Multiple sclerosis (MS) is a chronic disease which manifests as neurologic deficits which may be progressive or intermittent; however, the general overall course of the disease over the lifetime of the patient is one of progression. The clinical symptoms are the manifestation of acute and chronic demyelination of the central nervous system (CNS). The cause and pathogenesis of MS are unknown, but it is believed that MS is an autoimmune disease against the CNS which may be initiated by viral infections. Pathologically, the disease is characterized by multifocal inflammatory lesions with gliosis of the white matter tracts (and occasionally in gray matter) of the CNS. Females are affected more frequently than males. There is an increase in disease noted geographically. There is little disease activity in the tropic and subtropic regions. The incidence of disease increases among patient populations as the distance from the equator increases. Conditions to consider in the differential diagnosis include acute disseminated encephalomyelitis, neuromyelitis optica, systemic lupus erythematosus, anti-phospholipid syndrome, and acute hemorrhagic leukoencephalitis.
There are four classes of MS based on the clinical symptoms. Relapsing-remitting disease is characterized by acute flares of neurologic deficits followed by complete recovery and then a period of disease inactivity. Over time, remission from acute attacks may not be complete and the patient retains residual deficits. This marks the secondary-progressive stage of disease, and worsening of the patient’s residual deficits and disability is to be expected. Some patients initially have a form of disease which does not have periods of remission but rather progressively worsens and this is termed primary-progressive disease. Patients with progressive disease who also suffer acute flares of worsening disease have progressive-relapsing disease. Disease severity may be variable, with some patients suffering only minimal symptoms and experiencing a fairly productive life; whereas, other patients may become progressively more disabled and impaired during the course of their illness.
Initially, patients present with sensory abnormalities or more commonly complain of motor abnormalities of the lower extremities that manifest as constant tripping during walking or a feeling of heaviness and numbness of the legs. Physical examination will often reveal some degree of bilateral weakness or spasticity of the lower extremities plus hyperreflexia, clonus, and a positive Babinski sign. A lack of emotional response to what should be a traumatic occurrence is another manifestation that may be encountered initially and is termed “la belle indifference”. Other common presenting symptoms include paresthesias, optic neuritis (unilateral decrease in vision accompanied by photophobia and eye pain with movement), diplopia, retrobulbar neuritis, afferent pupillary defect (Marcus Gunn pupil), L'hermitte phenomenon (a sensation of an electric shock or a vibration radiating down the back and into the arms or legs-often induced by neck flexion), vertigo, impaired balance, pain, ataxia or any combination of these or other neurologic deficits. Common physical findings include action tremor, nystagmus, hearing loss to some degree, scanning speech and intranuclear ophthalmoplegia (INO). Bilateral INO (pathognomonic of MS) is characterized by bilateral abducting nystagmus with weakness of the adductors of the eye (in essence, the patient can not fully adduct one eye and an abducting nystagmus is noted in the contralateral eye). Symptoms are often exacerbated by stress or fevers.
Abnormalities noted on visual, brain stem auditory, and somatosensory evoked potentials may be helpful in establishing the diagnosis. A lumbar puncture should be performed as part of the work up. Cerebrospinal fluid evaluation often reveals a normal glucose, minimal WBCs, an elevated total protein, an elevated CSF immunoglobulin, an elevated Oligoclonal IgG. If identicle oligoclonal IgG bands appear in the CSF and a matched serum sample (with MS the bands should be in the CSF only), then another diagnosis should be considered. If the serum is positive for neuromyelitis optica antibody, then Devic's disease should be diagnosed. Other conditions associated with CSF oligoclonal banding include bacterial, mycobacterial, fungal and viral infections, Behcet’s disease, systemic lupus erythematosus, HTLV-1 associated myelopathy, lymphoproliferative disorders of the leptomeninges, and stroke. MRI scanning with gadolinium of the brain, brain stem, spinal cord and optic nerves may reveal the characteristic plaques.
Therapy to modify disease progression is available to patients in the form of interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, cladribine, fingolimod and others. Acute flares of disease activity are treated with corticosteroids. Some of the recommended high dose regimens include: methylprednisolone 1000 mg/day intravenously for 3 to 7 days and may be followed by an oral prednisone taper 1 mg/kg/day for 11 days the 20 mg/day for 1 day then 10 mg/day for 2 days then discontinue; or dexamethasone 96 mg orally for 5 days followed by tapering doses of 72 mg, 64 mg, 48 mg, 24 mg, 12 mg, 6 mg, 4 mg, 2 mg, 1 mg and 1 mg for the next 10 days. Therapy for specific symptoms is as follows:
SPASTICITY: Baclofen 10 mg QHS or BID increasing weekly by 10 mg increments until effect. If the patient notices increased weakness, decrease the dose by 10 mg increments until resolved. Doses as high as 200 mg per day in divided doses may be needed. If baclofen alone proves ineffective, changing to or adding a benzodiazepine (valium 1-2 mg TID increasing to 30 mg/day as needed) may prove effective. If baclofen and valium are ineffective, a trial of dantrolene (25 mg/day increasing to 100 mg QID) is indicated. Tizanidine (2-4 mg PO QHS and titrate to effect or 8 mg PO TID) may also be an effective alternative. Severe cases may require intrathecal baclofen delivered via a subcutaneous pump or surgical intervention.
TREMOR: Patients often manifest an action tremor which may respond to isoniazid (900-1200 mg/day), carbamazepine, ondansetron, primidone, glutethimide, baclofen, clonazepam, propranolol, choline, lecithin or weighted wrist bracelets.
FATIGUE: Amantadine 100 mg BID-TID is the drug of choice. Discontinue amantidine therapy after one month if no effect is noted and switch to pemoline (18.75 to 37.5 mg BID). Other options include modafinil, ritalin and serotonin reuptake inhibitors. Patients should be instructed to maintain a cool environment at home as excessive ambient temperatures may worsen fatigue.
DEPRESSION: Counseling and therapy directed at the underlying MS may be effective. Serotonin reuptake inhibitors and tricyclic antidepressants may also be effective. Depression in MS patients may manifest as a combination of surliness, antisocial behavior, excessive alcohol use, promiscuity, and suicidal attempts without evidence of sadness or anxiety. In patients with this atypical form of depression, carbamazepine may be a more effective form of therapy. Patients who manifest emotional lability (inappropriate laughing, crying, tearing, etc) may respond to amitriptyline (25 mg QHS and increasing to effect usually at doses less than 100 mg/day). If amitriptyline is ineffective, levodopa or bromocriptine may be helpful. Anxiety may respond to brief courses of benzodiazepines.
MANIA: These patients appear hysterical.
TRIGEMINAL NEURALGIA: This disorder is more common in MS patients than in the general population, and symptoms may be bilateral. Carbamazepine, phenytoin, or baclofen are effective therapeutic options. Refractory cases may respond to pimozide (2-6 mg BID).
PRURITIS: Often responds to low dose carbamazepine.
ATAXIA: May respond to isoniazid (800-1200 mg/day) plus pyridoxine (100 mg/day), anticonvulsants, propanolol HCl (20-40 mg TID) or ondansetron (4-8 mg QD to BID).
PAIN: An uncommon symptom at presentation, but it often manifests over the course of the disease. Carbamazepine, phenytoin, and benzodiazepines are effective first line agents for acute episodes of pain. Chronic pain may respond to NSAIDs and physical therapy but may require more aggressive forms of pain control. Burning pain may respond to high doses of amitriptyline or imipramine.
BLADDER DYSFUNCTION: Always consider urinary tract infections in MS patients. Initial therapy for patients without bladder outlet obstructive symptoms should include fluid restriction before activities where urination may not be easily performed, timed voiding, and a bedside commode. Catheterization is also an option but should not be used until all other options have been exhausted. Oxybutynin chloride, propantheline bromide, tricyclic antidepressants, desmopressin acetate, and tolterodine tartrate are potential therapeutic options. Patients with obstructive symptoms may respond to terazosin HCl (2-10 mg/day) or bethanechol chloride (10-50 mg TID-QID). Those who do not respond to treatment may require frequent catheterization. Bladder hyperactivity is extremely common and manifests as urgency, frequency, voiding irritation, and incontinence, which is a socially distressing symptom. When bladder contractions occur simultaneously with contractions of the urethral sphincter (termed sphincter dyssynergia), patients will have symptoms of hyperreflexia along with an elevated post void residual urine volume. Detrussor hypoactivity will manifest with a greatly elevated post void residual urine volume. Patients with small capacity bladders may respond to oxybutinin 5-10 mg PO TID or tolterodine 2 mg PO TID.