyelinating disease of the PNS rather than of the CNS, Guillain–Barré syndrome may resemble MS because it generally strikes young adults and causes paraparesis or quadriparesis (see Chapter 5). In contrast to MS, Guillain–Barré syndrome is characterized by a single, monophasic attack, lasting several weeks to months, of symmetric, flaccid, areflexic paresis.

Neuromyelitis Optica

In contrast to individuals with MS, those with neuromyelitis optica (NMO) characteristically suffer primarily or usually exclusively from the combination of visual loss in one or both eyes and paraparesis. They have underlying demyelinating lesions in one or both optic nerves and the spinal cord, i.e., unilateral or bilateral optic neuritis and myelitis. Compared to MS attacks, NMO attacks cause greater clinical deficits with more severe demyelination, but they are less likely to cause cognitive impairment or fatigue.

Also, in contrast, NMO patients’ serum contains an NMO antibody that is directed against aquaporin-4 on astrocytes. Their CSF may contain a moderate number of WBCs and their MRIs show a longitudinal plaque of demyelination in the spinal cord, but their brain remains relatively free of demyelination. Also, NMO patients tend to have other comorbid autoimmune illnesses, particularly lupus. Interferon treatment is ineffective. Neurologists treat acute NMO attacks with plasmapheresis and immunosuppressants.

Leukodystrophies

Destruction of CNS myelin, alone or in combination with PNS myelin, is the hallmark of an uncommon group of genetically transmitted illnesses, leukodystrophies. As with MS, leukodystrophies cause optic nerve, cerebellum, and spinal cord myelin degeneration that leads to progressively severe visual impairment, ataxia, and spastic paraparesis. In contrast to MS, the leukodystrophies are entirely genetically determined and cause unremitting physical and mental deterioration. Their symptoms usually first appear in infants or children, but occasionally not until the teen or young adult years. In those older victims, the leukodystrophies may present with behavioral problems, emotional changes, and cognitive impairment. Whether the leukodystrophies appear in infants or young adults, they cause dementia within several years.

Two well-known leukodystrophies are adrenoleukodystrophy (ALD) and metachromatic leukodystrophy (MLD; see Chapter 5). ALD, which is transmitted in a sex-linked pattern, typically first produces neurologic symptoms and adrenal insufficiency in boys between 5 and 15 years old. However, sometimes symptoms emerge only when the men carrying the defective gene reach 20–30 years. When ALD develops at this age, CNS demyelination may cause mania, gait impairment, and eventually dementia. In addition to CNS demyelination, which often has an inflammatory component, MLD causes peripheral neuropathy.

An oxidation enzyme defect in peroxisomes, which are intracellular organelles, causes ALD. The defect results in accumulation of saturated unbranched very-long-chain fatty acids (VLCFAs) in the brain, adrenal glands, other organs, and serum. Lorenzo’s oil, a widely publicized therapy developed by two self-trained biochemists whose son inherited the illness, reduces VLCFA concentrations; however, it fails to alter the disease’s course. Similarly, treatment by adrenal hormone replacement does not arrest the demyelination. Preliminary studies indicate that bone marrow or hematopoietic stem cell transplants, before symptoms develop, may prevent both brain and adrenal damage.

Infections

Several organisms, which are usually viruses, produce demyelination not by an actual infection of the CNS but by provoking an immunologic response that invades the CNS and attacks its myelin. For example, postinfectious encephalomyelitis, which is probably identical to acute disseminated encephalomyelitis (ADEM), occurs 1–4 weeks after an exanthematous or other infectious illness and consists of an extensive and destructive immune attack on cerebral and spinal cord myelin. ADEM affects children more frequently than adults, presumably because of their propensity to contract exanthematous illnesses. Unlike MS, ADEM consists of a single episode, i.e., it is a single, monophasic illness.

PML, a DNA JC virus infection, like MS, produces one or more large areas of CNS demyelination (Fig. 15-10) and multiple neurologic deficits. PML is usually a late complication of AIDS and other illnesses characterized by immunologic impairment (see Chapter 7). It also complicates medication-induced immunosuppression for organ transplantation and cancer chemotherapy as well as natalizumab treatment. The presence of CSF JC virus antibodies, which requires polymerase chain reaction testing, confirms the diagnosis of PML and many times obviates the need for a brain biopsy.

FIGURE 15-10 Surviving 20 years with a kidney transplant and enduring a decade of aggressive immunosuppression, a 40-year-old man insidiously developed right-sided hemiparesis and pseudobulbar speech and affect. His magnetic resonance imaging (MRI) scan showed an extensive area of hyperintensity in his left frontal lobe that extended through his anterior corpus callosum and involved a small area of his frontal lobe. However, unlike the MRI in multiple sclerosis, his MRI showed lesions that were patchy and extensive and not periventricular. The MRI appearance in this setting is indicative of progressive multifocal leukoencephalopathy (PML). He had the right hemiparesis from damage to the corticospinal tract of his left frontal lobe and the pseudobulbar palsy from the bilateral frontal lobe damage. Because the PML spared his cerebral cortex, he did not have aphasia.

Several other CNS infections directly or, through antibodies, indirectly attack CNS myelin and mimic MS. In particular, infection with the human T-lymphotropic virus type 1 (HTLV-1) causes a demyelinating myelitis that particularly affects the corticospinal tracts in the spinal cord (see Fig. 2-15), i.e., HTLV-1 myelitis. Thus, its clinical manifestations resemble MS involving only the spinal cord. HTLV-1, a retrovirus related to the human immunodeficiency virus (HIV), is endemic in the Caribbean islands and some areas of Japan. Sexual intercourse, pregnancy, and contaminated blood transmit HTLV-1, just like HIV; however, fewer than 5% of individuals infected with HTLV-1 develop symptoms. When it occurs, HTLV-1 myelitis typically produces a slowly evolving, painless, MS-like spastic paraparesis in residents of the Caribbean, where MS is uncommon. HTLV-1 infection rarely causes cognitive impairment or personality change. In infected individuals, antibodies to HTLV-1 are detectable in both serum and CSF, which typically shows an atypical lymphocytic pleocytosis.

Toxins

Numerous toxins preferentially attack CNS myelin. For example, a contaminant of certain homemade Italian red wines probably causes degeneration of the heavily myelinated corpus callosum, the Marchiafava–Bignami syndrome. Theoretically at least, Marchiafava–Bignami syndrome can damage the corpus callosum severely enough to produce the split-brain syndrome (see Chapter 8).

Chronic toluene exposure, whether from inadequate industrial ventilation or recreational volatile substance use, damages CNS myelin (see Chapter 5). Although appropriate industrial toluene levels should not produce problems, when individuals regularly inhale high concentrations, they develop cognitive disabilities, personality changes, and MS-like physical findings, such as ataxia, corticospinal tract signs, nystagmus, and even optic nerve impairment. MRI changes from toluene-induced demyelination, which may be more pronounced than ones from MS, correlate with cognitive and physical impairment.

A small group of lawyers and physicians, but not neurologists, have claimed that silicone breast implants cause MS, “multiple sclerosis-like symptoms,” chronic fatigue syndrome, cognitive impairment, chronic inflammatory demyelinating polyneuropathy, and other neurologic disorders. However, several major studies concluded that silicone breast implants do not cause any neurologic disease. Women who reported neurologic disorders after receiving the implants had no consistent pattern of symptoms, virtually no objective signs, and no significant laboratory abnormalities – except in the normal number of women who would be expected to have coincidentally contracted various neurologic illnesses. Also, women with unruptured implants reported the same incidence of postoperative neurologic problems as women with ruptured implants. Women in Sweden and Denmark who had the implants reported essentially the same incidence of neurologic symptoms as those who underwent breast reduction. In other settings, such as its use as cardiac pacemaker coverings, silicone has not been associated with neurologic disease. In individual cases, physicians have established more plausible alternative diagnoses – most often, depression and anxiety, carpal tunnel syndrome, neuropathies, and pre-existing MS.

Systemic Lupus Erythematosus

Like MS, lupus and other systemic vascular inflammatory and autoimmune diseases produce various neurologic symptoms that follow a chronic course punctuated by exacerbations. Of all of these diseases, lupus most often causes neurologic, especially neuropsychiatric, symptoms. Moreover, it may cause neuropsychiatric disturbances in the absence of either systemic physical or neurologic manifestations of the disease.

Also like MS, lupus predominantly strikes women more frequently than men (nine times more frequently) and it affects children as well as adults. Lupus affects the CNS as the initial organ of involvement in only about 5% of cases, but it eventually produces neurologic complications in 25–75% of all cases. The wide range reflects different age groups and diagnostic criteria in various studies. One explanation of the high prevalence of neurologic complications in some studies is that the American College of Rheumatology has considered tension and migraine headaches and mild cognitive impairment as “Neuropsychiatric Syndromes Associated with SLE.” Another is the complex, seemingly changing serologic testing.

When lupus affects the CNS, neurologists usually find that major neuropsychiatric symptoms are cognitive impairment to the point of dementia, thought disturbances to the point of psychosis, and mood disorders. These symptoms occur with or without other neurologic or systemic manifestations. Physical signs of CNS lupus, particularly seizures and strokes, frequently occur alone or accompany these neuropsychiatric complications. Uncommonly occurring neurologic complications include chorea and INO.

Lupus neurologic complications are associated with various serologic abnormalities: antiphospholipid antibodies, low albumin, and double-stranded DNA. CNS complications also induce CSF oligoclonal bands. MRIs may reveal white-matter signal abnormalities and cerebral infarctions. However, no laboratory test abnormality is necessary or sufficient to assure clinicians of the diagnosis.

Lupus affects the CNS in up to 85% of children hospitalized with the illness. Of children with CNS lupus, approximately 50% develop depression, inattention, memory impairment, psychosis, or other mental status abnormalities. They are also frequently beset by headache and delirium. Of lupus patients older than 50 years, by contrast, less than 20% have CNS involvement. Moreover, their manifestations are relatively mild and responsive to treatment.

Manifestations of lupus-induced PNS involvement, which occur alone or in conjunction with CNS involvement, include neuropathy and mononeuritis multiplex (see Chapter 5). Studies have attributed both the CNS and PNS neurologic complications to autoantibodies, immune complexes, arteritis or vasculitis, and intrathecal production of cytokines. Many complications clearly reflect cardiac valvular disease, a tendency to develop thromboses, opportunistic infections, hypertension, renal failure, or possibly the elaboration of false neurotransmitters. Sometimes, because steroids remain a mainstay of lupus treatment, steroid psychosis, rather than the underlying disease, explains the eruption of a thought disorder, change in mood, or abnormal behavior.