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#002: How can a rapid and clear diagnosis be made?

Today’s post is about the examinations that are needed at the beginning of the diagnosis of multiple sclerosis. Of course, there are very clear cases that have such a typical and clearly recognizable MS with relapses that it is easy to make the right diagnosis.

But there are also more difficult ones, where it is not that obvious. And remarkably many diseases can appear very similar to multiple sclerosis, at least for some time.

That’s why we have a whole module in the Multiple Sclerosis Management Master, where we have lectures on the different examinations and other diseases from which MS has to be differentiated.

Multiple Sclerosis Management Master (I study in German, the link goes to the international study program). 

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Table of Contents

Why is it so important to make a correct diagnosis early on?

Multiple sclerosis is a chronic disease that progresses continuously without intervention. How quickly and aggressively MS presents varies from person to person and also depends on one’s own lifestyle and components that we do not yet know exactly today and which I therefore refer to here as luck or bad luck.

It is a fact that a quick precise diagnosis provides the basis to then consider the best strategy and decide what can be done to counteract multiple sclerosis. After all, the sooner one intervenes, the better the long-term prognosis looks. This is because the inflammation in the brain destroys myelin, and the sooner this is prevented, the better. Because then the neurological reserve is preserved for longer. And it is probably a completely different motivation for many people to stop smoking or to exercise more if it is clear that this has a positive influence on the course of the disease.

What does differential diagnosis actually mean?

When a patient comes to the doctor, he does so because he has noticed something new and experiences a restriction or a deterioration in his everyday life as a result. The intensity should not play a role here. This change is called a symptom in the context of a disease.

Now symptoms are rarely absolutely specific. For example, I may have a headache because I hit my head, suffer from lack of sleep, be dehydrated because of increased alcohol consumption, have sunstroke, and so on. So, depending on the description of his patient, the doctor will do investigations and ask questions to narrow down the cause and help the person sitting in front of him.

Now in multiple sclerosis, there are many other conditions that can look similar to MS, at least in the early stages. From a total of nine causative directions, other diseases need to be distinguished.

As already mentioned, in the Multiple Sclerosis Management Master we deal over many lectures with the correct diagnosis and differentiation from other diseases. At this point, I would also like to emphasize again that physicians study in Germany for six years and then undergo a specialization training for several more years, and with good reason. The human body is complex and Google does not really know better than someone who has studied for a long time and continues to take part in further training.

Differential diagnoses

In order to give you an idea of where the other possible diseases come from, I will name them:

  • inflammatory demyelinating: ADEM, Anti-MOG, NMOSD, IPANS (inflammatory pandemyelination syndrome)
  • infectious: Lyme disease, PML, HIV, herpes zoster (shingles), COVID-19
  • autoimmune: vasculitis (inflammation of blood vessels), neurosarcoidosis (rare complication of sarcoidosis a systemic connective tissue disease), etc.
  • vascular (affecting blood vessels): Migraine, multiple emboli, etc.
  • metabolic (affecting metabolism): vitamin B 12 deficiency, copper deficiency
  • neoplastic (new formation of tissue in the body – cancer): CNS lymphoma, gliomas, metastases.
  • Spinal (spinal cord): Vascular malformations (congenital benign vascular malformations), spinal stenosis
  • Genetic: mucopolysaccharidoses (body lacks enzymes to break down and store complex sugar molecules), leukodystrophies (metabolic diseases of brain white matter), etc.
  • Psychosomatic: depression, chronic pain disorders, etc.

There are more diseases in most categories, I just gave examples. And depending on the examination, they can sometimes be delineated very quickly. For physicians, the principle is always that the diagnosis should be the most likely one and no other disease should be more likely. After all, rare diseases occur rarely and common diseases often.

Therefore, please do not complain if you have to undergo examinations or tests that do not fit your expectations of the diagnosis. The doctor has studied for a long time, reads up and possibly also consults with colleagues in order to make the right diagnosis. And he will usually start with the most likely and keep looking until the results match diagnostic criteria.

In MS, migraine is a typical example of differentiation. Migraine is much more common than MS, and no one should get medication for MS who „just has a migraine.“ At the same time, I don’t want to minimize migraine. What I am really concerned about is that misdiagnosis leads to mistreatment and possibly unnecessary medication, which is expensive and useless and has no effect on the actual problem.

MS diagnosis based on McDonald criteria

In order to be able to diagnose a disease with certainty, a specific definition is therefore required. Since multiple sclerosis is very complex and multi-layered, there is not one test or one criterion, but it is much more about a sum of results that then leads to the diagnosis. Over the decades and the thereby growing amount of knowledge around MS, these criteria could be refined more and more.

Today, the McDonald criteria are most commonly used to diagnose MS, named after New Zealand neurologist William Ian McDonald. These criteria are continually being refined, leading to ever earlier diagnosis, but also increasing the risk of being accidentally diagnosed with MS when one has a different disease.

Therefore, the overall impression remains important, which includes clinical findings, MRI evaluation, CSF findings, and paraclinical findings obtained with the aid of apparatus or technical devices.

As early as 1877, the French neurologist Jean-Martin Charcot defined MS as a disease that involves:

„…. temporally disseminated lesions in a variety of different anatomical regions ….“

That means inflammation occurring at different sites in the brain and/or spinal cord at different times. This has remained the basic definition to this day. In the meantime, however, thanks to MRI and other examinations, it is now possible to better detect these temporally and locally different inflammations, even if they do not yet cause the affected person any noticeable problems.

Typical MS symptoms at the time of diagnosis

Typical MS symptoms include:

  • Sensory disturbances (hypesthesia),
  • Uncontrollable trembling, mostly of the eyes (nystagmus),
  • Impaired coordination of movement (ataxia),
  • Optic neuritis (inflammation of the optic nerve),
  • Paralysis (paresis),
  • Increased inherent muscle tension (spasticity),
  • Bladder disorders and
  • Depression.

Of course, there are other symptoms as well. If rare MS symptoms are at the beginning of a diagnosis, caution is definitely advised, as it may be a different disease after all.

On the importance of MRI for MS diagnosis.

There are typical areas in the central nervous system that show lesions in MS, and the shape of the inflammatory lesions also indicates how likely MS or other disease is present.

Very simply explained, the brain and spinal cord are considered distinct regions. However, the brain splits even further when it comes to spatially distinct areas. If you ever want to compare it with your MRI findings, you might find the following information for the location of the inflammations:

  • Periventricular
  • Optical system
  • Spinal cord
  • Brainstem
  • Cortical/subcortical

A temporal distinction is given when, in the same MRI, one or more lesions pick up contrast and others do not.

CSF findings from lumbar puncture and oligoclonal bands

Oligoclonal bands, OKB for short, can be detected in up to 95% of all MS patients. This requires a lumbar puncture, i.e. the extraction of cerebrospinal fluid. This is done where there is no more spinal cord. So you don’t have to be afraid of the examination. At the time, I found it a disgusting feeling when the 10 to 15 ml of nerve fluid was taken from me. However, it did not hurt. At that time, as recommended, I drank extremely much water in a short time and lay still at the beginning. Except for an involuntary twitching of the legs, which passed a little later on the same day, I had no side effects.

But please drink a lot of water, preferably still water or very thin tea. This is a good prophylaxis against possible headaches.

By the way, oligoclonal bands also occur in other diseases. If they are not present, it is atypical for MS, but not impossible. And they can be interpreted in terms of diagnosis as being indicative of MS activity at an earlier time.

Electrophysiology for MS diagnosis (evoked potentials - VEP, SEP, MEP)

With evoked potentials, which can be measured visually (VEP, somatosensitively (SEP or SSEP) and motor (MEP), stimuli are emitted in a very simplified way at one point and measured via electrodes how fast they travel and whether there are differences. So very concretely with visual evoked potentials, you look at a screen with a checkerboard pattern, the arrangement of which keeps changing. The electrodes on the head measure when the information arrives and whether there are differences between the left and right eye. This is because optic neuritis in MS usually affects only one eye. By this test and the other two, SEP and MEP, one can detect an effect of the lesion, if there is one. However, there must also be a matching lesion on the MRI findings. Otherwise, there is another cause.

Blood tests - what the serum reveals

The blood, also called serum, is also interesting. It must be collected anyway for comparison with the lumbar puncture. But it can also be looked for antibodies, whether there is a vitamin B12 deficiency and much more. If several tubes of blood are taken or you have blood taken several times, try to look at it positively, because your doctors want to make the right diagnosis first, so that they can then treat you in the best possible way.

Further investigations for differential diagnosis in MS

Depending on what conditions are likely, you may also need to give urine or have other tests and exams done. If you are curious, ask your doctor why these tests are useful, and don’t do your own research on the Internet. Most of the time, the search engines will show you the scariest possibilities anyway, not the most likely ones.

Quoted from the German MS Patient Guide

Criteria for a definitive MS diagnosis in the relapsing-remitting course

But when is there actually a confirmed MS diagnosis? A well-prepared presentation of different options can be found in the German Multiple Sclerosis Guideline for Patients, which follows the McDonald criteria of 2017. I summarize the most important statements, which I have taken from the explanation of the just mentioned patient guideline and quote here. Due to the easy to understand explanation I stay with the German guideline as a blue print.

The following criteria are used to diagnose MS in the relapsing-remitting course (RRMS):

  • relapses occurred
  • conspicuous findings in the medical examination [neurological examination, depending on the symptoms further examinations like evoked potentials (visual – VEP, motor – MEP, somatosensitive – SEP or SSEP), rather rarely optical coherence tomography (OCT)
  • MRI findings possibly with temporal and spatial dissemination 
  • Oligoclonal bands (OKB) in the cerebrospinal fluid
  • Exclusion of other diagnoses

However, for diagnosing MS not all values have to be conspicuous, but a minimum sum has to be reached, which allows different combinations.

Important: MS diagnosis - the normal case

Normally, you will be diagnosed with MS if you have neurological symptoms and clinical findings typical of MS, your MRI shows appropriate lesions, and other diseases have been ruled out. Changes in the cerebrospinal fluid occur in up to 95% of people with MS and support the diagnosis, but are not necessary. Other tests may also provide clues as to whether it is MS or another disease.

Example case from patient guideline showing different possibilities for MS diagnosis.

Imagine the following situation: A 32-year-old woman goes to a neurologist because she has not been able to see properly in her right eye for two days. She has no previous diseases and has never had any neurological complaints. The neurologist finds a visual deterioration in the examination (= conspicuous examination findings) and makes the suspected diagnosis of optic neuritis (= relapse). He initiates the examinations recommended for suspected MS (see above).

Scenario 1

MRI shows MS-typical lesions in the brain and spinal cord (= spatial dissemination), two of these lesions take up contrast agent, one does not (= temporal dissemination). Oligoclonal bands (OKB) are detectable in the cerebrospinal fluid. There is no evidence of the presence of any other disease. The neurologist diagnoses MS.

Scenario 2

MRI shows MS-typical lesions in the brain and spinal cord (= spatial dissemination), two of these lesions take up contrast agent, one does not (= temporal dissemination). There are no oligoclonal bands (OCB) in the neural fluid. There is no evidence of the presence of any other disease. The neurologist gives the diagnosis of MS.

Scenario 3

MRI shows MS-typical lesions in the brain and spinal cord (= spatial dissemination), none of the lesions takes up contrast agent (criteria of temporal dissemination are not fulfilled!). There are no oligoclonal bands (OCB) in the cerebrospinal fluid. There is no evidence of the presence of any other disease. MS is suspected (for the time being diagnosis CIS = clinically isolated syndrome).

In the control MRI six months later two new lesions are visible (= temporal dissemination). Now the neurologist makes the diagnosis of MS.

Scenario 4

MRI shows MS-typical lesions in the brain and spinal cord (= spatial dissemination), none of the lesions takes up contrast agent (criteria of temporal dissemination are not fulfilled!). However, oligoclonal bands (OCB) are detectable in the cerebrospinal fluid. There is no evidence of the presence of any other disease. The neurologist diagnoses MS.

Scenario 5

MRI shows MS-typical lesions in the brain and spinal cord (= spatial dissemination), none of the lesions takes up contrast agent (criteria of temporal dissemination are not fulfilled!). There are no oligoclonal bands (OCB) in the cerebrospinal fluid. There is no evidence of the presence of any other disease. MS is suspected (first diagnosis CIS = clinically isolated syndrome).

One year later, a clear second relapse occurs with paralysis of the left leg, which the neurologist can also detect in the examination (= 2nd relapse; 2nd conspicuous examination finding). Now the neurologist makes the diagnosis of MS.

Important: An MS diagnosis can be made at the first relapse

As described in scenarios 1, 2 and 4, it is possible that an MS diagnosis is made after the very first relapse. Namely, if the criteria of spatial dissemination are fulfilled in the first MRI and, in addition, temporal dynamics are detected – either by temporal dissemination in the MRI or the presence of oligoclonal bands (OCB) in the neural fluid.

Diagnostic criteria for secondary progressive MS (SPMS)

Unfortunately, for secondary progressive MS, diagnostic criteria are not as clear. A common definition is as follows: Secondary progressive MS is when a person with confirmed relapsing-remitting MS experiences a slow, clinically objectifiable deterioration over six to 12 months independent of relapses.

Diagnostic criteria for primary progressive MS (PPMS)

According to the expert group, primary progressive MS is diagnosed when a person has slowly increasing MS-typical and clinically objectifiable neurological symptoms over at least one year and at least two of the following criteria are met:

  • at least one lesion in an MS-typical brain region (periventricular, cortical/juxtacortical, infratentorial)
  • at least two lesions in the spinal cord (i.e. „spinal“ = located in the spinal cord)
  • Detection of oligoclonal bands (OCB) in the cerebrospinal fluid.

MS-typical areas of inflammation in the central nervous system (CNS)

There are various diseases that can cause lesions in the brain. These are considered typical of MS only if they are located in very specific areas of the central nervous system: cortical/juxtacortical (in or bordering the cortex; green), periventricular (bordering the lateral ventricles; pink), infratentorial (brainstem and cerebellum; blue), and spinal (spinal cord; orange). In this figure, the ventricles, natural cavities inside the brain, are highlighted in yellow.

Images courtesy of TakePart Media.

What distinguishes a suspected MS from a confirmed MS diagnosis?

There are always people who meet some, but not all, of the criteria for an MS diagnosis. Then MS is suspected. These suspected cases usually fall into the following two categories: clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS).

Clinically Isolated Syndrome (CIS)

If a person has MS-typical symptoms, i.e. a relapse, and MS-typical lesions in the MRI (spatial dissemination), but no other criteria for an MS diagnosis are fulfilled, this is called clinically isolated syndrome (CIS) (clinical = detectable by medical examination, isolated = single, syndrome = clinical picture). A CIS can be the beginning of MS – but it does not have to be.

Radiologically isolated syndrome (RIS)

There are also people who have an MRI without having neurological symptoms suspicious of MS (e.g. to clarify headaches) and in whom MS-typical lesions are then found by chance. This is called radiologically isolated syndrome (radiological = visible in MRI, isolated = single, syndrome = clinical picture). RIS can also be the predictor of MS, but it does not have to be: In a study of nearly 500 RIS patients, about half developed MS over 10 years. The risk of developing MS was higher

  • in young people (under 37 years)
  • if oligoclonal bands were found in the cerebrospinal fluid, and
  • if the lesions were in specific locations (cerebellum, brainstem, spinal cord).

In people with RIS who had all risk factors simultaneously, the risk was significantly higher: 87 of 100 developed MS within 10 years. If none or only one of the risk factors was present, only about a quarter developed MS during this period. However, since there are few comparable studies, these values should only be understood as estimates.

Citation block Multiple sclerosis patient guideline completed

MS Diagnosis Summary and Tips

I hope you now understand better why more or less complex examinations are sometimes necessary. And remember, immediately after a lumbar puncture, drink lots of water or thin tea to quickly replace the nerve fluid that was removed. This will help prevent headaches. In case of bladder disorders, take appropriate precautions.

The MRI scan is also very important, both to make a definite MS diagnosis and to check the progress and effectiveness of the diseas-modifying therapy. I know some people are afraid of this, so please address it and then a sedative can be administered, for example.

And if you have just been diagnosed with MS yourself, please be aware that it can be treated quite effective nowadays and future will probably be way better than you think in the first time.

Thanks again to the Deutsche Hirnstiftung for funding and to Dr. Insa Schifmann and Prof. Dr Christoph Heesen for creating the Multiple Sclerosis Patient Guideline.

See you soon and try to make the most of your life,


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I show you how to make the best of your life with MS from family to career to hobbies. Thanks to science and research, a lot is possible nowadays.

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