Treatment of Acute Exacerbations

There is currently no cure for multiple sclerosis (MS) but effective strategies are available to manage the disease and improve overall function. Treatment management has two main objectives1: to relieve symptoms acutely and to prevent further disease progression. Acute exacerbations and symptomatic treatments of MS represent an important part of management, as, in combination with disease-modifying treatments, they improve quality of life for MS patients.

Emergency department management: Interventions consist of stabilizing patients following airway, breathing, and circulation principles. Initiate supportive care, seizure precautions if necessary, identify and treat precipitants (infections, trauma). Patients may receive plasmapheresis, IV immunoglobulin, and high-dose steroids in the ED or during hospitalization. 

Acute treatment for MS includes:

a.) IV steroids: High-dose IV steroids are the standard treatment in acute exacerbation of MS and have been found to be more effective than oral steroids2. Steroids decrease the inflammation associated with the demyelinating process and can hasten recovery from an acute attack. Methylprednisolone (Solu-Medrol) is most commonly used, followed by prednisone taper. Recommended dosage for IV methylprednisolone is 500–1,000mg/day for four days, until clinical improvement.
b.) Emergent plasmapheresis3: Plasmapheresis is a therapeutic plasma exchange. It is reserved for patients in acute episodes of demyelination and who are resistant to steroids or when contraindications to steroids treatment exist4. The procedure is performed with a flow machine that exchanges the patient’s plasma with either donor plasma or albumin solution and returns the red blood cells to the patient. Benefits may potentially be due to clearance of all immunological factors (cytokines, antibodies). It also effects the ratio and function of a specific type of myelin regulatory T cells, resetting them and inducing cell unresponsiveness5.

Symptomatic treatment of MS: involves both pharmacologic and non pharmacologic measures.

Cognitive dysfunction: Its decline has an important impact on patients’ quality of life and social relationships. Patients can present with symptoms of impaired memory, comprehension, problem-solving skills, or speech. Clinical trials conducted with donepezil (Aricept) did not show improved memory. Treatment is supportive with speech and occupational therapy.

Fatigue: It is one of the most common symptoms of MS, affecting 76 to 92% of MS patients, and it is also one of the most disabling. Fatigue can also be a side effect from many of the medications used in MS, such as anticonvulsants, muscle relaxants, sedatives, analgesics, and immune modulators. There are no FDA-approved treatments, but off-label options include:

  • Amantadine is the first-line treatment; the recommended dosage is 100mg orally twice daily. Amantadine has been shown to be effective at relieving fatigue in 40% of patients with that complaint6.
  • Methylphenidate is a stimulant approved for attention deficit disorder. The disadvantage is that it is a controlled substance due to its potential for abuse. Recommended dosage is 10 to 60mg per day, divided in two to three doses throughout the day.
  • Fluoxetine (Prozac) is a good option for patients with depression, as it addresses both problems.
  • Modafinil (Provigil) is a non-stimulant drug approved for narcolepsy and shift workers. It was shown to be helpful at relieving fatigue in MS patients. Recommended dosage is 200mg once in the morning. Armodafinil (Nuvigil) is the longer-acting form and is another option.
  • Non-pharmacologic measures include incorporating rest periods daily, work simplification, use of cooling garments, and regular exercise as tolerated.

Depression: Selective serotonin reuptake inhibitors are the first-line treatment. Tricyclic antidepressants are second-line, and their anticholinergic effects may help patients with bladder spasticity and chronic pain.

Spasticity: 

  • Baclofen (Gablofen, Lioresal) relieves flexor spasms and pain, clonus, and muscular rigidity. It is titrated from 10–140mg/day.
  •  Second-line treatment include benzodiazepines (Diazepam, Clonazepam), which are a good option for patients with sleep disorders.
  • Dantrolene sodium (Dantrium) acts directly on skeletal muscles to diminish spasticity; however, it is associated with muscle weakness and hepatotoxicity.
  • Gabapentin (Neurontin) is useful for patients with concomitant neuropathic pain. It is titrated from 300 to 3,600mg per day. It causes significant sedation and is an expensive option.
  • Tizanidine (Zanaflex) is a centrally acting alpha-adrenergic agonist used to treat spasticity. It is titrated from 2 to 32mg per day and causes sedation and muscle weakness.
  • For refractory cases, invasive treatments include IM botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement.

Pain: Thirty to 50% of MS patients will experience pain during the course of their disease. Pain medications account for 30% of symptomatic treatment for MS7.

  • Primary pain: Is secondary to the demyelination process and is often described as a shooting or burning pain. Tricyclic antidepressants are first-line drugs for this type of pain. Anticonvulsants are second-line agents and include phenytoin, gabapentin, and carbamazepine.
  • Secondary pain: Is a musculoskeletal pain due to misuse of muscle and joints affected by spasticity, impaired balance, or poor posture. NSAIDs and other analgesics can be used; narcotics are not recommended.

Sexual dysfunction: Is a common symptom for male patients with MS, and it is often associated with other symptoms such as depression, bowel dysfunction, or spasticity. Mainstay treatment includes oral phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil). Patients refractory to medical treatment have the alternative option of penile prostheses.

Optic neuritis: Intravenous methylprednisolone (IVMP) may hasten recovery of visual function8. It also decreases the incidence of MS over a two-year period and decreases the incidence of recurrent optic neuritis. Recommended dosage is 1gm per day for three days.

Heat intolerance: Fever should be treated aggressively with antipyretics. Other approaches to heat intolerance are non-pharmacologic and include:

  • Avoid exposure to heat by planning outside activities early in the morning or in the evening hours. When necessary, wear cooling garments, light-colored clothes, and hats.
  • Avoid exposure to heat from saunas and hot tubs, hot showers, and baths.
  • Avoid exposure to excessive humidity, and use dehumidifiers indoors.
  • Use air-conditioning when possible.

Gait disturbances: The only FDA-approved drug shown to improve motor function in MS is dalfampridine (Ampyra)9. The mechanism of action is restoration of action potential conduction by blockade of an unspecified subtype of potassium channels located in demyelinated axons. Dalfampridine is associated with an increased risk of seizure even in patients without a history. It is eliminated through the kidneys; therefore, poor renal function is a contraindication due to risk of seizures induced by poor clearance and resulting high levels of the drug. The recommended dosage for this oral, sustained-release medication is 10mg/twice daily.

Badder dysfunction:

  • Failure to store: Non-pharmacologic interventions include scheduled voiding, limiting fluid intake, and avoiding diuretics such as caffeine. Pharmacologic options include anticholinergic medications (oxybutynin) or injection of botulinum toxin A (Botox) into the bladder.
  • Failure to empty: This is due to a large, flaccid bladder and inability of the urinary sphincter to relax. Symptoms are urinary urgency or frequency, hesitancy, nocturia, incomplete emptying, and recurrent urinary tract infections. Treatment options include intermittent catheterization or alpha-blockers (Prazosin).
  • Combined dysfunction: This occurs secondary to dyssynergia between the detrusor and the sphincter.
  • Refractory bladder dysfunction: Additional studies to consider: urinalysis, renal ultrasound, voiding cystourethrography, renal scan, or urodynamic studies. 

Bowel dysfunction: The most common problem is constipation, but some patients also complain of diarrhea. Constipation may be secondary to neurogenic bowel, decreased mobility, or poor fluid intake.

Non-pharmacological approaches for constipation:

  • Increase fluid intake to 8 to 10 cups daily and increase dietary fiber intake to 15g.
  • Patients should adopt a consistent bowel program after a specified meal, to take advantage of the body’s gastrocolic reflex. They should follow an exercise program, walk, or perform chair exercises. Sitting upright instead of lying down is beneficial, as it permits gravity to help in evacuation.
  • Abdominal massage in the direction of bowel peristalsis can help stimulate a bowel movement. Direct rectal stimulation can also be helpful to stimulate a bowel movement: It is performed by inserting a lubricated finger into the rectum and moving it from side to side along the wall of the rectum. 

Pharmacologic approaches for constipation:

  • Stool softeners decrease surface tension and allow water to enter the stool. Available options include docusate sodium.
  • Bulk formers increase the weight of the stool. Available options include Metamucil, Citrucel, and FiberCon.
  • Laxatives work by increasing peristalsis and work within 8 to 12 hours. Available options include mineral oil, Milk of Magnesia, and Peri-Colace.
  • Rectal suppositories provide rectal stimulation and act within 1 hour. This is a good option for patients with neurogenic bowel or poor abdominal muscle tone. Available options include glycerin and bisacodyl.

Pharmacologic approaches for diarrhea: Diarrhea is usually a side effect rather than a symptom of MS. Causes include overuse of laxatives or stool softeners, fecal impaction, or bowel irritation.

  • Bulk formers: psyllium
  • Drugs that decrease bowel motility: Diphenoxylate, Atropine. 

Tremor: This is a difficult symptom to manage for MS patients. Therapies used have had little success and include: propanolol, ondansetron, benzodiazepines, anticonvulsants, isoniazid, and primidone.

Surgery: Mainly reserved for relieving symptoms such as dysphagia with gastrojejunal tube placement, severe limb spasticity or contractures with adductor tendon release, and neuropathic pain with rhizotomy. Intrathecal pumps are also placed surgically for delivery of medication such as baclofen (these carry the risk of malfunction and overdose).