Multiple Sclerosis.

  • Multiple Sclerosis is a disease characterized by multifocal areas of demyelination in the brain and spinal cord which presents with episodic neurologic dysfunctiom.

 ETIOLOGY/ PATHOGENESIS

  • Annual incidence varies by location and ranges between 1.5-11 in 100,000 people.
  • Occurs 2 fold more frequently in women than in men.
  • Presents more often in the 3rd-4th decades of life.
  • Most common in people of North European descent and whites acquire the disease twice as often as African Americans in the US.
  • The lifetime risk of MS is increased to 2 to 4% in individuals with a first-degree relative with MS compared with the general population risk of 0.1%.
  • Most cases are characterized by multifocal areas of demyelination and gross gliotic scar in the brain and spinal cord. Classic locations of these plaques, are the optic nerves, periventricular white matter, deep white matter, juxtacortical white matter, corpus callosum, cerebellar peduncles, and dorsolateral spinal cord.
  • Four distinct subtypes of MS can be discerned.
  • Type I lesions: perivenular inflammatory infiltrates consisting mainly of T cells, with early preservation of oligodendrocytes.
  • Type II: lesions: similar to type I but have an additional humoral component with immunoglobulin G (IgG) deposition and complement activation.
  • Type III lesions: are not based around venules and havr prominent loss of myelin-associated glycoprotein, with evidence for oligodendrocyte apoptosis.
  • Type IV lesions: have inflammatory infiltrates more similar to types I and II and also have oligodendrocyte loss as in type III.

 PERTINENT HISTORICAL FINDINGS/ CLINICAL SYMPTOMS

  • MS can present in many ways initially masquerading as a variety of different illnesses.
  • Classically, a young white person, most likely a woman, has an acute to subacute onset of impaired vision or sensation. Also common are the following: fatigue, depression, bladder urgency, weakness, impaired balance, and impaired coordination. Because the symptoms of the first attack are generally mild most patients do not seek medical care.
  • Paresthesias of a limb that are circumferential and do not follow a dermatome which often manifest distally and then ascend to involve more proximal parts of the limb, spread to the contralateral limb, or progress from a leg to an arm.
  • Lhermitte’s sign: an electrical sensation moving down the spine into the limbs on flexion of the neck.
  • Loss of sensation is seen in more advanced cases. Burning, electrical, or deep aching sensations are also common.
  • There are three major clinical types of MS: relapsing remitting, secondary progressive, and primary progressive.
  • 85 to 90% of patients present with relapsing remitting MS. Characterized by acute or subacute episodes of new or worsening old neurologic symptoms that increase in severity, plateau, and then partly or completely remit. Patients may either have no detectable residual deficit, or may accumulate significant permanent disability from an attack.
  • Most patients convert to secondary progressive MS after 20 to 40 years. This stage is characterized by at least 6 months of progressive worsening without evidence of a relapse. Some patients have interposed relapses distinct from their periods of progressive worsening; however these episodes become less frequent with time.
  • Primary progressive MS occurs in 10-15% of patients is characterized by progressive deterioration from the onset for at least 1 year without a history of distinct relapses, occur. More common in middle-aged men and typically has more involvement of the spinal cord and fewer inflammatory brain lesions.
  • Progressive relapsing MS refers to a fairly uncommon variant of MS (6%), in which a relapse ensues after an initially primary progressive course.
  • Acute progressive MS (Marburg’s disease) causes acute or subacute progressive neurologic deterioration leading to severe disability within days to a month in a patient with no prior history of MS. Rare form of the disease which may progress to a quadriplegic, obtunded state with death as a result of intercurrent infection, aspiration, or respiratory failure from brain stem involvement.

 PERTINENT PHYSICAL EXAM FINDINGS

  • Sensory Abnormalities: Loss of vibration perception, most prominent in the feet, and incomplete spinal cord levels to pin prick or vibration, which are often more notable in a graded fashion rather than at a distinct level. Patchy or nonanatomic focal areas of impaired sensation can occur described as bizarre sensations such as water dripping or bugs crawling.
  • Optic neuritis: visual symptoms in one eye. Patients complain of pain over the lateral eyebrow and worsening on lateral eye movement. Described as looking through frosted glass or a veil. More severe cases may result in total loss of light perception. In most acute cases there is no immediate changes are visible on the optic disc, but there should be a relative afferent papillary defect (Marcus-Gunn pupil) with paradoxical dilation of the affected eye to direct light. Patients usually spontaneously recover substantial vision after weeks to months.
  • Visual impairment from impaired tracking of eye movements owing to brain stem or cerebellar disease most commonly occurs in the setting of an acute lesion affecting the medial longitudinal fasciculus, which is the neurologic pathway. Patients may have diplopia or just blurred vision, especially when they look off to one side rapidly, such as when looking over one’s shoulder while driving.
  • Internuclear ophthalmoplegia: slowed or absent adduction of one eye with abducting nystagmus of the other eye. It may occur bilaterally or may exist in milder forms, such that the adduction lag is imperceptible to the human observer. Blurred vision from cerebellar damage with nystagmus is very common in MS and is often worse on extreme lateral or vertical gaze.
  • Motor Symptoms: Weakness and impaired coordination in a leg, with ascending involvement from distal to proximal and commonly spreading to the contralateral leg or ipsilateral arm.
  • Heat-induced fatigue and weakness, as manifested by focal symptoms (slapping of a foot or dragging a leg) occurring after 15 to 20 minutes of exercise and resolving with rest.
  • Early – absence of associated hyperreflexia and plantar extensor responses (Babinski’s sign). Later, – spastic gait (either hemiparetic or paraparetic), muscle cramps, and clonus (sustained reflex loop), sometimes occurring with positional changes.
  • Ataxia, Appendicular dysmetria resulting in tremor on reaching for an object is a common cause of impaired coordination and dexterity. Lower extremity and truncal ataxia may result in a wide-based (drunk) gait.
  • Myokymia (wormlike muscle movements) under the skin, especially around the face, however, is fairly common.
  • Bladder dysfunction: isolated or mixed patterns of urinary frequency, urgency, incontinence, and/or retention. Urinary tract infections resulting from bladder dysfunction.
  • Bowel dysfunction: constipation, bowel incontinence secondary to an incompetent anal sphincter is less common and most often occurs as an isolated episode of fecal urgency, sometimes related to dietary change or diarrheal illness.
  • Sexual dysfunction: in men, erectile dysfunction is frequent. In women and men, loss of libido and inability to achieve orgasm can occur as a result of medication, loss of sensation, heat-induced worsening of symptoms, physical barriers to intercourse (impaired mucosal moisture, spasticity, and pain), depression, or disorders of body image.

 DIFFERENTIAL DIAGNOSIS

  • The differential in multiple sclerosis is extensive. See table.

Conditions that can be Mistaken for MS and Other Diseases of Myelin

Vascular Disease

Small vessel cerebrovascular disease

Vasculitides

Arteriovenous Malformation

CADASIL

Antiphospholipid antibody syndrome

Structural Lesions

            Craniocervical junction posterior fossa or spinal tumors

Cervical spondylosis or disc herniation

Chiari malformation or syrinx

Degenerative Diseases

            Hereditary myelopathy

Spinocerebellar degeneration

Infections

            HTLV-1 infection

HIV myelopathy or HIV-related cerebritis

Neuroborreliosis (Lyme disease)

JC virus/progressive multifocal leukoencephalopathy

Neurosyphilis

Other Inflammatory Conditions

HIV = human immunodeficiency virus; HTLV = human T-cell lymphotropic virus; MRI = magnetic resonance imaging, CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Adapted from: Cecils 23rd edition

DIAGNOSTIC EVALUATIONS

  • Diagnosis is dependent on demonstrating evidence of at least two inflammatory demyelinating lesions referable to different locations within the CNS, occurring at different times (usually ≥1 month apart), and for which no better explanation exists.
  • Criteria allow for the diagnosis to be made on clinical grounds if exclusionary tests are performed. However, clinical evidence of a lesion requires objective findings on examination, not just a symptom. See table below

 2005 REVISIONS TO THE MCDONALD DIAGNOSTIC CRITERIA FOR MS

Clinical Presentation Additional Data Needed for Diagnosis of MS
Two or more attacks; objective clinical evidence of two or more lesions None
Two or more attacks; objective clinical evidence of one lesion Dissemination in space, demonstrated by:
(1) MRI or
(2) Two or more MRI-detected lesions consistent with MS plus  positive CSF or
(3) Await further clinical attack implicating a different  site
One attack; objective clinical evidence of two or more lesions Dissemination in time, demonstrated by:
(1) MRI or
(2) Second clinical attack
One attack; Objective clinical evidence of one lesion (monosymptomatic presentation; clinically isolated syndrome) (1) Dissemination in space, demonstrated by:
(a) MRI or
(b) Two or more MRI-detected lesions consistent with MS plus  positive CSF and
(2) Dissemination in time, demonstrated by:
(a) MRI or
(b) Second clinical attack

Adapted from Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846

  • 95% of patients with clinically definite MS have an abnormal brain MRI, and the presence of high-signal, bright lesions
  • Specific MRI findings allow for confirmation of disease disseminated in space (different parts of the brain or spine) as well as fulfilling evidence for dissemination in time. Lesions generally range in size from 2 mm to 2 cm; larger plaques occasionally resemble a tumor. Typical locations include the periventricular area, the corpus callosum, the cerebellar peduncles, the brain stem, the juxtacortical area, and the dorsolateral spinal cord.
  • Cerebrospinal Fluid: Examination of the CSF is useful in many cases but is not mandatory in patients with a typical clinical presentation and MRI evidence of disseminated disease. CSF evaluation includes cell counts, total protein, glucose, oligoclonal bands with a paired serum sample, and an IgG index.
  • The presence of myelin basic protein is not specific for MS because it can be elevated secondary to any disruption of CNS tissue. Oligoclonal bands in the CSF or an elevated IgG index provides evidence for intrathecal production of immunoglobulins, and oligoclonal bands are common in MS but can occur with infection or other immune-mediated processes; the test lacks both specificity for MS.
  • Evoked Potential Tests : May be useful in some situations to document objective evidence of slowed conduction owing to demyelination in locations different from those recognized clinically. However, visual evoked potentials, brain stem  auditory evoked potentials, and somatosensory evoked potentials are less sensitive and less specific for MS than is high-resolution MRI.

 MEDICAL MANAGEMENT 

  • Depression and emotional lability: antidepressant therapy with one of the “activating” serotonergic or noradrenergic drugs (fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, or bupropion).
  • If anxiety and panic symptoms predominate, use paroxetine.
  • Patients with concomitant pain or insomnia may benefit more from a sedating tricyclic (amitriptyline or nortriptyline) given at bedtime.
  • Spasticity: baclofen (5 to 160 mg in divided doses) or tizanidine (2 to 32 mg in divided doses). Either drug should be started as a single agent at a low dose, generally three to four times a day, but a larger dose at bedtime is often the best tolerated and may target nocturnal symptoms.
  • Bladder urgency: anticholinergics such as oxybutynin (5 to 20 mg in divided doses) or tolterodine (1 to 4 mg), but these agents can cause temporary urinary retention. Urinary retention may be improved by removing drugs known to induce it. Primary urinary retention is difficult to treat with drugs, but external sphincter spasm can be treated with α1a-adrenergic receptor blockers such as tamsulosin (0.4 to 0.8 mg) and doxazosin (1 to 8 mg). Bethanechol (10 to 150 mg in divided doses) may be tried for an atonic bladder, but intermittent catheterization is often required.
  • Painful dysesthesias and paroxysmal dystonic spasms may be managed effectively with antiepileptic drugs (gabapentin, 300 to 5400 mg/day in divided doses; pregabalin, 75 to 600 mg/day in divided doses; or carbamazepine, 100 to 2400 mg/day in divided doses) or tricyclic antidepressants (amitriptyline, 10 to 150 mg; or nortriptyline, 10 to 50 mg). Patients with trigeminal neuralgia may respond to these drugs or to baclofen, misoprostol, botulinum toxin, or decompression surgery.
  • Sexual dysfunction in MS is often multifactorial. Patients with erectile dysfunction usually respond well to the phosphodiesterase inhibitors, which enhance penile vasodilati. Education regarding the use of lubrication, alternative sensory stimulation, and the adverse effect of heat can improve sexual function.
  • Corticosteroids (e.g., intravenous methylprednisolone, 1 g/day for 3 to 5 days) shorten the duration and severity of symptoms from an acute exacerbation but have no effect on long-term disability. Oral corticosteroids used in equivalent dosage are probably equally efficacious and safe.
  • Intravenous immunoglobulin and plasma exchange have been reported occasionally to benefit steroid refractory patients, but randomized placebo-controlled trials have failed to show consistent benefits, perhaps because only patients with type II disease (humoral component) are likely to respond.
  • Six disease-modifying agents have been approved by the U.S. Food and Drug Administration: interferon-β (IFN-β)1b (Betaseron), IFN-β1a (Avonex), IFN-β1a (Rebif), glatiramer acetate (Copaxone), natalizumab (Tysabri), and mitoxantrone (Novantrone). The first five agents were approved for relapsing remitting MS, and mitoxantrone is indicated for worsening forms of MS and for secondary progressive MS.

 SURGICAL MANAGEMENT (when applicable)

  • Not applicable

EMERGENCY MANAGEMENT (when applicable)

  • Not applicable

 PATIENT EDUCATION/ MAINTENANCE – PREVENTION

  • Before Nonmedical treatment of MS is a critical part of managing the disease.
  • Patients derive benefit from a health care team approach consisting of an experienced MS physician, nurse, social worker, therapist, and counselor, with appropriate referral to other subspecialties as needed.
  •  Alternative and complementary therapies are commonly used by patients with MS, and the risks and benefits of these approaches must be discussed with the patient.
  • Before considering a symptomatic drug therapy, the patient should be educated about the purpose of the drug and its side effect profile. On learning that these drugs have no long-term impact on disease activity, patients may elect not to use them for relief of symptoms alone

h9991221  multiple-sclerosis-s13-mri-brain-and-spinal-cord

17089  Multiple-Sclerosis

Dr. Zachary Lahlou

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