An acute attack or exacerbation or relapse, as defined by Schumacher and colleagues,⁶ is a focal disturbance of function, affecting a white matter tract, and lasting for more than 24 hours. Typically, an acute exacerbation tends to progress over a period of a few days, reaching a maximum in less than 1 week, and then slowly resolving. Complete recovery from an attack is common early in the disease.

The mean annual frequency of relapses has been shown to be between 0.4 and 1.1 relapses per patient per year.⁷^–¹² The average attack rate in the first year was found to be 1.5 to 2.3 relapses per patient per year, falling with age and duration¹³ of disease. The relapse frequency starts to decrease by the second year of the disease.¹⁴ The interval between two relapses can be a minimum of 1 month (as defined by Schumacher⁶) to more than 35 years. A typical relapse lasts for about 6 weeks. Recovery starts by the second week in most patients. The earlier a relapse starts to recover, the better is the total recovery.¹⁴

A pseudo-relapse is acute-onset worsening of preexisting symptoms or signs or reappearance of symptoms or signs in the same location as a prior attack, with lesser or equal severity. The usual causes are physiological, primarily fever, urinary tract infection, or vaccination. Table 76-1 compares true and pseudo-relapses.

TABLE 76-1 True Relapses Versus Pseudo-relapses

Parameter	True Relapses	Pseudo-relapses
Onset	Acute/subacute	Acute more likely
Duration	Weeks likely	Days rather than weeks
Previous deficit	Not necessary	Likely
Fever associated	Not likely	Usually

Courtesy of Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997.

Relapses and their associations or precipitating factors have been studied by many. Relapses have been claimed ¹⁵ but unproved to be more common in warmer months. Large studies have not documented significant reduction in the relapse rates during pregnancy, but the overall relapse rate is higher in the first 6 months postpartum, especially during the first 3 months.¹⁶^–²¹ Relapse rates are not influenced by breastfeeding.¹⁹

In some instances, relapses have been associated temporally with immunization.²² Large studies failed to confirm increased relapse risk after immunization in the MS population.²³ However, in clinical practice, postimmunization relapses have been documented.

On the other hand, infections have been found in most studies to be temporally associated with increased relapse rates in the postinfectious phase,²⁴^–²⁶ and it is a common observation that MS patients present typically 3 to 4 weeks after an infection, with a true or pseudo-relapse. Relapse rates were not increased postsurgically or postanesthesia in most studies.^27,²⁸ Stress and life adversities have been claimed to be associated with increased relapse risk, but this is difficult to assess objectively.²⁹^–³¹ There are no data to support the notion that physical trauma can precipitate relapses or “unmask” dormant MS that otherwise would have remained silent.^15,^27,^28,³²

A small number of patients complain of deterioration in functional capacity in the luteal phase of the menstrual cycle. Slight temperature elevation during this phase may be responsible,³³ and tiredness and fatigue may worsen preexisting deficits.

Following a period of this “relapsing-remitting” course, the majority of these patients (over 80% in 25 years) relentlessly develop gradual worsening with progressive accumulation of disability. Accordingly, these patients, formerly in the RRMS category, merge to conform the SPMS category.

Primary progressive MS (PPMS) is characterized by a subacute or chronic onset of unremitting neurological dysfunction with gradual worsening (i.e., progression) over years, with cumulative fixed disability and hardly any reversal of acquired neurological dysfunction. Overlapping exacerbations may occur in PPMS at any time in the early years or even decades after clinical onset, but tend to be uncommon.

Although the above categories encompass most clinical presentations of MS, individual variations are very common. There may be attacks in PPMS, and sometimes SPMS may begin after one single attack, labeled single attack progressive MS.³⁴

There may be relapses with very little recovery, accumulating rapid neurological disability. It is also not uncommon to encounter patients who have had one or two relapses followed by a disease silence and minimal or no disability for many years.

Benign MS: This subcategory of RRMS tends to be common in women with a younger age of onset who had sensory symptoms as the presenting feature. An Expanded Disability Scale Score (EDSS) score of less than 3 for more than 10 years of MS diagnosis was considered as benign in a study by Redekop and Paty,³⁵ and they found 24% of the 536 patients studied in British Columbia belonged to this category. Freedom from either attacks or progression for decades can be considered to be typical of benign MS. It is most easily recognized in hindsight.

Acute malignant MS:¹⁴ Some patients often have a polysymptomatic onset and progress rapidly to severe disability, death, or both within months (very rare) or a few years (uncommon). Even this most malignant clinical course cannot be reliably predicted at onset. The distinction between acute malignant MS and acute disseminated encephalomyelitis can be difficult. New lesions manifest clinically or on MRI and progression beyond 2 months are features more consistent with a diagnosis of MS than acute disseminated encephalomyelitis. In addition, in the adult, acute disseminated encephalomyelitis is much less common than MS, so that most patients with the acute malignant progression will turn out to have MS.

Opticospinal MS (Devic’s disease, neuromyelitis optica):¹⁴ Reported very frequently from the orient, opticospinal MS predominantly involves attacks and progressive worsening in the optic and spinal systems. This variant is characterized by an earlier age of onset, early progression, minimal or no recovery of neurodeficit after an attack, and poor prognosis.

Pure motor, motor-cerebellar, motor-sensory, or combinations therein are seen as clinical presentation, with unilateral or bilateral optic neuritis or even gradual deterioration of vision. This variant is often debated to be a separate disease entity unrelated to MS.

Lennon and associates ³⁶ from the Mayo Clinic, Rochester, Minnesota, studied 102 North American and 12 Japanese patients with neuromyelitis optica against controls, including MS, optic neuritis, myelopathies, and other conditions, for the presence of neuromyelitis optica IgG antibodies. They claim that this is a specific marker autoantibody for neuromyelitis optica, distinguishing the latter from MS. Based on the prevalence of this marker, the group also comments that Asian opticospinal MS is the same entity as neuromyelitis optica.

Progressive and chronic cerebellar MS have both been believed to be variants of PPMS.

Progressive spinal MS: This is commoner in older men and is characterized by either pure motor or motor and sensory deficits. It usually typifies itself as Laboratory-Supported Definite MS (LSDMS), as it is difficult to document dissemination clinically.

Chronic cerebellar MS: This presentation is most disabling in MS, especially if truncal ataxia accompanies it. These patients have a poor prognosis. There may be wide, sometimes self-injurious tremors, or violent shakes of the whole body, which makes it difficult to take care of such a patient in nursing homes or even hospitals.

Cerebral MS: Some of the patients develop predominantly cerebral lesions, which clinically manifest as dementia, personality changes, impaired judgment, and/or amnesic states. These may be early symptoms and have a severe impact on a person’s work environment and hence should be actively dealt with.

Childhood MS is rare (less than 4% of cases). Youngest cases reported include 10-month-old, 24-month-old, and 4-year-old children. This variant is further more frequent in females (3:1). Vertigo is a frequent presenting feature. Most patients will have a remitting sensory onset. Deterioration is slower, and the youngest patients have the best prognosis for disability. About 82% of childhood MS patients have positive oligoclonal banding in the cerebrospinal fluid. In an excellent review of childhood MS, Banwell ³⁷ writes that the onset of progression in MS beginning before the age of 16 years is later as compared to adult-onset MS, by an average of 15 years.

CLINICAL FEATURES OF MULTIPLE SCLEROSIS

The common presenting symptoms in MS are summarized in Table 76-2.

TABLE 76-2 Common Presenting Multiple Sclerosis Symptoms

Consciousness and Cognition

Although uncommon, acute major brainstem relapse or acute widespread cerebral demyelination has been associated with stupor or coma. This usually keeps the company of severe neurological deficits like paraparesis, quadriparesis, or brainstem abnormalities. The rarity of depressed consciousness as a presentation demands a thorough search for other etiologies.

Cognitive and psychiatric changes in MS have traditionally been underemphasized. Studies have demonstrated that minor deficits in cognition are quite common (up to 70%), even in early MS (up to 50%).³⁸^–⁴⁰ Dementia can be an accompaniment of severe disabling MS of long-term duration. Lesions seen in the corpus callosum on the MRI scan are also well correlated with cognitive defects. Periventricular lesions and the width of the third ventricle are described to be the most frequent MRI correlates with cognitive deficits.⁴¹

Euphoria is commonly a manifestation of subtle or obvious cognitive change.⁴² Focal cortical deficits such as aphasia, apraxia, and agnosias have been reported uncommonly. The most frequent cognitive abnormalities in MS are subtle defects in abstraction and memory,⁴³^–⁴⁶ attention, and word finding.⁴⁷ These are usually associated with emotional lability and decreased speed of information processing.^45,⁴⁶

Traditional tests for dementia designed for use in neuronal degenerative diseases such as Alzheimer’s disease are not sensitive to the changes seen in MS.⁴⁷ The most sensitive bedside measures for cognitive defects in MS have been tests such as the repetition of seven numbers forward or backward, serial 7s or 3s, and visual recognition tests.^48,⁴⁹ Verbal working memory is specially susceptible to impairment in MS.⁵⁰

Mood disorders are frequent in patients with MS. An association may exist between MS and bipolar disorder.⁵¹^–⁵³ A survey in the University of British Columbia Multiple Sclerosis clinic shows that 38% of patients with MS have been depressed or could have bipolar disorder.⁵² Other forms of psychosis are rare but can be seen. Some patients develop hypomanic behavior with steroid therapy, commonly used to treat relapses.

Sleep Disturbances

Studies have shown that patients with MS are more likely than control subjects to have sleep disturbances.⁵⁴ The sleep problems may be due to nocturnal spasms. They may also be a major contributor to fatigue that is so common in MS. Overall, patients with MS have poor sleep efficiency with frequent awakening. Periodic leg movements are also frequent and may contribute to the sleep disturbances.⁵⁵ Incontinence and other bladder symptoms like nocturia may further deteriorate sleep quality and duration. Narcotic symptoms are common.⁵⁶

Fatigue

Fatigue, a frequent and disabling feature of MS,^57,⁵⁸ is considered a state of exhaustion distinct from depressed mood or physical weakness.⁵⁹

It could be one of two types:

1. Fatigability: A single muscle or group of muscles becomes weaker after repetitive use and recovers after rest. This type of muscle fatigue resembles that of myasthenia gravis. It is like Uhthoff’s phenomenon, which occurs with increased body temperature.

2. Lassitude: This is a persistent sense of tiredness. Sleep usually helps, but extensive sleep may also not restore well-being. It may occur without any neurological change but with new large MRI lesions.

This is one of the most challenging symptoms to both evaluate and treat in MS patients. Fatigue may or may not accompany an attack. It may also be a transient phenomenon, with sudden appearance, often “knocking down” the patient mid-day. Severe fatigue appearing de novo and persisting beyond 24 hours could be considered as an attack and may improve with steroids.

Seizures

Convulsive seizures occur in about 2% of MS patients. One half of the seizures are probably due to the MS lesion itself, and the other one half are due to chance association. Seizures in MS are usually easily controlled with anticonvulsants. Patients with seizures tend to have more subcortical or temporal lobe lesions or both than do control MS patients without seizures.⁶⁰

Headache

Headache is a frequent complaint in MS.⁶¹ Occasionally, acute headache occurs in the pseudotumor, acute-onset type of relapse. One type of headache seen sometimes in MS is hemicranial and may be associated with an acute pontine lesion.⁶² Most patients with MS who have headache probably have tension headache due to muscle spasm in the neck and the scalp muscles or have migraine or are depressed.¹⁴ Pain on eye movement due to optic neuritis may also be responsible for headache.⁶³

Cranial Nerve Involvement in Multiple Sclerosis

Pupillary Defects

Most of these defects are related to the afferent pupillary defect (or Marcus Gunn pupil) (Fig. 76-1). Fixed dilated pupils associated with or independent of other elements of a third nerve palsy are extremely rare. Central Horner’s syndrome is occasionally seen.⁶⁴

Figure 76-1 Afferent pupillary defect (Marcus Gunn pupil).

Loss of Vision

Acute loss of vision due to optic neuritis is a common feature of MS and is mostly unilateral. This is also a common clinical presenting feature. About 50% to 70% patients with optic neuritis proceed to develop MS in future; Table 76-3 shows major trials documenting this.

TABLE 76-3 Risk of Multiple Sclerosis in Follow-up Studies of Patients With Isolated Optic Neuritis

Optic neuritis may be retrobulbar, chiasmal, or even retrochiasmal. Many patients recover functionally normal vision after optic neuritis, even in the face of severe residual optic atrophy.^78,⁷⁹ Visual field deficits in MS tend to be central, but occasionally a clinician can encounter paracentral or peripheral scotomata or quadrantanopic or hemianopic defects. Homonymous hemianopias can occur in MS but are unusual; when seen, they should raise the possibility of coexistent tumor or vascular disease. Fortunately, legal blindness in MS is unusual (less than 5%).⁸⁰

Many patients experience a dimming, blurring, or obscuring of vision associated with exercise and heat. Uhthoff first described this symptom.⁸¹ The transient appearance or worsening of neurodeficits (most typically, visual impairment, but any functional system can be involved) on exposure to any form of heat (atmospheric, hot shower, exercise, fever, or even hot food or drinks) is known as Uhthoff’s phenomenon, and is a very common accompaniment to relapses.

Pain is usually seen as an accompaniment to acute optic neuritis ⁸² and may be due to traction of the origins of the superior and medial recti on the optic nerve sheath. Besides the blurring of vision and central scotoma, relative afferent pupillary defect (RAPD), color blindness, and sometimes Pulfrich phenomenon are clinical signs found in most MS patients. The Pulfrich phenomenon ⁸³ is a subjective correlate of conduction delay in one optic nerve. A pendulum oscillating in front of a normal individual will appear to traverse an ellipse if a neutral density filter or a piece of dark glass is placed over one eye. A patient with unilateral optic neuritis may see this illusion without a filter: the disease delays conduction just as does the filter.

Anosmia may be found on examination in many MS patients,⁸⁴ although this may not be voluntarily reported by the patient.

Unilateral or bilateral loss of taste is infrequent. Paty and Ebers have observed this in several patients, and this was the presenting complaint in one patient. This symptom always remitted,¹⁴ in their observation.

Ocular Motility Disorders in Multiple Sclerosis

The most common in this group is nystagmus.⁸⁵^–⁸⁸ The frequency of occurrence of nystagmus in MS has been reported to be between 28.3% and 63%. Nystagmus in MS may be acquired pendular, gaze evoked, rebound, torsional, periodic alternating, or another type. Optokinetic nystagmus is never impaired in isolation.¹⁴ The most common is the nystagmus that accompanies internuclear ophthalmoplegias.

In many MS patients, inappropriate initiation of saccadic eye movements during fixation or change in gaze position results in saccadic intrusions (square wave jerks, saccadic pulse, and double saccadic pulses) and saccadic oscillations (macro-square wave jerks, macrosaccadic oscillations, and ocular flutter).⁸⁹ A square wave jerk consists of a small amplitude conjugate saccade away from fixation followed by a saccade back to fixation after a latency delay of about 200 milliseconds.

One of the most common ocular paresis in MS is sixth cranial nerve paresis. This may even be a presenting feature and mostly resolves completely.

Oculomotor nerve pareses are uncommon presentations of MS but are known, and Paty and Ebers ¹⁴ reported it as an initial presentation in two cases.

Paresis of fourth cranial nerve as an isolated feature is rare.¹⁴

Another common abnormality of eye movements in MS is internuclear ophthalmoplegia, bilateral (most frequent) or unilateral.¹⁴ Internuclear ophthalmoplegia manifests as partial or complete paresis of adduction on the side of lesion, with ataxic nystagmus in the other (abducting) eye (Fig. 76-2). Skew deviation and vertical nystagmus (upbeat on gaze up or downbeat on gaze down) may also occur. Bilateral internuclear ophthalmoplegias are associated with vertical nystagmus in one or both directions. One-and-a-half syndrome (Fig. 76-3) and wall eyed bilateral internuclear ophthalmoplegia (Fig. 76-4) have been reported often in the MS literature. Lateral gaze pareses are also a common manifestation of MS. Visual suppression of the vestibulo-ocular reflex is often abnormal.

Figure 76-2 Internuclear ophthalmoplegia.

Figure 76-3 One-and-a-half syndrome.

Figure 76-4 Wall eyed bilateral internuclear ophthalmoplegia.

Trigeminal Motor and Sensory Symptoms

Facial sensory loss can occur in as many as 10% of MS patients.¹⁴ This can be a presenting feature as in a relapse or a lingering transient symptom. Trismus has also been reported.⁹⁰ Trigeminal neuralgia is discussed later in the section on pain.

Facial Palsy

The acute development of a peripheral facial nerve paresis is an uncommon but recognized feature of MS.¹⁴ It occurs in less than 4% of patients and almost always recovers spontaneously and completely. Recovery from an MS-associated facial palsy is usually not associated with autonomic abnormalities such as crocodile tears; however, aberrant reinnervation, myokymia, and the phenomenon of intrafacial synkinesis are all commonly seen. Acute facial palsies are accompanied by other brainstem findings such as a sixth nerve palsy, lateral gaze palsy, or deafness. Paty and Ebers have seen one case with remitting bilateral facial myokymia that was disabling because the patient could not open his eyes. The symptom responded to carbamazepine therapy.

Deafness

Central lesions resulting in impaired hearing commonly occur, but persistent complete deafness is unusual in the absence of another etiology.⁹¹

Vertigo

This is a relatively common symptom. As many as 50% of patients have intermittent episodes of vertigo. In a review of initial symptoms in MS by Paty and Ebers,¹⁴ it was found that onset with vertigo as a symptom favored a long-term, more benign outcome.

Dysphagia

Mild dysphagia is common.¹⁴ It usually coexists with dysarthria, often in the setting of pseudobulbar palsy. Dysphagia is usually due to desynchronization of the swallowing mechanism.

Dysarthria

Cerebellar dysarthria is a common component of relapses but is usually late to occur in the progressive phase.¹⁴ There is intention tremor of the voice, which can be demonstrated by having the patient sustain a vowel sound for 10 to 15 seconds. The variation in the intensity and sometimes pitch of the sound is easily heard; the frequency is usually 5 to 7Hz, similar to other cerebellar tremors. Patients may show elements of combined cerebellar and pseudobulbar (spastic) dysarthria. Some patients have only spastic speech. Pseudobulbar dysarthria is caused by spastic vocal cords, which result in a high-pitch, low-volume speech, in which consonants are slurred. These patients do not have the oscillating tremor or the explosive variability associated with cerebellar speech. Some patients with MS develop dysarthria after several minutes of sustained speech. This effort-induced symptom tends to recover after a few minutes of rest.

Breathing Disturbance

Rarely, MS patients have a peculiar air hunger, usually associated with severe fatigue. Serious respiratory problems other than pneumonia and bronchitis are uncommon. Howard and colleagues ⁹² described 19 patients who developed respiratory complications an average of 5.9 years after onset. Of these, 12 required mechanical ventilatory support, and 5 recovered. Six patients died after an average of 17.7 months.

Motor and Sensory Findings

Sensory loss is the most frequent of all neurological findings in MS.¹⁴ It is present in 90% of patients at some time during the clinical course. The distribution of sensory loss between upper and lower extremities can vary. Isolated transient facial numbness is frequently seen. Unremitting unilateral facial numbness is more likely due to isolated trigeminal neuropathy. It is also unusual for a sensory segmental level of pain or temperature loss to persist, even in advanced cases. However, during acute exacerbations, a sensory level can be seen in 10% to 15% of patients. When persistent abnormalities in touch, pain, and temperature sensation do occur, the pattern of loss is likely to be a patchy one. In contrast, posterior column or discriminatory sensation testing can be very useful. From 85% to 95% of patients with MS have an abnormality in posterior column sensation at some time during their clinical course. The sensation loss is often prominent in the lower extremities, but bilateral predominant upper extremity impairment is common.

The useless hand syndrome (Table 76-4) is a particularly interesting sensory manifestation that is usually seen in patients with predominant upper extremity proprioceptive loss.⁹³ Even though the useless hand syndrome can occur in other disorders, it is highly characteristic of MS. It is common to see young adults with MS develop lack of discriminatory sensation in one upper extremity to the extent that the extremity becomes functionally useless despite normal crude sensation, motor, and cerebellar function. The useless hand syndrome in MS usually resolves spontaneously, although it can be extremely disabling while present. It usually begins with either tingling or lack of fine sensory discrimination in the fingers. The patient notices an inability to recognize objects in the pocket or purse. The patient can then develop impairment of hand function because of the inability to distinguish various subtleties in tactile sensation and lack of feedback control of movement.

TABLE 76-4 Useless Hand Syndrome Characteristics

Loss of dexterity presenting symptom

Vibration and proprioception loss usually profound

Usually unilateral but can be bilateral

Acute in onset (80%)

Strength usually normal (must be examined with visual control of movement)

Cerebellar function usually normal (again, with eyes open)

Usually recovers completely

The useless hand syndrome is typically accompanied by pseudo-athetosis, a situation in which the hand cannot be maintained in a steady position with the eyes closed. The lack of proprioceptive sense, even to a subtle degree, results in or exacerbates spontaneous movement of the hands when visual feedback is removed.

Lhermitte’s Symptom

This is the occurrence of tingling and “electric current-like” sensation in the arms, down the back, into the legs, or in all the three areas, associated with forward flexion of the neck.^14,^94,⁹⁵ This symptom occurs in 3% of patients at the onset of the disease and probably occurs in 30% to 40% of patients overall at some time during the clinical course. It is most frequently associated with MS, although it is not specific to this disease. Symptoms are usually precipitated by forward flexion of the neck but can also be brought on by forward flexion of the spine or even other minor movements. This symptom may sometimes occur spontaneously. In unusual circumstances, Lhermitte’s symptom can be disabling in the absence of other significant neurological deficits, usually because of its frequency, duration, or intensity. Such disabling symptoms usually respond somewhat to gabapentin, carbamazepine, or benzodiazepine therapy.

Paroxysmal Symptoms

Many patients have brief symptoms of a paroxysmal nature. Transient symptoms such as hemiparesis, positive or negative sensory phenomena, or dysarthria are not well recognized by non-neurologists as features of MS.

Other paroxysmal symptoms in MS include ataxias, vertigo, painful and disturbing paresthesias, dysesthesias, monocular blurring or blindness, pain, and weakness. Paroxysmal motor phenomena include not only weakness but also spasticity and spasms, tonic seizures, akinesia, diplopia, dysarthria, and chorea in addition to focal and generalized seizures.^96,⁹⁷

Paroxysmal symptoms in MS characteristically have an abrupt onset, short duration, and a tendency to stop spontaneously. They can recur up to 50 times per day or more. In some patients, paroxysmal symptoms can be very frightening, disabling, or both. Disabling paroxysmal symptoms usually involve an overwhelming sensation of tingling, numbness, or generalized weakness. The episode can climax in a brief period of akinesia. Fortunately, paroxysmal symptoms in MS respond well to benzodiazepines or anticonvulsants. As they tend to be self-limited, prolonged therapy is usually unnecessary.

The best known of these paroxysmal disturbances is the painful tonic spasm. This is usually manifested by tonic flexion or extension of a limb with a writhing movement reminiscent of paroxysmal athetosis.⁹⁸ The muscular tension in the limb is so high that it becomes quite painful. A particularly difficult situation can be due to the paroxysmal loss of neurological function, as in paroxysmal monoparesis or hemiparesis or paroxysmal blindness. Paroxysmal itching has also been described.⁹⁹

Pain in Multiple Sclerosis

There are two major categories of pain (Table 76-5): paroxysmal (such as trigeminal neuralgia) and chronic.^14,¹⁰⁰ Less than one half of the patients have musculoskeletal pain of various types. It makes sense that patients with weak muscles and poor support of the spine would have such pains (e.g., low backache, neckache, joint pains). Pain can be seen at the onset of MS.¹⁰¹

TABLE 76-5 Types of Pain in Multiple Sclerosis

Paroxysmal or phasic pain

Chronic neurogenic pain

Dysesthetic leg pain

Radicular

Phantom limb

Pain as a chronic symptom is more frequently seen in patients with MS of longer duration and is usually associated with spasticity. The most common form of this neurogenic pain is usually described as “persistent extremity pain.” The pain is usually greatest in the lower extremities, although occasionally a painful radicular syndrome in the upper extremity can be present.

Pain of trigeminal neuralgia has been well discussed in MS. The trigeminal neuralgia features in MS are essentially the same as in idiopathic trigeminal neuralgia.¹⁰⁰ Interestingly, trigeminal neuralgia in MS is more frequently bilateral (32%) than idiopathic trigeminal neuralgia (4%).¹⁴

Weakness and Spasticity

Weakness in MS is usually pyramidal in distribution but can be remarkably focal.¹⁴ For example, marked interosseous weakness can occur with preservation of thenar muscle strength. The weakness is usually more distal than proximal. Foot drop may be seen in the presence of normal proximal strength.

Spasticity is one of the more frequent features encountered in MS. As many as 90% of patients will develop some signs of spasticity during the clinical course. In some patients with severely weak legs, spasticity is actually useful for walking or standing. Weak legs may be able to support considerable weight because of involuntary contraction of the antigravity muscles; attempts to treat spasticity may be counterproductive in such patients. Occasional patients have a syndrome of severe increase in muscle tone with a paradoxical reduction in deep tendon reflexes. This is due to a combination of extrapyramidal and pyramidal lesions.

Cerebellar Features in Multiple Sclerosis

As mentioned earlier, cerebellar involvement may produce one of the most disabling forms of the disease.¹⁴ Cerebellar intention tremor is usually related to lesions in the cerebellar outflow pathways. Cerebellar manifestations include intention tremor, titubation, gait ataxia, and dysarthria. Action tremor may be superimposed on intention tremor. The intention tremor may be severe enough to appear even with an intention to move, thus manifesting practically at rest. The characteristic tremor in MS is the oscillating tremor at 5 to 7Hz perpendicular to the direction of the movement. Besides this, clumsiness, dyssynergia, and dysmetria are present.

Basal Ganglionic Features

Basal ganglionic features are very rare and late to appear, if at all, in MS. Tremor is the most common symptom, although hypokinesia, dyskinesias, dystonias, and speech abnormalities may occur. Rigidity is uncommon.

Amyotrophy (Muscle Wasting) in Multiple Sclerosis

Amyotrophy is considered an uncommon clinical finding in MS.¹⁰³ However, autopsy studies have shown that it is quite common. The three most common causes described are:

1. Disuse occurs due to corticospinal or basal ganglionic involvement.

2. Pressure palsies occur due to posture in weak or wheelchair-bound patients. Bilateral ulnar palsies are common. Patients with paraplegia or distal hand weakness commonly use elbows to turn in bed or to transfer.

3. Syringomyelia has often been reported in MS patients,^104,¹⁰⁵ and this contributes to the third cause. Also, MS lesions may involve the lower motor neuron pathways in the spinal cord. This phenomenon explains the amyotrophic lateral sclerosis-like syndromes in MS patients. Very few cases of MS and amyotrophic lateral sclerosis (some with even Parkinson’s disease) have been reported.

Gray matter plaques, now being increasingly recognized in MS, may also explain myoatrophy.

Peripheral Neuropathy

This is very uncommon, and many researchers have described subtle electrophysiological findings suggesting peripheral neuropathy in MS patients.¹⁰⁶^–¹⁰⁹ Chance occurrences of clinical peripheral neuropathy and acute and chronic inflammatory demyelinating polyradiculoneuropathy have been described.

Autonomic Disturbances in Multiple Sclerosis

Nearly 3% of patients of MS present with isolated bladder symptoms.¹¹⁰

Urgency, frequency, and hesitancy are the most common features. Different combinations of detrusor-sphincteric dyssynergia manifestations are seen. Urinary tract infections worsen the symptoms significantly and are a great concern in MS patients with bladder problems. Incontinence is also common.

Forty-three percent of MS patients have been shown to have constipation.¹¹¹ Fecal incontinence occurred at least once in 51% of patients and once per week or more frequently in about 25% of patients. The overall prevalence of bowel dysfunction was 68%. In a small number of patients, malabsorption,¹¹² incontinence, and frequent diarrheal episodes¹¹³ are also reported.

Sexual dysfunction is another major concern in MS and can also be a presenting symptom.¹¹⁴^–¹¹⁸ There is a high degree of correlation between sexual dysfunction and urinary dysfunction in MS. The reported prevalence is 80% in males and 33% in females.¹¹⁹ Male sexual dysfunction in MS is usually organic, but psychosocial factors are important, too. Female patients may have decreased arousal, decreased libido, lesser frequency of orgasm, fatigue, and decreased sensation.¹²⁰ Males complain of erectile dysfunction, decreased sensation, fatigue, decreased libido, and orgasmic dysfunction. The prognosis of neurogenic erectile dysfunction is poor. Other treatable causes should always be excluded.

Nonsphincteric Autonomic Problems

These can be quite troublesome in some patients. Postural hypotension is common. A cyanotic hue or bluish-red mottling in paretic limbs, especially legs, with some edema may also be commonly seen. Other less common symptoms in this category include hypothermia, paroxysmal atrial fibrillation,¹²¹^–¹²³ orthostatic hypotension,¹²⁴ exercise-induced tachycardia, and breathlessness.¹²⁵ These symptoms are believed to be contributed by lesions in the ascending autonomic pathways in the brainstem or spinal cord.¹²⁶ Yokota and colleagues¹²⁷ reported abnormal sympathetic skin responses in 75% of MS patients studied.

Chronic hypothermia is sometimes seen.¹²⁸ Paty and Ebers¹⁴ described six cases, some of which were severe enough to produce obtundation or coma. It may be precipitated by urinary or other infection. Patients usually respond to warming measures and antibiotics. Hypothalamic MRI lesions may be seen. Electrolyte disturbances and syndrome of inappropriate antidiuretic hormone secretion have also been reported.

As MS can affect white matter anywhere in the brain and spine, many unusual presentations are possible and have been reported in the literature (Table 76-6).

TABLE 76-6 Unusual (but Not Rare) Presentations of Multiple Sclerosis

Natural Progression

Relapsing-Remitting Multiple Sclerosis

In the RRMS category, the mean age at symptomatic onset is 29 years, with the majority of patients in the age group between 20 and 39 years. This compares well with reports from other researchers such as the Lyon, France, group, where the mean age at onset was 31 years (SD, 10 years; range, 5 to 67 years).^129,¹³⁰ In a study at the Mayo Clinic, the median age at onset was reported to be 37.2 years (range, 16.7 to 65.3 years) for men, 35.4 years (range, 17.3 to 59.6 years) for women, and 36.2 years (range, 16.7 to 65.3 years) overall.¹³¹ In approximately 10% to 15% of our patients, onset is before the age of 20 (mostly in their late teens, although pediatric MS is more often recognized), whereas about 5% of patients have MS onset after the age of 49 years.

A selective gender predilection is commonly seen in MS, as it is often reported in other autoimmune conditions. The male-to-female ratio is 1:2, and there is a much more conspicuous female preponderance among younger RRMS patients compared with persons with older progressive MS cases. In a study from the Mayo Clinic, newly diagnosed MS cases over a period of 15 years from 1985 through 2000 included 38 men and 94 women, with the male-to-female ratio being 1:2.4.¹³¹ Another study from Lyon, France, reported a male-to-female ratio of 1:1.7.^129,¹³⁰

The attack rate in the early years of MS is an important predictor of long-term outcome. In London, Ontario studies, the mean annual attack rate in the first year after onset was 1.5 in the total population. However, attack rates vary greatly in different studies, particularly when patients are specifically selected (e.g., for participation in clinical trials) or represent selected subgroups (e.g., hospitalized, and so on). Several studies serve to illustrate such variation. Of course, the relapse rates reported differ for treated and untreated patients. Table 76-7 compares the reported relapse rates in some relevant trials.

TABLE 76-7 Baseline Annual Relapse Rates Reported in Different Multiple Sclerosis Studies

Year	Senior Author	Annual Relapse Rate Reported
1971	Gudmundsson¹⁵⁷	0.14
1982	Patzold⁷	1.1
1989	Goodkin¹³²	0.64
1994	Durelli¹³³	0.94
1995	Johnson¹³⁴	2.90
1996	Jacobs¹³⁵	1.20
2003	Russo¹³⁶	0.87
2004	Kalanie¹³⁷	1.0

Interestingly, although there may be variation when surveying untreated populations as well, figures tend to be more closely grouped. However, it is typical for there to be a remarkable drop in the relapse rate after the second year. In 1952, McAlpine ¹² described attack rates of 1.23 in the first year and 0.42 in the second year. Now, early studies from our London, Ontario geographically based cohort demonstrated attack rates of 1.57 in the first year and 0.35 in the second year for the natural history cohort.¹³⁸ Most studies report a reduced attack rate with time. It is therefore difficult to assess the true worth and efficacy of disease-modifying agents like interferons and other drugs with respect to reduction in attack rates.

The subsequent disease course is less unpredictable for populations compared with any given individual patient. Relapses occur varying frequency in various patients. The frequency of relapses varies even in a given patient at different times. However, there is a clear tendency for the frequency of relapses to be greater in the initial years, and the recovery more complete.^13,¹³⁸^–¹⁴¹

With the passage of time, relapses may leave behind more neurological and functional deficits. The contribution of attacks to progression is unclear. After this early relapsing phase, most patients enter the progressive phase of the disease. After the first decade from onset, over 50% of patients whose disease was initially relapsing-remitting enter a progressive phase of MS. Approximately a cumulative 90% develop progressive disease after 25 years of follow-up.¹⁴² It has been commented that if followed up long enough, eventually nearly all RRMS patients will be found to have developed the progressive form of the disease. Our personal observations have shown a mean duration of conversion from the time of the first attack to the onset of the progressive form of the disease is approximately 11 years, although it has been reported to be up to 19 years.^143,¹⁴⁴

After entering this phase, progression appears to be independent of, although worsened by, the accumulated neurodeficits due to, relapses. Gradual, relentless worsening of predominantly the pyramidal and cerebellar systems ensues, often complicated by sphincter and sexual dysfunction. Additionally, cortical types of deficits as described earlier may occur. Disturbances of brainstem functions, including deglutition, set in, and aspiration becomes common. This phase is discussed in detail in the following text.

PROGRESSIVE MULTIPLE SCLEROSIS

Curiously enough, but consistently over many study years, the progressive profile of both the phenotypes of MS has been demonstrated to have remarkable similarities in its clinical features. It makes sense to discuss the natural history of progression of MS, whether primary or secondary, under one heading—that of progressive MS. However, certain distinctions between the primary and secondary progressive MS classes and certain facts about them are of particular interest and are worth separate discussion.

Clinically, PPMS begins at a relatively later age compared with RRMS. Its onset peaks in the late fourth decade in contrast to early fourth decade in RRMS. The female preponderance in RRMS is not as prominent as in PPMS, with a female-to-male ratio of 1.3:1. Progression appears to worsen at a faster pace, but this may be apparent only in the early years. The progression rates in both groups are similar once progression begins.^34,¹²⁹

Relapses in the preprogressive phase of SPMS do not seem to significantly impact the later speed or severity of the progressive phase. Of course, the preexisting neurodeficits (relapse remnants) may exaggerate the disability on initial assessment. Worth noticing, though, is the fact that in individuals with one single attack predating the progressive phase of MS, the severity of the inaugural attack may be negatively associated with the onset of secondary progression (involvement of more than three neurological systems due to attack is associated with earlier onset of progression).^34,¹⁴⁵

Progressive MS presents most commonly as subtle pyramidal-cerebellar dysfunction gradually evolving over months or years in a frank myelopathy. The diffuse involvement of these two systems, added with the transient sensory phenomena, make it very difficult to localize the lesions. This in fact aids the physician by alerting the presence of a myelopathy, which should raise the possibility of a diagnosis of MS even when there is no prior history of relapses. In all classes of MS, progression predominantly involves the pyramidal system, followed by the cerebellar system. This “chronic progressive myelopathy” is a characteristic presentation of most PPMS patients. Posterior columns are next in frequency of initial presentation, and cranial nerves are commonly only involved in very late stages. In progressive MS, cortical and bulbar functions and, to a greater extent, basal ganglionic functions appear preserved until very late in the disease course in most cases.

Progression does not seem to begin specifically at the sites affected by earlier relapses. The site of the original attack has been suspected of becoming a locus minoris resistentiae where progression begins.¹⁴⁶ However, most researchers agree that there appears to be no demonstrable relationship between the site of the initial clinically evident expression of disease and the location of the progressive deficit. In our samples, patients with optic neuritis, brainstem, and spinal sensory MS onset are all characterized by an overwhelming predominance of distal central motor dysfunction at outset of the progressive phase of the disease. Progression is seldom joined by overlapping relapses in its march, but when relapses occur, they tend to behave like RRMS relapses, with typical temporal profile and partial or complete recovery.

On the pyramidal-cerebellar background of progressive MS, sphincter and sexual dysfunction, as well as posterior column sensory deficits, add to the patient’s misery. Severe visual deficits are usually rare.

Over the years, disability accumulates and patients reach for a cane. This happens on an average of about 8 to 12 years after the beginning of the progressive phase. At this stage, the progression seems to relatively stabilize for some time, but this appearance of stability probably represents the limitations of the present disability scale used.^14,¹³⁹ Table 76-8 shows the median time in years from onset of MS to reach selected levels of disability.

TABLE 76-8 Time in Years From Onset of MS to Reach Selected Levels of Disability

Although the time interval for PPMS patients to reach an EDSS score of 3 is less, they have comparable time intervals (with RRMS patients) to reach an EDSS score of 8.

The next hallmark of progression is wheelchair dependence, which usually comes approximately 10 and 20 years from the onset of progression.¹³⁹ Around this period, many things can happen simultaneously. The patient may develop many medical conditions that usually accompany this age group. Lack of mobility, stress of disability, need for catheterization, and resultant infections increase a patient’s morbidity for life-threatening consequences. Falls, aspirations due to bulbar weakness, depression, memory retrieval deficits, and emotional lability occur more frequently. Coexisting morbidity for strokes and cardiac, pulmonary, or renal disease may further complicate the scene.

An EDSS score of 10 means death due to MS, and this is usually reached after an average of 18 to 30 years from onset of progression.

DISABILITY IN MULTIPLE SCLEROSIS

The EDSS has been designed to objectively evaluate MS patients.^147,¹⁴⁸ This is necessary when longitudinally evaluating patients in clinical trials for comparable outcome measures. The EDSS is based on assessment of clinical deficits in various functional systems of the central nervous system, rating them according to severity, rating the ambulation capacity and in its absence the use of upper limbs, and scoring the total not by addition but by overall review of the individual system scores and deficits in ambulation and effective use of hands. The functional systems included are visual, sensory, pyramidal, cerebellar, brainstem, bowel-bladder, cerebral, and others. EDSS has 20 scoring points from 0 to 10; each point after 1 is divided in two.

The key milestones in EDSS are as follows:

Score 1 represents objective evidence of minimal involvement of only one functional system, with only signs and no functional disability.

Score 3 represents moderate involvement of one functional system with or without mild involvement of others. This is associated with minimal disability.

Score 6 means that a cane or unilateral support is required for walking, this represents ambulation disability.

Score 8 represents wheelchair dependency, with a relatively good use of hands still maintained.

An EDSS score of 10 represents death due to MS.

The EDSS is not linear in its function. Also, with lack of comparability of neurodeficits in various neurological systems, the scale has to depend mainly on the disability in ambulation as a comparable criterion. After the score of 5, the scale mainly depends on ambulation, with progression in other systems being sidelined.¹³⁹

On the other hand, the scale still is the best available tool for comparable longitudinal evaluation of MS patients, as it offers hard outcome parameters eventually reached by most MS patients over the course of their disease progression. However, there is tendency to (1) progress relatively slowly from scores 1 through 3 and (2) linger on for relatively longer time periods over two grades, scores 6 and 7. Obviously, these facts do not mean that the progression pace retards at these stages; they only convey a desperate need for better quantification of progression in the absence of pyramidal and cerebellar parameters.

In RRMS, the initial deficit, as mentioned, is quite variable due to diverse neurological system involvements of different degrees; hence, the score of 3 on the EDSS grossly represents a disability level signifying moderate compromise in at least one functional system, with or without mild deficits in others. This level forms a good comparable level for natural history evaluation. The mean duration taken by the patients to reach this level is discrepant in RRMS and PPMS, quite understandably, given the late onset and probably faster early progression of PPMS.^14,^139,¹⁴⁹

The mean time for an RRMS patient to reach an EDSS score of 3 is 6 to 8 years, whereas that for a PPMS patient is 1 to 2 years. This observation may differ depending on whether the patient was observed retrospectively or prospectively.^14,^139,^149,¹⁵⁰

The next level generally used for comparison is EDSS score 6, and the score is reached by most RRMS patients in 9 to 15 years, whereas most PPMS patients reach this score in 3 to 5 years.¹³⁹

Most RRMS patients achieve wheelchair dependency or an EDSS score of 8 in their progressive (SPMS) phase, and the time required for this varies from 18 to 30 years. PPMS patients reach this score in an average 20 years from onset of progression.¹³⁹

The Mayo Clinic group reported recently that the median time from diagnosis to EDSS score of 3 and 6 was 17 and 24 years, respectively. Only 25% of patients with RRMS were expected to reach an EDSS score of 3 within 20 years based on Kaplan-Meier plots of time. The median time expected for SPMS patients to reach EDSS scores of 3, 6, and 8 was about 3, 10, and 38 years, respectively. The median time from diagnosis to EDSS scores of 6 and 8 for patients with PPMS was 3 and 25 years, respectively.¹⁵¹ In a study from Lyon, France, it was reported that the median time from onset of MS to the assignment of a score of 4, 6, and 7 was 8.4 years (range, 7.8 to 9.6 years), 20.1 years (range, 18.1 to 22.5 years), and 29.9 years (range, 25.1 to 34.5 years), respectively. Runmarker and associates¹⁵⁵ reported comparable results (see Table 76-8).

These observations are analogous to the data published by our group, with minor variations. The median interval from onset of disease to reach each of these scores was significantly longer in females than in males and in patients with a younger age at onset of MS. The interval was also longer in those with an initial relapsing remitting course of MS, in those with complete recovery from the first relapse, and those with longer first interattack intervals. Interestingly, the median intervals to reach these target scores were significantly longer for cases with isolated optic neuritis at onset compared with those with isolated long tract dysfunction.¹²⁷

A series of studies drew a very useful conclusion: Approximately 50% of patients with MS are still able to ambulate independently after 15 years of disease.¹³⁷

PREDICTORS OF PROGNOSIS, LONG-TERM OUTCOME

Given the fact that in their later course both RRMS and PPMS have similar paces of progression and the disabilities are comparable, many predictors have been evaluated in the early course ^138,^139,^145,¹⁵² (Table 76-9).

TABLE 76-9 Prognostic Factors in Multiple Sclerosis

Better	Worse
Female	Male
Onset: RRMS; optic neuritis, sensory; complete recovery	Onset: polysymptomatic, motor, incomplete recovery
Younger age at onset	Late onset
Longer interattack intervals in early course	More frequent attacks in early course
Long time to DSS 3	Short time to DSS 3

DSS, Disability Status Scale (Kurtzke) (comparable with Expanded Disability Scale Score).

Relapsing remitting course, early age, and complete recovery from first attack; optic neuritis at onset; sensory onset; and female sex are predictors of favorable long-term outcome in MS.

The most important and reliable predictors of unfavorable long-term outcome in MS were found, in some studies, to be (1) attack rate in the first year of MS, (2) shortness of first interattack interval, and (3) rate of development of early disability (EDSS score of 3).

Late age at onset, male gender, polysymptomatic onset, incomplete recovery from first attack, and brainstem, cerebral, and/or cerebellar involvement are predictive factors for an adverse outcome.

In the PPMS patients, it has been shown that an involvement of three or more neurological systems at onset and the rapidity of early progression are adverse prognostic factors, shortening the time span to an EDSS score of 8.

A shorter time of achievement of an EDSS score of 3 from the onset denotes faster early accumulation of disability. This has been associated in many studies with an earlier achievement of further milestones of disability (i.e., EDSS scores of 6 and 8) compared with those who had slower early accumulation of disability.

A positive oligoclonal banding, although a very important aid for diagnosis, was not a significant predictor of long-term outcome.

MRI is increasingly changing the way we evaluate MS patients in recent years, and new techniques are widening our understanding of MS in multiple dimensions. The typical MRI lesions seen with demyelination aid in documenting time and space dissemination so vital in the diagnosis of RRMS. Although correlations are so far relatively and disappointingly poor, measures such as T2 hypointensities in gray matter, white matter atrophy, residual brain volume, spinal cord atrophy, early lesion load, and magnetization transfer ratio analysis of normal appearing brain tissue have all been directly associated with increased disability in MS.¹⁵³

Comorbidity with other diseases definitely negatively affects long-term outcome.

MORTALITY IN MULTIPLE SCLEROSIS

Mortality in MS is not significantly different from the age-matched general population in the early, low disability years of MS. As the disease ages, MS-specific complications set in. The cause of death in about 50% patients of MS is due to some complication of MS, most commonly, pneumonia and urosepsis. In the other one half of patients, the common causes of death are the same as in the general population and include acute myocardial infarction, stroke, and malignancy. A significant minority of MS patients commit suicide, and this could be due to increased incidences of depression and disability.¹³⁹

A study of the mean time to death in MS patients revealed that the mean time to death in PPMS patients was shorter (22.3 years) compared with non-PPMS patients. It was also stated that approximately two thirds of patients of PPMS die due to direct complications of MS, and the other one third die from various other causes.

A greater propensity of MS patients to succumb to depression, fatigue, and other medical conditions, combined with multisystem neurological deficits, may be responsible for a minor shortening (≈5 years) of total life span compared with the normal population. There does not seem to be any difference in the causes of mortality when RRMS (and subsequent SPMS) patients are compared with PPMS patients ¹⁵⁴ (Table 76-10).

TABLE 76-10 Primary Causes of Death in Multiple Sclerosis Patients Listed on 312 Death Certificates in the London, Ontario, Natural History Cohort ¹⁵²

Cause of Death	No. of Deaths (N = 312)
Pneumonia	99
Multiple sclerosis	43
Cancer	43
Heart disease	28
Septicemia	19
Respiratory failure	15
Stroke	15
Cardiac arrest	13
Suicide	6
Pulmonary embolism	4
Aspiration	3
Cachexia	3
Gastrointestinal bleeding	3
Accident	2
Dehydration	2
Respiratory arrest	2
Other^* (1 case each)	12