CNS Patient A


The following is a description of a patient that was presented in the Journal of the American Medical Association, 1998, volume 280, number 16.

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Doctor's Comments:

Mr J is a 29-year-old, married engineer who works in a biomedical laboratory.....A few months after Mr J developed Bell palsy, which resolved fully, he noted weakness in his right leg while skiing. The weakness progressed, and he consulted a neurologist when he returned home. Physical examination and magnetic resonance imaging (MRI) were compatible with demyelinating disease. During the subsequent year, Mr J noted slowly progressive weakness associated with exercise, again primarily involving the right leg. He experienced some difficulty with urination, in both initiating and ending the stream. He observed some tremor in his right foot. He experienced difficulty with sexual function on occasion, but his bowels have not been affected. There has never been diplopia or evidence for involvement in other parts of the body.

Mr J's father has Crohn disease and there is a history of hypertension in other family members but not MS or other chronic illnesses. The patient does not smoke and uses alcohol sparingly. Prior to his illness he felt entirely well, with no past history of infection, work exposures, or undue stress.

On initial physical examination, Dr C noted a mild limp, weakness in the right lower extremity, clonus (see below) in the ankle, and up-going toes bilaterally. The patient was normotensive and mildly overweight, without other findings of note. Magnetic resonance imaging of the head was compatible with demyelinating disease.

The symptom clonus mentioned above occurs in various central nervous system disorders with skeletal muscle (motor) problems, such as multiple sclerosis or ALS. Clonus is a hyperactive spinal reflex due to reduced descending information from the brain, especially the cerebral cortex. Thus, in general, clonus indicates that the problem is arising in the brain rather than peripheral nerves. CLICK HERE (http://www.nejm.org/doi/full/10.1056/NEJMicm1203111) to see a video illustrating clonus. In this case, it was caused by damage to the cerebral cortex from a stroke. Click on the small picture to run the video. (Notice how the author assumes you know what "dorsiflexion" and "gastrocnemius and soleus" mean.)

Patient's Comments:

It first started when I was on a ski trip. I started to have muscle weakness in my left leg to the extent that I had a hard time skiing downhill. But as the trip went on, I noticed that the weakness migrated from my left leg to my right leg, to the point where even just moving along fairly flat traverses between mountains, I could barely stand up. I would fight and try to get back up, but I would just fall over. That's when I knew something was wrong, so I just took it easy for the rest of the trip. I came back and talked to my doctor, and he referred me to a neurologist.

Climbing stairs was difficult, and I noticed that when walking from home to the train I had to take things slowly. I became very cognizant that stairs have handrails�little things you don't appreciate until suddenly you need them. But other than that, it really wasn't that bad in terms of going back to work. At my lab, I found myself doing less socializing during the first few weeks until I got a little better because I didn't want to wave a flag to people saying, "Wow, he's limping�what's going on?" So I kept to myself or tried to dart in and out of places and not really see people when I was moving around, just so as not to raise the issue.

My wife was nervous when we found out because I don't think she knew�and I certainly didn't know�what this really meant. You keep waking up, hoping that things will get better, and you measure days in terms of how much strength you have and what you feel like. Can I walk 10 steps and not find myself limping? That's definitely a milestone I notice, even today. When I walk I'll find myself thinking, "I don't think I really had any kind of limp that time."

The questions I have are about what therapy to follow. Because the symptoms weren't that incapacitating, do I immediately take a drug or do I wait to see what happens? That was confusing, because one of my neurologists was leaning more toward starting therapy much earlier�a couple of weeks after I was diagnosed. He wanted me to start taking Avonex [interferon beta-1a] right away. That prompted me to request a consultation with a doctor who specialized in MS, and that doctor said, "MS moves slowly. It advances in the order of months and years, not days. So, we can take some time to see how it evolves." So I didn't take anything.

My biggest concern with the future is that I'll find myself in a wheelchair. That is a big part of my motivation to start therapy now, because I want to be proactive, because I definitely do not want to find myself with MS progressing to the extent where I can't walk without assistance. That motivates me to stay on top of the popular press, keep my eyes and ears open, and see my neurologist every 6 months to keep track of where I stand with my disability. So if something does start to deteriorate, they'll be right on top of it and we can proceed from there.



QUESTION: Does this patient have ataxia?
ANSWER

QUESTION: What might be the significance of the "upturned toes" observation?
ANSWER





Doctor's Comments

Mr J seems very upbeat. But I only have a tiny window into his life and I really cannot say in good conscience that I know how the realization of this illness has affected his life in the deeper sense...

Mr J was diagnosed as having MS about 14 months ago, at the age of 28 years. The diagnosis was suspected on clinical grounds and confirmed with a cranial MRI scan. Patients with MS face unpredictable, intermittent neurologic symptoms, and many develop permanent impairment and progressive neurologic disability. The diagnosis of MS, consequently, is a serious and often traumatic experience for patients and their families. Stress and depression commonly add to the burden of the disease. Accurate information and a proactive, informed approach to monitoring and managing the disease will reduce the impact of MS over the years...

Multiple sclerosis is a common autoimmune disease characterized by recurrent patches of inflammation in optic nerves, brain, and spinal cord. Myelin and axons are damaged at sites of inflammation. Episodic neurologic symptoms in the relapsing-remitting disease stage can give way later to progressive neurologic impairment and disability. The number of MS patients in the United States has been estimated at 350,000. Symptoms begin between ages 20 and 50 years in 90% of the cases, with the peak onset at age 33 years. Three women are affected for every 2 men. The first symptom is optic neuritis in 20%, numbness in 20%, weakness in 20%, and gait imbalance in 20%. Mr J developed facial weakness as the initial MS manifestation. This is an uncommon first symptom in MS patients but has been reported. A myriad of relatively uncommon initial presentations herald the onset of MS in about 20% of the cases. At least 70% of patients improve to a varying degree following the initial symptoms.

Fifty percent of patients are unable to carry out household and employment responsibilities 10 years after disease onset, 50% are unable to walk unassisted after 15 years and 50% are unable to walk at all after 25 years. About 10% have disabling cognitive impairments. Ten years after symptom onset, employment levels decline to around 20% to 30%. About 10% of patients have benign disease, with intermittent neurologic symptoms but little disease progression and minimal disability. How can we predict Mr J's prognosis? Because of the pronounced individual variability, accurate prognostic markers that could be used to counsel patients and guide treatment decisions early in the disease are greatly needed. In groups of patients, benign disease has been associated with sensory symptoms or optic neuritis at onset, good recovery from relapses, and infrequent relapses during the first several years. The prognosis is less favorable with symptomatic onset at an older age, progressive disease from onset, or poor recovery from relapses. However, clinical features are only weak predictors of subsequent disease severity and their value for assigning prognosis to individual patients is limited. Radiological severity of disease at the time of first symptoms predicts both MRI and clinical disease progression. Magnetic resonance imaging findings are increasingly used for assigning prognosis and to decide whether an individual patient should be treated with disease-modifying therapy at the time of diagnosis. The extent of MRI abnormality in Mr J's case suggests that he is at risk for future clinical disease progression and supports the use of disease-modifying therapy.



QUESTION: Does this patient seem to have the relapsing/remitting form or the progressive form?

Answer

QUESTION: Does this patient have optic neuritis?

Answer



Tests and Diagnosis

Doctor's Comments

The diagnosis of MS is straightforward in a patient such as Mr J. He is otherwise healthy, had 2 episodes of central nervous system (CNS) symptoms, neurologic impairments indicative of CNS disease on examination, and a confirmatory cranial MRI. Typical MRI lesions, such as those seen in Mr J's case, appear as round or ovoid foci of bright signal .... distributed in the periventricular white matter, corpus callosum, optic nerves, brainstem, and spinal cord. Involvement of the corpus callosum is helpful diagnostically because it is not seen with cerebrovascular disease. Cerebrospinal fluid (CSF) shows increased IgG .. Sensory-evoked potentials demonstrate optic nerve, auditory, or sensory pathway involvement but are superceded by MRI in most cases...

Some patients acquire a diagnosis of MS because of nonspecific neurologic symptoms like weakness, fatigue, or tingling. Absence of objective neurologic signs at any time, inconsistent weakness or sensory loss, disability out of proportion to objective findings, and normal MRI scan results raise the possibility of psychogenic illness. It may be necessary to follow up such patients over time before a definitive diagnosis is made.

Treatment

This patient was placed on interferon 1-beta, which induces many genes related to the immune system. For example, it has an anti-inflammatory effect, including improving the integrity of the blood brain barrier. It usually causes flu-like side-effects.

Other possibilities in this case include ocrelizumab, which depletes B cells, or glatiramer, which is a set of synthetic polypeptides that alters T cell function, possibly by mimicking myelin proteins. It must be injected regularly.


QUESTION: Why not simply give this patient a corticosteroid to reduce the inflammatory nature of the disorder?

Answer


QUESTION: Are interferon 1-beta and glatiramer disease modifying drugs?

Answer