Clinical Features of Multiple Sclerosis
Multiple sclerosis is an illness characterized by relapses of neurological deficits followed by remissions with varying degrees of recovery [1-6]. The occurrence and severity of the exacerbations are unpredictable, although several factors are recognized as increasing the risk of attacks. Patients experiencing their initial attacks of MS are more likely to recover “fully,” but an experienced neurologist can virtually always find residual evidence of the previous neurological deficit, no matter how complete the recovery seems to have been. For example, retrobulbar neuritis heralds the onset of illness in 10-15% of MS patients. The severity of the visual impairment varies greatly, with a very small percentage of patients suffering complete loss of light perception. Recovery of vision generally occurs, but occasionally, especially if complete loss of vision occurs, there may be little or no recovery. A skilled examiner can find neurological deficits such as an afferent pupillary defect (Marcus Gunn pupil) and color desaturation (impaired color vision) in the vast majority of patients with a history of retrobulbar neuritis who seem to have recovered normal visual acuity.
Multiple sclerosis is typically manifest by recurrent acute onset of neurological difficulties reflecting damage to multiple areas of the brain and spinal cord, defined clinically as “attacks” or “relapses” [1, 2, 4]. Symptoms associated with these events typically remit, but subsequent relapses occur unpredictably and may become more obviously associated with residual disability [1, 3, 4]. It is this dissemination in time and space that is so characteristic of multiple sclerosis and its principal diagnostic feature [6-9]. Interval progression between, or in the absence of attacks of illness, signifies the onset of secondary progressive multiple sclerosis (SPMS) . However, approximately 10-15% of the overall patient population will develop a progressive form of illness without relapses, usually appearing in midlife, termed primary progressive multiple sclerosis, PPMS [2, 10]. This form of illness is slightly more common in men. This progressive form of MS is approximately three times more common in Irish and Ashkenazi Jewish populations [2, 10]. Should one or more exacerbations occur after onset of primary progressive illness at outset, patients may be designated as having “relapsing progressive MS” . Although in the past, there has been no agreement that SPMS and relapsing progressive patients differ in any fundamental way; evidence from new studies shows differences in the microscopic neuropathology of RRMS, SPMS, and PPMS. Lesions associated with acute relapse in early disease are cellular with abundant CD3+ T cells and do not show smoldering microglial disease activity. In contrast, in PPMS the central nervous system (CNS) is largely devoid of focal cellular collections and smoldering lesions and markers of microglial activation predominate. Secondary progressive patients have a mixture of four types of microscopic lesions with the presence of CD3+ T cells, antibody in plaques, and microglial activation as well as inactive plaques. The majority of the MS population will experience relapsing-remitting illness, but residual persistent disability may variably follow despite remission [11-13]. The presence of residual disability following exacerbations does not signify the onset of secondary progressive illness, however.
Increases in body temperature, or illness, in MS may result in the transient reappearance of neurological symptoms (Uhthoff phenomenon). Despite a previous remission of clinical manifestations of MS, those same symptoms may appear with overheating . Although the Uhthoff phenomenon is not an exacerbation, these phenomena in MS patients are commonly misinterpreted as such. Occasionally heat exposure appears to acutely worsen the severity of an exacerbation and, in other circumstances, worsens a minimal or subclinical event making it more clearly apparent clinically . These events probably reflect the ability of heat to impair the blood-brain barrier, allowing activated lymphocytes and immunoglobulins to enter the brain and spinal cord .
The most common initial symptoms of MS are sensory disturbances and fatigue but are often ignored by patients and physicians alike. Perceptions of numbness and tingling by the patient may not be accompanied by obvious abnormalities on initial examination, especially if the patient is not examined completely by a neurologist at the onset of their symptoms. Almost half of initially recognized exacerbations principally affect ambulation. Acute paraparesis varies greatly in degree and in symmetry of the weakness. In many MS patients with motor weakness found by examination, they describe their difficulty as a “heaviness” in their “leg(s).” Alternatively, they may seem only to stumble when their foot catches an uneven area on a sidewalk. The difficulty is often initially recognized only by a family member or a friend during ambulation. Gait problems may be due to motor difficulties and/or, ataxia. Ataxia may occur as a result of vestibular, cerebellar, or sensory impairments. Thus, gait difficulty may reflect motor deficits or ataxia due to one or more problems within the brainstem or spinal cord.
About one out of five or six MS patients will have unilateral retrobulbar (optic) neuritis as their initial clinical difficulty [2, 11]. Other common symptoms at onset include diplopia, facial weakness and/or facial myokymia, vertigo, bladder, and bowel symptoms. Seizures will eventually occur in 10% during the clinical illness but rarely (about 1%) are a presenting sign of illness . Some symptoms, such as hearing loss and impaired night vision, can be seen in MS and also acute disseminated encephalomyelitis (ADEM). The speed of recovery is variable and may be slow over several months or may not occur at all. Other less commonly recognized symptoms include extrapyramidal symptoms and a family of paroxysmal manifestations .
Recurrent brief (paroxysmal) stereotyped manifestations in MS include paroxysmal dystonia or “tonic seizures,” paroxysmal dysarthria, paroxysmal akinesis (“paroxysmal falling”), pains (including trigeminal neuralgia and glossopharyngeal neuralgia), and other difficulties [2, 16]. Lhermitte’s sign is precipitated by neck flexion and typically consists of transient shocklike sensations radiating down the neck and back, often into the limbs. It is commonly recognized as a sign of MS especially when it occurs in the young, although it may occur with compressive cervical disc disease or spinal tumors. Except for Lhermitte’s sign, these paroxysmal symptoms seem to occur in a minority of patients and are often not recognized as part of the spectrum of illness. When recognized, these paroxysmal phenomena are of great diagnostic value since they are rarely associated with other illness. When viewed in a cross section of a patient population, they are evident in only about 3% of patients. We have found, however, that with long-term follow-up that paroxysmal phenomena will eventually occur in up to a quarter of patients. Occasionally paroxysmal dystonia involves all four limbs and the truncal muscles as well and may be accompanied by severe pain. Fortunately there is usually a prompt and complete response to carbamazepine in a 400 mg per day dosage, but a course of parenteral corticotrophin may be needed. Unfortunately, many such patients are incorrectly diagnosed as having an acute psychiatric problem. These paroxysmal symptoms are commonly attributed to ephaptic transmission (cross talk between damaged/demyelinated axons), but we suspect that they may be due to inflammatory mediators such as leukotriene C, and other leukotrienes, produced by macrophages. Leukotrienes are extremely potent depolarizing agents. Often the time course of these paroxysmal events approximates that of an exacerbation and, if so, should be considered to be exacerbations.
Although fatigue and fatigability become more prominent with time, especially during periods of disease activity, they may be prominent presenting signs of MS. Anxiety, depression, and cognitive issues, also, may dominate the presentation of illness and may delay disease recognition. In our experience cognitive problems and accompanying emotional reaction occurring early in the course of illness are more important than physical disability as reasons for social dislocation and patients leaving studies or their workplace. A substantial proportion of patients are dismissed as “functional” early in the course of their illness due to their observed emotional status. A recent oral presentation reported the association of MS with schizophrenia and bipolar disorder, with a rate ratio of 1.42 for schizophrenia and 1.73 for bipolar disorder .
A bewildering variety of manifestations may occur in MS, singly or in combination with other difficulties. These include limb weakness, “useless limb” syndrome due to severe proprioceptive loss, memory impairment, word-finding difficulty, acalculia, tremor, unusual nonphysiological patterns of sensory loss, and sexual impotence, among others [2, 11]. Motor impersistence is common in the MS population and accompanies proprioceptive impairment. Geschwind also suggested that frontal lobe involvement was a likely contributing factor (Norman Geschwind - personal communication).