Multiple Sclerosis_2
Short Summary

21-year-old female with an acute onset of a unilateral sixth cranial nerve deficit. Brain MRI showed at least a dozen white matter lesions, one of them contrast-enhancing. Sensory evoked potentials showed a bilateral increase in latency. Multiple sclerosis was diagnosed, and the patient was treated by corticosteroids, followed by improvement of symptoms. The first follow-up revealed no focal neurological signs with a history of a transitory unilateral lower limb hyposthenia. On the second visit, a horizonto-rotatory nystagmus and irregular paraesthesia in the right toes are documented. Spinal MRI showed a new and contrast enhancing lesion.

Patient's Questions
1)    What are the most useful treatment indications, recommended for the pathology in question?

2)    Centers of excellence in Italy and abroad?

3)    Names of the most qualified Italian or European specialists for this pathology?
Medical Background

Female , 21 years old
No significant conditions in past medical history.
Onset of headaches at the end of December 2006 and subsequent visual defect until the appearance of double vision looking to the left. After arriving at the Emergency Room of San Donato Hospital in Arezzo, the patient was therefore hospitalized for tests on December 2006.
Upon admission, the objective neurological exam pointed only to a left sixth cranial nerve deficit.
Examinations performed during hospitalization:
-           Cranial CT (December 2006): negative, so in-depth diagnostic study with brain MR was recommended;
-           brain MR (January 2007): left bulbopontine seat hyper-intense focal lesion in long TR sequence of the size of 9 x 5 mm complete with pathological contrast-graphic enhancement. In supratentorial location, focal lesions in the left occipital seat, periventricular, at the callosal-septal interface, right frontal joint, and at the level of the synovial centers for a total of at least a dozen inactive lesions…;
-           CSF test (10/01):
•           Appearance              clear
•           Total proteins (LCR)            25 mg/dL        (15 – 45);
•           Glucose (LCR)                      55 mg/dL        (40 – 60);
•           Cell count                              0.3cells/mcgL (up to 2);
•           Sediment                               no pathological findings

-           Carotid and Vertebral Color Doppler (December 30, 2006): normal.
Auditory evoked potential normal; visual evoked potential normal.
Sensory evoked potential: bilateral increase of the P3a wave latency.
Blood chemistry screen: normal except for total cholesterol 230 mg/dl (vn<200) and triglycerides 152 mg/dl (vn<150).
Cortisone therapy was started during hospitalization, with improved symptoms; this treatment was continued at home following discharge on January 2007, according to a diminishing scheme.
In light of the tests performed during hospitalization, Multiple Sclerosis was diagnosed, so the hospital physicians informed the patient that treatment was unnecessary as long as new symptoms connected with the disease did not appear. 
The patient underwent periodic neurological check-ups on a regular basis with Dr. X, whose reports follow:
-           (05/2007): “during today’s check-up the patient had no focal neurological signs, EDSS is 0. Anamnestically recent sense of transitory hyposthenia for a few hours in the right lower limb not to be attributed to the demyelinating disease. The diagnosis of Relapsing-Remitting Multiple Sclerosis is reconfirmed; said diagnosis backed by the positive NMR, the number of plates and owing to recent enhancement evidence of pontine plate consistent with the finding of positive CSF due to the presence of some oligoclonal IgGs. Brain and bone marrow MR check-up with gadolinium in 6 months. Specific treatment is not recommended.”

-           (01/2008): “with today’s check-up, the neurological objectivity shows only spontaneous horizonto-rotatory nystagmus when looking to the right, result of the past pontine lesion. There are no coordination, strength and sensitivity findings (irregular paraesthesia in the fourth and fifth toes of the right foot seem to be of peripheral significance). Neuro-radiological follow-up to be scheduled soon is recommended.”
The pathology was stable until the brain-encephalic stem + cervical + dorsal column NMR of March 2008: “Check-up test in patient with diagnosis clinically defined as demyelinating disease. It is impossible to compare with past history due to non-availability of images. No active lesions are seen in today’s check-up. Multiple lesions of the periventricular white matter, right front-parietal joint area, semioval centers, left occipital region and callosal-septal interface are appreciated. Other lesions are found in FCP on the level of the middle left cerebellar brachium and bulbopontine seat. The ventricular system and the thickness of the callosum are normal.
The study of the bone marrow shows no pathological enhancements. Some plates near C2, C4 and D2 are appreciated, doubtful alteration of signal in C6-C7, no medullary atrophy.
However, in June the patient started to complain of persistent and continuous tingling in the feet with consequent execution of a cervical + dorsal column NMR on June 19, 2008, with evidence of active injury, the relevant finding of which is provided below: “Check-up of patient with demyelinating disease, compared with previous one of March 2008.
A new lesion close to C3-C4 in the rear portion of the bone marrow is appreciated with contrast-graphic enhancement, indicative of plate activity. The rest of the bone marrow lesion remains unaltered.” 
On June 2008 the patient started a cycle of cortisone, the dosage regimen of which is provided:
Urbason 20 mg                                 1 injection for 6 days + ½ vial for 4 days
Limpidex 15 mg (gastroprotective agent) 1 tablet for 30 days.
On July 2008 the patient will be examined again by a specialist, and at that time should commence a treatment that at this point has been declared absolutely necessary.

Expert's Opinion

Question 1: Diagnosis
The diagnosis of Multiple Sclerosisis made clinically on the basis of two episodes of neurological signs or symptoms that involvetwo or more areas of the central nervous system over time. The current McDonald criteria also incorporate magnetic resonance imagingdemonstrating multiple areas of involvement in the brain and/or spinal cord. Over time, one would expect to see new lesions appear. The appearance of these lesions is fairly characteristic. They enhance brightly with contrast. Other diagnostic clues include abnormalities in the spinal fluid showing evidence of breakdown of myelin, and disturbances in electrophysiological studies (evoked responses) of the nervous system.
The medical records provided are consistent with a diagnosis of multiple sclerosis of the remitting-relapsing variety.
Over the past decade, a number of new drugs have introduced to try and reduce the number and severity of relapses and the number of new lesions appearing on magnetic resonanceimaging. It is hoped, but not yet proven that these drugs can reduce the progression of the disease. The timing of these drugs and the duration of treatment remains under study.
Current treatment for multiple sclerosis includes:
Beta interferons. Interferon beta-1b (Betaseron) and interferon beta-1a (Avonex, Rebif) are genetically engineered copies of proteins that occur naturally. They are believed to help fight viral infection and regulate the immune system.
Betaseron is injected subcutaneously every other day. Rebif is injected subcutaneously three times a week. Avonex is injected intramuscularly once a week.
These medications help reduce, but will not stop the flare-ups of multiple sclerosis. The long-term benefits remain to be determined. The drugs are not combined.
The Beta interferons do not reverse damage. Some people develop antibodies to beta interferons. The antibodies make the interferons less effective, or even ineffective. Some of the side effects make the drugs poorly tolerated by some people.
Some doctors prefer to observe patients at high risk with follow-up examinations and with MRI scans to document progression before recommending long-term therapies with beta interferon.
Glatiramer (Copaxone). This medication is an alternative to beta interferon for patients with relapsing remitting MS. This drug is injected subcutaneously once a daily. Side effects may include flushing and shortness of breath.
Natalizumab (Tysabri). This drug is administered intravenously once a month. It works by blocking the attachment of immune cells to brain blood vessels, and reduces the inflammatory activity in the brain. There have been several reports of a rare but fatal disorder called progressive multifocal leukoencephalopathy. For this reason, it is recommended only for people whose condition hasn't responded to other forms of MS therapy. In the United States the use of the drug has been tightly regulated.
Other treatments.
Mitoxantrone (Novantrone) is used for treatment of aggressive forms of relapsing remitting MS, as well as certain forms of progressive MS. It is infused intravenously, typically every three months.
It is typically not used for longer than two to three years, and typically reserved for patients with severe or rapidly advancing disease who don't respond to other treatments. Close monitoring is critical because of cardiac side effects.
Cyclophosphamide (Cytoxan) has also been prescribed for severe, rapidly progressing MS. This use is not FDA approved in the United States, however.
Medications for progressive MS
The symptoms of progressive MS may be improved by:
Corticosteroids. oral or intravenous corticosteroids reduce inflammation in nerve tissue and shorten the duration of flare-ups. The benefit of long-term corticosteroid therapy in multiple sclerosis isn't established.
Muscle relaxants. Baclofen (Lioresal) and tizanidine (Zanaflex) may help reduce spasticity.
Plasma exchange (plasmapheresis). Plasma exchange may help restore neurological function in sudden severe attacks of MS that does not respond to high doses of steroid treatment. Plasmapharesis involves removing plasma from the blood stream and reinfusing the blood cells with other fluid. Replacing the plasma may dilute the activity of the destructive factors in the immune system, including antibodies that attack myelin. Plasma exchange has no proven benefit beyond three months from the onset of the neurological symptoms.
Questions 2 and 3
I do not feel qualified to offer the names of experts or centers in Italy, other than to say that the state of neurology in the major university hospital is very advanced, and the treatment of multiple sclerosis stands at a very high level, consistent with the protocols and standards practiced in Europe and in the United States.
The same can be said in the United States. In general there are multiple sclerosis clinics in which physicians focus their interest on the disease. The outstanding centers include:
-       In Montreal, Canada: The Montreal Neurological Institute
-       In Boston, Massachusetts:
o    The Beth Israel Hospital
o   The Massachusetts General Hospital
o   The Brigham and Women’s Hospital
-       In New Haven, Connecticut: The Yale New Haven Hospital
-       In New York City:
o   The Mount Sinai Hospital
o   Columbia Presbyterian Hospital
o   New York Hospital
o   New York University Medical Center
-       In Baltimore, Maryland: The Johns Hopkins Hospital
-       In Rochester, Minnesota: The May Clinic
-       In Palo Alto, California: Stanford Medical Center.