Multiple Sclerosis–making the diagnosis

I still continue to get many questions from the readers of my blog regarding multiple sclerosis (MS). A significant majority of them write to me because they are concerned they may have MS either because of white matter lesions found on a MRI scan of the brain or because they are plagued by various non-specific signs and symptoms. Though I have written about this before, I thought this shall be a good time to go over how the diagnosis of MS is made. What are the symptoms that raise the suspicion for MS, what are the clinical signs on examination that suggest MS and finally what are the tests that may help to confirm the diagnosis.

Before I dwell deeper into this topic, please remember: THE DIAGNOSIS OF MS IS A CLINICAL ONE. Meaning that it can be made on the basis of a history and clinical examination itself. No tests are needed in such a situation to confirm the diagnosis.  Of course as it is often in medicine–it is always not that easy.

So let us begin—

Clinical history: Are there any points in the clinical history of the patient that suggest the diagnosis of MS? Patients with MS may give a history of neurological symptoms and signs (remember signs are elicted on clinical examination-meaning when the doctor examines you) that wax and wane (relapsing and remitting MS). A patient may present with acute loss of vision in one eye along with pain in the eye  (I am talking about optic neuritis). As the doctor dwells deeper into the history, the patient volunteers that a couple of years ago he had a similar problem in the other eye which had resolved on its own and he had not been investigated further. Hmmm–now we have history of 2 attacks separated in time. As a neurologist this makes me think of MS as a possible diagnosis. The problem with MS though is that it may present with non-specific signs or symptoms or rather it may present with signs and symptoms that localize to different parts of the central nervous system (CNS). By CNS I mean the brain and the spinal cord. So for example patients may present with numbness on weakness on one side of the body (this localizes to the contralateral motor or sensory cortex), problems with the bladder (incontinence–this usually localizes to the spinal cord), problems with balance and coordination (their gait is off and they may have a prominent tremor in their limbs–this localizes to the cerebellum or the brain stem), double vision (this localizes to the cranial nerves which control the movement of the eyes). Virtually any part of the central nervous system can be involved–hence the presentation is at times non-specific. BUT WHAT HELPS US AS DOCTORS IS WHEN WE GET HISTORY WHICH SUGGESTS A DISEASE DISSEMINATED IN SPACE AND IN TIME. Meaning a disease process which is involving different parts of the central nervous system and which has shown evidence of multiple attacks separated by time. REMEMBER MS IS NOT A MONOPHASIC ILLNESS (it relapses and remits!!!)

Clinical examination: So what are the clinical examination findings which make me as a neurologist think of MS in  a patient. There are certain neurological signs which have been said to be pathogonomic of MS (meaning the presence of these signs virtually seals the diagnosis of MS). These include certain eye signs. Bilateral internuclear opthalmoplegia (INO) (who said neurology was easy!!!) is one such sign. This is an eye-sign in which the patient’s eyes do not move as directed by the examiner. One eye fails to adduct (that is move inwards) while the other eye  abducts (moves outwards) but the abducting eye shows a nystagmus (shaky side to side movement). Other eye signs such as an afferent pupillary defect (this is elicted by shining a penlight into the eye) also raise suspicion for MS. What we as neurologists look for though is this–we look for signs that suggest the disease is disseminated in the CNS. REMEMBER WHAT I TOLD YOU ABOUT MS. IT IS A DISEASE WHICH IS DISSEMINATED IN TIME AND SPACE.

Tests: so when a diagnosis of MS cannot be made on the basis of history and examination alone, we as doctors have to fall back on tests to rule in or rule out the diagnosis. No test seals the diagnosis of MS by itself. They just help to add to our certainity. I shall discuss the various tests namely –imaging studies such as MRI scan of the brain and spinal cord., evoked potential studies such as visual evoked potential (VEP), somatosensory evoked potential (SSEP), brain stem auditory evoked potential (BAEP), spinal fluid (CSF) examination in the next post.


Nitin Sethi, MD

Multiple Sclerosis-a question and an answer

 One of readers emailed me this question. My response to it follows.

Riddler on October 17, 2008 said: Edit Link

Hello Dr,

I am a 28 asian/indian female. I was brought up in India for large part of my file.
I had symptoms of blind spots in my vision sometime back. The condition persisted for 2 days before I scheduled an appointment with my opthamalogist. He suspected that I have optic nueritis and advised me for a MRI. Now the lab technician says that I have a few lesions in my brain and asked me to consult a nuerologist. I have a pending appointment. My eye became completely normal in about 10 days from onset. By googling I found that it might be a case of MS.

Is it always the case optic nueritis + MRI lesions = MS? Is there anything else I should be looking at? I’ve had problems of vitamin deficiencies in the past. I have had some tongue rashes, gastro problems. Nothing serious but minor issues though.


Dear Riddler,

                                      patients who have optic neuritis usually do not complain of blind spots, rather they have acute/sudden loss of vision (usually in one eye, though in a condition called neuromyelitis optica they may have optic neuritis in both eyes). This condition may be painful (complaint of pain in the eye). Not all patients who have optic neuritis have multiple sclerosis. There can be many other causes of optic neuritis namely other infectious and inflammatory conditions. Patients who present with optic neuritis and are in the right age group (eg a woman in her 20s or 30s presenting with optic neuritis), need to be worked up for multiple sclerosis. Usually we order a MRI brain, to see if there is evidence of multiple sclerosis (read my posts on white matter lesions in the MRI brain of MS patients at As I have stated repeatedly, not all white matter lesions on the MRI represent multiple sclerosis.

In answer to your question, yes some vitamin deficiencies can cause blind spots and lesions in the brain. My advise to you would be to see a neurologist, the diagnosis of optic neuritis can be confirmed with the aid of certain tests like visual evoked potentials (VEP). Then the MRI can be interpreted in the right context.

Personal Regards,

Nitin Sethi, MD

Developmental delay Vs developmental regression

Today I consulted on a 4-year-old boy who presented for evaluation of developmental delay.  As I tried to explain to the worried parents that their son had developmental delay due to a static encephalopathy, it dawned on me how hard it was for the parents to follow me. So here in this post I thought I would discuss the differences between developmental delay versus developmental regression. I shall also give an overview of the various causes of developmental delay and regression and how to go about investigating these children.

So lets keep this simple. What do we mean when we say developmental delay. Simple it means that the child is delayed in his or her developmental milestones. As we all know children acquire motor and language skills as they grow. These set of skills appear more or less at fixed times. For example a baby can sit by the age of about 8 months. Other motor developmental milestones include the age where the baby starts to support his head, crawl, roll over, stand, stand up without support, walk and so on. Pediatricians check for these milestones when you take the baby in for well baby visits. Similarly there are language milestones like when the child starts to speak  ma ma da da etc and when the child is able to form short sentences.

So it follows that developmental delay can be of a few types. A child may just have delay in the motor milestones, in others the motor milestones may have appeared at the right time but there is delay in language and other cognitive milestones. In still other there is delay in both motor and language skills (we refer to this as global devlopmental delay).

So what is developmental regression? Developmental regression is said to occur when a child who has been normal in his developmental and has met all the milestones starts to regress and starts losing the acquired milestones. Such a child may stop talking or stop walking and so forth.

As you can imagine the causes for developmental delay and those for developmental regression vary. Another couple of terms need clarification. We neurologists love to use terms called static encephalopathy and progressive encephalopathy in relation to developmental delay.

Static encephalopathy what does this mean? Let me explain with the aid of an example. Suppose you have a child who suffered some brain insult at or near the time of birth. Lets say he had hypoxia (lack of oxygen) to the brain. This child shall have developmental delayed but this shall remain static. The child is not going to progressively go downhill, infact as he ages if good intervention is carried out, it is more than likely that he would start to catch up wih his peers. He may never become completely ” normal” but he is not going to go downhill. His brain took a hit but now is trying to get back.

Progressive encephalopathy: let us assume another child. As compared to the first child, this child has a progressive neurological or systemic condition. Let us for example say he has a metabolic disease which leads to progressive brain damage. This child is going to go downhill as he ages. The brain is going to go “more bad” as time goes by.

Now that we have done with the medical jargon, let us try to make sense of some of the causes of developmental delay and developmental regression. There can be numerous causes of delay. The baby may have suffered some brain damage at or near the time of birth (during the antenatal period when the brain is developing or near the time of birth). Examples include conditions as diverse as mother abusing alcohol during the antenatal period (fetal alcohol syndrome), drugs used during the antenatal period may also harm the developing fetal brain. Hypoxia (lack of oxygen to the brain) is one of the common causes of cerebral palsy which presents as a static encephalopathy and developmental delay. This hypoxia may result from a difficult child birth or complications during labor and delivery. Inborn errors of metabolism, certain genetic disorders constitute other causes of developmental delay. Unrecognized seizures can also cause delay in development. Absence seizures is one such cause.

Developmental regression too has numerous causes.

How does one work up such children? The work up starts with a detailed history and physical examination. Your doctor shall go in depth into the birth history to find any cause. Family history is taken, where any drugs used during pregnancy? Then the child is examined to document is he delayed just in motor skills or is there global delay. After that the work becomes more complicated. Blood work to rule out inborn errors of metabolism, genetic and karotype testing, MRI scans of the brain and EEG may be ordered to zoom in to the diagnosis.

If the final cause is static encephalopathy, then there is nothing”active” to treat. What happened has happened. Now we need to concentrate on early intervention services to bring the child up to par. Physical therapy, language therapy, special education is what we need to stress on.

If the final cause is a progressive encephalopathy then of course depending upon the cause we need to treat. Is the cause treatable?

My advise to parents dealing with this difficult situation: find a good doctor, a pediatrician or pediatric neurologist who can help in getting to the bottom. Do not get disheartened, there are many interventions out there for your loved one. Seek treatment early rather than late as you want to halt a progressive encephalopathy early before too much irreversible brain damage occurs.

Nitin Sethi, MD

Is it or is it not multiple sclerosis?

Since my posts on multiple sclerosis are getting many hits from readers, I thought that I would in this post describe how a definitive diagnosis of MS is made.

First and foremost, a definitive diagnosis of MS can be made just clinically without any other imaging studies like MRI or the need for invasive tests like lumbar puncture (spinal tap). How you may ask?

Well if by history you have had two attacks suggestive of MS which are disseminated in time and space, then a definitive diagnosis of MS can be made. Let me explain this in simple language. Lets assume you go to your doctor because you have been having numbness in your right arm. Your doctor examines you and finds that apart from sensory loss in the right arm, you have other examination findings such as you have ataxia (your gait is off and unsteady), you have incoordination and tremor in your right arm, your eyes do not move well and you have what we call internuclear opthalmoplegia. Hmm sorry for all that medical jargon, let me try to make it more simple. What I am trying to say that your examination findings are suggestive of not one but multiple sites of pathology in your brain.

Numbness right arm localizes to the sensory cortex on the left side of your brain.

Ataxia might be due to midline cerebellar problem

Right arm tremor localizes to the right cerebellum (cerebellar pathways are double crossed in the brain)

The eye findings and internuclear opthalmoplegia localizes to the midbrain.

So you have signs that whatever your disease is it is disseminated in space (SPACE AS IN DISSEMINATED IN DIFFERENT  PARTS OF THE BRAIN). Your findings cannot be explained by one single lesion rather by multiple small lesions.

So you have met the first criteria to make a definitive diagnosis of MS-dissemination in space. (OF COURSE DISSEMINATION IN SPACE SHALL ALSO BE CLEARLY SHOWN IF YOU DO A MRI SCAN)

 Now how do we prove you have dissemination in time?  Well that is done by history. Lets assume your doctor now asks you ” Miss Smith have you ever had a problem with your eye before? Did you ever lose vision in one eye?”

Miss Smith: ” Now that you ask doctor Sethi, yes. When I was 18, I had an episode where I had pain in my left eye and lost vision rather abruptly. By the time I saw my doctor, it had started to improve by itself and I did not think much of it.”

Viola!!! here the history is telling you that Miss Smith has in fact had dissemination in time. Likely she had an attack of optic neuritis when she was 18 which had resolved by itself.

So as a doctor examining Miss Smith, I now know that her disease is disseminated in time (she has had attacks in the past) and also in space (from my examination findings I know that she likely has multiple lesions in the brain, only then I can explain all her findings).


Of course as part of her management I would do a MRI study of the brain and some doctors might still do a lumbar puncture. 

 Additional tests like MRI brain, spinal tap and evoked potentials (visual and somatosensory evoked potential) are needed when either of the above 2 is missing. Either Miss Smith has had just one clinical attack or her examination finding are suggestive of one lesion.

Nitin Sethi, MD

MRI white matter abnormalities

This is to Nancy

Dear Nancy, thank you for your comment to the post on white matter abnormalities on MRI does it represent MS? While it is hard for me to comment on your case specifically, the MRI report reads suspicious for MS. The reason is the lesions are periventricular (around the ventricles of the brain) and such lesions are at times more specific for MS.

I would though correlate this information with your age, your symptoms and importantly your history and clinical examination findings. If there is suspicion for MS from your history or clinical findings, then I would recommend doing further tests to either rule in or rule out the diagnosis of MS. Tests like spinal fluid examination, visual evoked potential and somatosensory evoked potential. As I stated earlier one can see these white matter lesions in patients who have vascular risk factors like hypertension and diabetes mellitus. I am not sure whether the drug you mentioned for RA has been implicated in causing them. You should follow up with your doctor, who would guide you in how to interpret these MRI findings.

Please refer to the MS articles on my website for further information. Feel free to drop me an email if you have any further questions. I wish you my very best.

Personal Regards,

Nitin Sethi, MD

MRI white matter lesions: does it represent MS?

MRI white matter lesions

Many times I get consulted by patients or their relatives when their MRI brain report reads multiple scattered white matter lesions seen. The radiologist’s report usually further reads that these can be seen in primary demyelinating conditions like multiple sclerosis or in vascular disorders. Patient’s and caregivers are naturally worried when they get this MRI report and do not know what to do and how to proceed further. So I thought that here I shall talk about these white matter abnormalities seen on the MRI. What is their significance? Do they represent evidence of multiple sclerosis?

White matter signal changes on the MRI essentially means that on the MRI, the white matter  showed some scattered bright spots. White matter in the brain refers to the fiber tracts that carry information to and fro from the brain.

My first question when somebody asks me what next and what does this mean is to ask them why was the MRI done in the first place. If the MRI was done because there was a clinical suspicion of multiple sclerosis then these white matter lesions may indeed have significance and may represent radiological evidence of MS plaques. Let me explain this with an example. You go to your doctor, you have signs and symptoms that suggest MS (example you may have had an attack of optic neuritis), when the doctor examines you he is able to elict signs in the examination compatible with a diagnosis of MS, then he orders an MRI to see if you do have evidence of white matter lesions in the brain. In a case like this the presence of white matter lesions/ signal changes in the MRI is obviously important. Here it likely does suggest the presence of MS. That said and done I again want to re-emphasize that the diagnosis of MS is made on the basis of clinical history of previous attacks, CSF (spinal fluid) examination and MRI, not just on the basis of the MRI alone. Also there are certain criteria which have to be satisfied on MRI to make a definite diagnosis of MS. These radiological criteria for MS include the number of lesions on  the MRI, their location and their size.

Thus it is important to remember that a person who is noted to have white matter lesions on a brain MRI does not necessarily have MS. White matter lesions can be seen in numerous other conditions and they are more commonly seen as we grow older. The thinking behind this is that they represent microvascular ischemic changes in the brain (the smaller caliber blood vessels in the brain showing signs of ischemia or decreased blood flow). Hence these white matter abnormalities on MRI are more commonly seen in patients who have microvascular and macrovascular risk factors such as a history of hypertension, diabetes and high cholesterol (dyslipidemia/ bad lipid profile).

White matter signal changes on MRI may also be seen in patients who have infectious and other inflammatory conditions. They have been reported in the MRI of patients with a history of migraine headaches (migraine too is a vascular disorder and that may explain the connection).

So I want to end by saying that the presence of these white matter signal changes on brain MRI has to be correlated to the history, clinical examination and other ancillary investigations. Your doctor shall help you in going about this in a methodical manner. I repeat these white matter lesions do not suggest MS in each and every case they are found.

 Dr. Sethi

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Issues that come up during MS treatment

Let us now talk about some issues which come up when you are diagnosed with MS.

1) What happens next?

so you are diagnosed with multiple sclerosis what now? Do you need to start  some multiple sclerosis drug immediately? This is a tough question and something which only your doctor can best decide after reviewing all investigations and MRI brain scans. Multiple sclerosis is in its typical form has a relapsing and remitting course. By that I mean, a patient may present with an acute attack of MS like weakness or unsteadiness or loss of vision in an eye (optic neuritis) but then the attack remits and the patient may come back to his or her baseline with at times no residual signs and symptoms. Then there may be a length of time when the patient experiences no fresh attacks. So the question is when do we start treating the disease. Research has shown that even though the patient may have no clinical attack (no overt manifestations of MS), the disease is still relentless and proceeding in the brain. How do we know this? Simple if you repeat the MRI in even an asymptomatic patient, the MRI shall show new lesions (meaning new plaques are seen in the brain MRI suggesting radiological progression of the disease).

Further research has also shown that these lesions (plaques) in the brain add up and contribute to the final disability. The more the number of plaques in the brain (we refer to this as the plaque burden), the more is the final disability and the cognitive difficulties experienced by the patient.

So now the thinking among MS specialists is to treat early and to treat aggressively. The longer you wait, the more is the damage to the myelin and axons (nerve bundles) in the brain. That said and done each patient’s disease behaves in a unique way. There are a small group of patients who have what is called as benign MS. These patients show little or no disease progression over years both clinically and radiologically. Why some patients have this benign form of the disease no one knows but remember it is very difficult if not impossible to know at the onset if a patient is going to have a benign form of MS or not. Hence usually MS specialists would recommend treating right from the onset.

2) Which interferon to use and which is better?

This is another issue which comes up during MS treatment. There are 3 different kinds of interferon available on the market: interferon beta 1b (marketed as Betaseron) and interferon beta 1a (marketed as Avonex and Rebiff).  Without going too much into detail, there is some evidence to suggest that interferon beta 1 b (Betaseron) may be more effective than interferon beta 1a (Avonex).

Betaseron has to be given three times a week (every alternate day) and it has to be injected subcutaneously (under the skin). Avonex on the other hand needs to be given just once a week and it is given intramuscular (inside the muscle and thus more painful shot than a subcutaneous shot). That said and done since Avonex is given once a week it is far more convenient and does not interfere with a patient’s lifestyle as compared to something which needs to be given three times a week.

There is also the issue of neutralizing antibody formation. Simply put it has been seen that if someone takes interferon for a long time, the body starts to form antibodies against it. These antibodies have been referred to as neutralizing antibodies and if a patient has a high titre of these antibodies, it may neutralize the effect of the interferon (meaning make the interferon less effective). Some research has shown the patient’s who take Betaseron develop neutralizing antibodies at a higher rate as compared to those on Avonex or Rebiff. Again your doctor shall guide you through this decision making process.


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