Dr. Bhan - Independent Medical Opinion

This is in response to your letter dated August 5, 2011 requesting an independent medical opinion.

Firstly, I should state I am Royal College (Canada) certified neurologist licensed to practice in the province of Nova Scotia. I am an Associate Professor in the Department of Medicine (Division of Neurology) and the Program Director for the Neurology Residency Training Program at Dalhousie University. As of July 2003, I am the Director of the Dalhousie Multiple Sclerosis Research Unit in Halifax. Our MS clinic (along with a satellite MS clinic in Sydney, Cape Breton) provides care to almost all of the MS patients in Nova Scotia. I personally follow close to 1000 patients with multiple sclerosis.

For the purpose of this independent medical opinion, I have reviewed all of the information that was sent to me by your department. This includes:

• Consultation letters from various consultants involved in the Appellant's illness that began in August 1998.
• Letters and hand written notes from various physicians involved from June of 2000 (with the onset of neurological symptoms).
• Correspondences between Veterans Affairs, the Appellant and his lawyer.
• All the documents related to the Veterans Review and Appeal board.

I have also reviewed the pertinent literature as it relates to this report.

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A) Review of the Appellant's medical assessments from 1998 to June 2000, with salient points noted.

It appears that the Appellant's problems began on August 3, 1998. Earlier that day he participated in a golf charity tournament and was feeling fine. That evening, he had onset on profound fatigue, diffused aches and pains, cough, nausea and pain in the right ear. A military physician saw him on August 10 and the impression was that of a viral upper respiratory tract infection.

On September 1, 1998 he was reassessed and by this time he reported a worsening of symptoms with onset of weight loss. Examination was unremarkable. Blood work was organized and eventually he was referred to Dr. Wayne Poon (Internal Medicine specialist). This occurred on September 29, 1998 and as per Dr. Poon's consultation letter, the symptoms were as described above. Physical examination revealed a "fairly fatigue looking gentleman". Neurological examination was normal. There was slight abdominal tenderness. The rest of the physical exam was normal. Laboratory testing showed consistently elevated ESR (erythrocytic sedimentation rate) ranging from 65 to 94 mm/h. There was also mild anemia. CMV, IgM, monospot and malaria smears were all negative. Urinalysis was normal as well. Dr. Poon's impression: "persistently elevated ESR raises concern of a chronic infection including bacteria endocarditis, osteomyelitis or an occult infection". He ordered further investigations including blood cultures and a gallium scan. He then referred the Appellant to his partner in the clinic (Dr. Tom Aldor - another internal medicine specialist). Dr. Aldor saw the Appellant on December 18, 1998 and he performed a full history and physical examination. He also performed sigmoidoscopy, which appeared to be unremarkable. Again the impression was that of an "inflammatory illness" but the anatomic location of this infection continued to be elusive. Further investigations were planned.

Follow up January 6, 1999: "Fatigue continues; has "difficulty staying awake", and abdominal soreness. Still has bouts of coughing which culminate in vomiting. Significant weight loss mentioned. Examination was reportedly normal. CT scan of the abdomen, pelvis was completely normal. January 22, 1999, follow up with the Dr. Aldor: The Appellant reported feeling somewhat better. At this stage Drs. Aldor and Poon decided to refer the Appellant to an infectious disease specialist.

Dr. John Embil (Infectious disease specialist) did extensive work up and as per letter dated March 18, 1999 he states: "The Appellant's problem remains unresolved. Multi serologies have been drawn and are negative, specifically toxoplasmosis IgG, VDRL, chlamydia IgM, adenovirus, influenza A, influenza B, CMV". He did report that EBV lgG titers were high and signifies past infection with EBV (Epstein Barr Virus). Upon reevaluation, he comments on the presence of all the "fibromyalgia tender points". As such he was referred to Dr. Glen Thompson (rheumatologist).

Dr. Thompson's impression was that of fibromyalgia and restless leg syndrome. He made note of mild decreased vibratory sensation distal to the ankle consistent with a peripheral neuropathy. He made recommendations for treatment (physiotherapy, exercises, and medication for restless leg syndrome).

March 4, 1999 note from Dr. Chris O'Connor (Fellow in respiratory medicine): "With regard to the Appellant's respiratory symptoms, he likely has a component of mild reactive airway disease. Investigations were done and no significant abnormalities were found".

On March 16, 1999 he was seen by Dr. L. E. Nicolle (another infectious disease specialist) for a second opinion from Dr. Embil. Dr. Nicolle initially wondered about dengue fever. However he could not confirm this diagnosis. He recommended a referral to a hepatologist (specialist in liver diseases), because of elevated serum alkaline phosphatase levels.

April 14, 1999 consultation with Dr. G. Y. Minuk (consultant in liver disease): He wondered about primary sclerosing cholangitis and did extensive investigations which were negative. Therefore no liver diagnosis was confirmed. Meanwhile bone scan showed some abnormalities and as such a referral was made to medical oncologist.

Dr. J. B. Johnston (oncologist): This appointment took place on April 19, 1999. Impression was that "The Appellant is a 40 year-old man with night sweats, weight loss and fatigue. He has persistently elevated ESR and abnormalities of alkaline phosphatase. Recently found to have a bone scan abnormal. We agree that hematological investigations are necessary, as certain forms of leukemia can present this way. He will return to the Cancer Foundation Clinic after the bone marrow aspiration and biopsy is done". These tests were all normal and Dr. Johnston in his noted May 10, 1999 noted, "in summary I am sorry to say that our marrow studies did not come up with any evidence of an underlying lymphoproliferative disorder or other hematological disease to explain this patient's symptoms".

On June 11, 1999 the Appellant did have a neurological assessment done by Dr. W. K. Ilse. The referral was made because the rheumatologist (Dr. Thompson) had detected mild findings of a "neuropathy". Dr. Ilse briefly summarized the Appellant's symptoms. The pertinent negatives mentioned are: the Appellant denied having any sensory symptoms, any disturbance of sphincter dysfunction, any visual/ocular or other bulbar symptoms. Balance was normal and there was no disturbance of hearing. There were no problems with cognitive deficits or confusion or loss of consciousness. Neurological examination was essentially normal. Mention is made of "pupils are equal and reactive, visual fields are full without extinction; eye movements were full and normal without nystagmus. Power of the muscles of mastication and those of facial expression are normal and there is no weakness of tongue protrusion nor of neck flexion or extension. There is no lingual fasciculation or atrophy and speech is normal. Appendicular muscular bulk, tone and power are symmetrically normal for patient habitus, and tendon reflexes are also symmetrically normal, with flexor plantars. Primary sensory modalities were intact. Stance, gait and coordination are normal". The report goes on to describe that the EMG studies were all normal. His/her interpretation: "The screening electrodiagnostic examination of this patient fails to document any correlate of this patient's symptoms, as reported. There is no feature of the patient's presentation, or the history that he affords, that this is particularly suggestive of a neuromuscular junction transmission defect, and this has not been elsewhere raised, there is no electrodiagnostic evidence of this at the time. As fatigue may sometime have central origins this patient has been sent of multi-modality evoked potential assessment, however, in the absent of a positive result on this, of any symptoms other than reported, a significant neurological contributor to patient status would be unexpected". In short, Dr. Ilse did not find any evidence of neurological problem (central or peripheral).

June 25, 1999 assessment by Dr. R. J. Warrington (allergy and clinical immunology specialist): Impression and recommendations: "This patient's complex and prolonged history may be related to post EBV or CMV viral syndrome. On review of most recent notes in his HSC chart, reference is made by Dr. John Embil of a very high IgG titer to EBV. Also in his differential is connective tissue disease." Dr. Glen Thompson is currently following him. Dr. Warrington confirmed presents of fibromyalgia tender points on examination. His brief neurological examination was normal.

From June 1999 to June 2000 there are no medical notes to see how the Appellant was doing. However, in the consultation note from Dr. Christopher Bourque (neurologist) dated June 29, 2000, there is a reference made to this. In the second paragraph he writes: Gradually he began to improve. but now two years later he still does not have the kind of energy he had before.

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B) My summary and impressions of the Appellant's medical assessments from 1998 to June 2000.

The Appellant at age 39 had abrupt onset of profound fatigue, malaise, diffused aches and pains, sweating, nausea, cough with some sputum, abdominal pain and profound weight loss. Physical examination revealed at times a fatigue looking young man, normal vital signs, and essentially normal physical examination except for the tender points of fibromyalgia. Over the next few months he was seen by numerous specialists (two internists, two infectious disease specialists, a respirologist, a hepatologist, a rheumatologist, an immunologist, an oncologist and a neurologist). Numerous investigations were done. His ESR was consistently elevated for several months and eventually settled. EBV IgG titer was very high (indicative of previous infection of Epstein-Barr virus). There were non-specific findings on gallium scan and bone scan, but with further assessment by the appropriate specialist, these findings were felt to be inconclusive.

It seems like the consensus was that the Appellant had suffered from some sort of an infectious or post infectious illness that was quite protracted. Eventually he also developed features of fibromyalgia (non-restorative sleep, aches and pains and diffused tender points).

There was gradual improvement to the point that in June 2000 he only had residual problems with fatigue and some aches and pains.

A few times in the correspondence between the physicians and lawyers it has been mentioned that "no stone was left unturned" to try and get to the bottom of this man's illness. I would totally agree with this statement.

It is hard to know what was communicated between the physician and the patient during any or all of these visits with specialists. However, it is clear from the Appellant's notes that he was extremely frustrated, at times did not feel that he was taken seriously and more importantly was very scared and frightened for his life. I can certainly appreciate how this could happen given the nature of some of the consultants' specialties (especially medical oncology). Therefore it seems certainly probable that this is where his problems with stress could have started.

One final note: Many of the specialists in their consultation letters report that "neurological exam was normal". In general, these consultants would have performed a "screening neurological examination" and to me this indicates that no gross or obvious neurological findings were noted. The rheumatologist did comment on "decreased vibratory sensation distal to the ankle consistent with a peripheral neuropathy". This is a more subtle neurological finding, and is often present in patients with multiple sclerosis. However, a few months later when seen by Dr. Ilse (neurologist), the neurological examination was reported as normal. No mention is made of any decrease in vibratory sensation in the feet. As such, I am inclined to disregard the rheumatologist's finding and conclude that his neurological exam was indeed normal prior to the year 2000.

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C) Review of the Appellant's neurological illness and the subsequent medical assessments from June 2000.

Around mid-June, while on duty in Germany, the Appellant had onset of numbness in the left-side of the face, inside of the mouth and left half of the tongue. After a couple of days (on June 15, 2000) he sought medical attention and was seen by a local dentist who in turn recognized this as a potential neurological problem and referred him to a neurologist. Neurological assessment was done on the same day and the report states: "pronounced hypoesthesia in the trigeminal nerve distribution, completely including the face, the inner parts of the mouth and tongue. Corneal reflex diminished. Difference in the masseter muscles from right to left. Reflexes in arms and legs normal. No paresthesias or ataxia. No signs of any sensory dysfunction excluding the trigeminal nerve". A CAT scan of the head with intravenous contrast was done on the same day and was normal. The neurologist's impression was "the primary cause of the lesion of the nerve trigeminal is still unknown". Further neurological diagnostic testing including blood and liquor (cerebrospinal fluid) investigations needed. In the report he does not mention MRI, but I have no doubt that an MRI was recommended.

There is a note from the same date (June 15, 2000), from a service colleague (at the base in Germany) to Dr. Lee Chapman (military physician in Winnipeg). It states "enclosed are the CAT scan and neurology reports of subject provided today in Germany. The doctor believes it is a temporary condition lasting for three months. He also suggests a test of his spinal fluid to eliminate other abnormalities". At the top of the note is "PS- the Appellant needs to see a neurologist upon his return next week (Dr. Thompson, if possible)."

The Appellant is flown back to Canada and on June 20, 2000, there is a note from Dr. Chapman on his assessment of the Appellant. It states: "41-year-old male developed left­ sided facial numbness overnight June 7, 2000. Both upper and lower face affected with no other deficits. Seen by German neurologist because of overseas at the time, CT scan normal. No family history of MS. No previous neurological abnormalities. Decrease sensation persists but is lessening". His impression: "Idiopathic trigeminal neuropathy? Rule out MS". Plan consultation to Dr. Bourque. On the same note, it states that a referral was faxed to Dr. Bourque on June 22, 2000 and the appointment was given one week later.

The Appellant was under the impression that the MRI had to be done "urgently", but nowhere is this mentioned (not in the German neurologist's note; not in the correspondence from a service colleague to Dr. Chapman and not in the referral note from Dr. Chapman to Dr. Bourque).

June 29, 2000 consultation with Dr. Bourque (neurologist): The pertinent findings: "Apart from the reduced sensation in the left side of the face, and possibly diminished coordination in the fingers of the left hand, no other abnormalities were seen. CT scan from Germany was reviewed and no abnormalities found". Dr. Bourque mentions that the differential diagnosis includes "demyelinating disease, or if the symptoms are linked to his prior illness, perhaps a systemic problem such as infectious cause or a collagen vascular disease". Additionally he wondered about sarcoidosis or a neoplastic process. He mentions that "I'll be arranging for MRI as well as blood work, writing to you subsequently and that there is no physical reason why he cannot work now although I am anxious to investigated him further".

Approximately two months after seeing Dr. Bourque the first MRI scan was done (August 24, 2000). This showed a few white matter lesions. The report states: ''the findings are not entirely specific regarding etiology". Possible demyelination disease or multiple sclerosis was considered. MRI of the spinal cord was normal.

On September 21, 2000 (almost a month after the first MRI was done), the Appellant was seen by Dr. Bourque in follow up. The left facial numbness had improved. He still had profound fatigue. He mentioned to Dr. Bourque that normally he would play 40 rounds of golf in a summer but that particular summer had only played twice. Dr. Bourque goes on to recant a number of blood test that he ordered and these were all normal. He mentions the MRI scan shows several lesions raising the issue of demyelination (multiple sclerosis) as a possibility. He recommended repeating the MRI as well as getting evoked potentials done.

October 11, 2000, follow up with Dr. Bourque: the Appellant gave a history of diplopia for several days (with horizontal separation of objects). Examination showed mild eye movement abnormalities. Dr. Bourque felt that this was another mild attack of demyelinating disease in the brain stem. He did not feel steroids were indicated. He was awaiting repeat MRI scan results and evoked potential testing. There is a hand written note by Dr. Chapman from October 23, 2000: The diagnosis of MS has been confirmed. Repeat MRI scan on October 10, 2000 showed progression of lesions. Patient has started amantadine for fatigue with good response. He is awaiting MS clinic evaluation for interferon treatment.

December 14, 2000, follow up with Dr. Bourque: He notes that amantadine did not help the fatigue. He gave the Appellant a prescription for modafinil for fatigue. Since last seen in October, the Appellant reported another attack. He had weakness in the left leg with some transient symptoms in the left arm. Fatigue continued to be a problem. Examination showed diminished feeling in the left side of the face, weakness in the left leg and patchy sensory loss over the left leg. Dr. Bourque comments that "I gave him some information on prophylactic medications and I will be reviewing him again next week". He will be seen in the multiple sclerosis special therapy clinic in January, but I do not think we have to wait until then before initiating medication as this man will be funded through the Armed Forces.

There is a hand written note from a nurse on January 9, 2001. "Some teaching was given regarding the auto injector and the Appellant was started on interferon therapy".

October 17, 2001 Dr. Stewart takes over his care as the primary physician. She writes to Dr. Melanson (MS specialist in Winnipeg) and basically asks specific questions regarding MS prognosis and as to what the Appellant's limitations are and will be.

November 5, 2001 Dr. Melanson's consultation letter: She reaffirms the diagnosis of MS and comments that it is relapsing remitting type of MS. At that time the ongoing symptoms were those of fatigue and tiredness. There was also pain in the back of legs and hips. Bottoms of the feet had a burning feeling. He also had muscle cramps especially while resting. There was also some mention of memory problems. Examination showed mild diminished sensation in the left side of the face, diminished rapid alternating movements in the left arm, weakness in the left leg and brisk reflexes. She marked the EDSS score in the "range of 2". She then mentions the inherent uncertainty of MS prognosis in general. She states that in the majority of cases, patients start to progress and that "in approximately 50 % of the patients who have the disease for 20 years they will be wheelchair bound". This in turn is reflected in Dr. Stewart's medical report to Income Security Program of Human Resources Development Canada (for CPP disability). This is also the report that the Appellant mentions in the final paragraph of his letter. After reading the statement that "approximately 50% will eventually be wheelchair bound and that once released from the military it would likely be very difficult for him to maintain substantial gainful employment," he goes on to state: "this was the last nail in my coffin. I knew she didn't mean it the way I interpreted it but I couldn't help but think that this was the beginning of the end. Somehow the reality hit home after that and it was the confirmation that I have nothing to look forward to and my life as I knew it was over. I felt so alone and scared and the memory flood back in. It is these memories that consume me to this very day. Every time something goes wrong with everyday happening or my health takes a bit of a dive the flood gates open. I can't just deal with the problem at hand my whole past always has to flash right in front of me like a bad rerun".

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D) My summary and impressions of the Appellant's neurological illness and the subsequent medical assessments

• The Appellant had onset of left face/mouth/left half of tongue numbness. I would like to point out that in one note from a service colleague (stationed in Germany) to Dr. Lee Chapman, he mentions "partial paralysis of the left side of the face". It seems that the term "partial paralysis" shows up on several letters since that time. This is not correct and in fact the Appellant had left facial numbness (medically known as hypesthesia). This problem is no better or worse then facial paralysis, but I am mentioning this just to keep the record straight.
• Within a couple of days of the onset, he sought medical attention and was referred and seen the same day by a dentist in Germany. The very same day, he is referred and seen by a neurologist who makes a diagnosis of "trigeminal hypesthesia" - which means diminished sensation in the face/mouth. A CT scan of the head is done the same day (with intravenous contrast) and is normal. The neurologist recommends further testing in the form of spinal fluid assessment, blood work and MRI scan. In his note, there is no mention of MRI, but I am certain that would have been his recommendation. It is my impression that thus far, the Appellant's assessments were done urgently and much faster than would have happened if he were seen here in Canada. For example, it is possible that in Canada he would have been referred and seen by a dentist on the same day, but highly unlikely that he would have seen a neurologist and have CT scan on the same day (unless seen in a hospital emergency department). In effect, he actually got expedited care. Furthermore. by seeing the neurologist and having a CT scan. acute serious neurological entities (like tumor. large aneurysm. stroke. arteriovenous malformation etc) were ruled out.
• A service colleague faxed over the referral information to Dr. Lee Chapman on the same day (June 15, 2000). Dr. Chapman saw the Appellant five days later on June 20, 2000. His differential diagnosis was correct i.e. trigeminal neuropathy (isolated involvement of the trigeminal nerve for which there are many causes) and rule out MS. A referral for neurological consultation was written out the same day and faxed to Dr. Bourque on June 22, 2000. A week later Dr. Bourque (certified neurologist) saw the Appellant. As a specialist should, Dr. Bourque had an extensive differential diagnosis. However, at the top of his list was demyelinating disease (multiple sclerosis). Because of the previous possible "infection or post infectious illness" that the Appellant had had, it was reasonable to try and consider if the current neurological problem had an infectious etiology. Because of the high ESR noted previously, Dr. Bourque also brought in the possibility of collagen vascular disease and other entities like sarcoidosis and even a neoplastic process. Since the rest of the neurological examination was normal (except for the diminished feeling in the left side of the face), and a CT scan with contrast was normal (ruling out any acute sinister neurological disease), there would have been no reason to get an urgent MRI scan.
• As it turned out, the first MRI was done less than two months after Dr. Bourque's assessment (and just over 2 months after the first assessment in Germany). By Canadian standards this is an acceptable wait time for an MRI. The average current wait time for MRI scan in this country (when ordered routinely for suspicion of MS) is anywhere from six weeks to six months. This wait time fluctuates and changes from province to province and there are many factors involved. More importantly, these wait times are relevant for more recent years (perhaps the last five years, as numerous MRl scanners have been installed in most cities). Prior to that, wait time for MRl scan was much longer (anywhere from three months to eighteen months). Therefore considering that the Appellant's onset of neurological symptoms was in the year 2000, two-month wait for the first MRI scan is clearly acceptable, and possibly an expedited process. Similarly seeing a neurologist in the Canadian setting within a week of referral (which is what transpired here), is an expedited neurological consultation. The wait time to see a neurologist (for something like facial numbness where the CT scan has already been done and is normal), can be from several weeks to several months.
• The first MRI scan was not totally diagnostic and Dr. Bourque possibly did not want to confirm a serious diagnosis such as MS, without further data (clinical, repeat MRl and electrophysiological). It is true that small white matter lesions can be seen on MRI brain scans in the normal population. Therefore a repeat MRl scan was ordered as were multimodality evoked potentials. This is what transpired during the follow up visit September 21, 2000.
• On October 11, 2000, the Appellant present with double vision. Examination showed mild eye movement abnormalities. Dr. Bourque presumed that this was an attack involving the brain stem. Given the mild nature of symptoms he did not feel that steroids were necessary. The repeat MRl scan was done on October 10, 2000. This showed new lesions when compared to the previous MRl scan. Again the findings were considered "entirely non-specific in etiology". However, demyelination due to multiple sclerosis was most likely the cause. Other possibilities were considered as well as per the MRI report. The next review with Dr. Bourque was October 30, 2000. It is during this visit that he disclosed the diagnosis of multiple sclerosis to the Appellant. . He suggested a referral to the multiple sclerosis special therapy clinic at the Health Sciences Centre in Winnipeg. Another assessment was done on December 14, 2000. At that time there was suggestion of left leg weakness with some transient symptoms to the left arm. This would indicate another attack of multiple sclerosis. Dr. Bourque gave him information regarding disease modifying therapy (used the word "prophylactic medications"). At this stage, the Appellant had an appointment to see the MS Clinic in Winnipeg in January. Around this time, symptomatic treatment was attempted as well. Amantadine did not work for fatigue and therefore modafinil was tried. Eventually the Appellant was started on Rebif sometime in January/February 2001.
  
  In summary, I feel that all his assessments were done in a timely or even expedited manner. This includes seeing a neurologist on the day of referral (in Germany), neurologist in Canada (within two week of the original assessment). The follow up assessments (September 21. October 11. October 30, December 14, 2000) were all done within a timely manner.
  
  Contrary to what has been suggested in various letters of correspondence, I feel that the Appellant got the initial and repeat MRI scan in a timely (if not expeditious) manner. This is not uncommon in my experience when dealing with patients who work for the Department of National Defense and in my opinion, our men and women in action deserve this special treatment. This is exactly what was rendered in the case of the Appellant as well.

Unfortunately, the Appellant's expectations were totally different based on possible misperceptions. I am not sure about the exact cause of these misperceptions, but can pontificate. Firstly, the neurologist in Germany apparently suggested an MRI right away. This could well be the standard of care in Germany i.e. as in the United States, investigation (tests) are done immediately whether there is a necessity or not. A CAT scan with contrast medium was completely normal. As I explained previously, this would rule out any of the acute neurological processes (tumor, stroke, aneurysm, arteriovenous malformation etc.). This is clearly mentioned in the CT scan report from Germany. In the brief note that I have (dated June 15, 2000) from the German neurologist, the impression is that of "primary cause of lesion of nervus trigeminus still unknown. CT normal. Further neurological diagnostic inclusive blood and liquor (which means cerebrospinal fluid) examination". There is no mention of an MRI and certainly not an urgent MRI. I have absolutely no doubt, that MRI was suggested, but I am not sure where the need to do it urgently came from. As I have mentioned previously, the need for "urgent MRI" is not in the German neurologist's note: not in the correspondence from a service colleague to Dr. Chapman and not in the referral note from Dr. Chapman to Dr. Bourque). Secondly, the Appellant somehow got the impression that immediately after arrival in Canada, there would be an MRI done. Someone should have explained to him that he would first need to see a neurologist, and then an MRI would be arranged. There are reasons for this: a) there are different types of MRI sequences that can be done depending on what the neurologist is thinking in terms of differential diagnosis; b) once the MRI is done, one needs a neurologist to interpret the findings on MRI. Thirdly, there is a misperception that many patients have i.e. that the MRI will immediately and conclusively yield a diagnosis. Often, that is not the case. In fact in multiple sclerosis, we need that second or even the third MRI, to confirm the diagnosis. Finally, the Appellant feels that there was a delay in making the diagnosis of multiple sclerosis. I would like to stress that the average time to diagnosis of multiple sclerosis (in the Western world) is six to twelve months. This is in the era of MRI scanners. Prior to MRI era, the average time to diagnosis was several years. In the Appellant's case, the time to diagnosis from onset of symptoms was about four months. I would have to say that this is pretty good by any standards.

Before answering the specific questions you have posed, I would like to briefly mention a couple of other issues related to the Appellant's medical problems. In 1999, based on rheumatological assessment, a diagnosis fibromyalgia was made. I am presuming this is on the basis of diffused aches and pain, non-restorative sleep and the presence of 18/18 of the tender points for this particular condition. Although he did improve on a number of fronts (from the initial onslaught of symptoms in August 1998), it seems that aches and pains, fatigue and muscle tenderness along with a non-restorative sleep pattern have continued. In fact even after the diagnosis of multiple sclerosis was firmly established he was referred to a rheumatologist again (by Dr. Melanson, the MS specialist). This assessment was done in 2002 and again the opinion was that of "soft tissue rheumatism". Examination mentions "18 out of 18" trigger points. Furthermore, on a number of occasions reference have been made to depressive symptomatology with some treatment given for the same. Finally, from several notes, it is clear that the Appellant smokes cigarettes (this is generally mentioned as half a pack per day). To sum up some of some of the comorbidities, this gentleman appears to have depression, fibromyalgia and has been a long standing cigarette smoker. I cannot comment as to whether these comorbidities/habit are ongoing.

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E) Answers to your specific questions.

1. What are the known casues of multiple sclerosis?

The simple answer is that as of November 2011, the exact cause(s) of multiple sclerosis remains unknown. However, a lot of putative factors have been identified and the level of evidence for each of these factors varies from very strong to inconclusive.

In essence, multiple sclerosis is an inflammatory/degenerative disease that affects the central nervous system (brain and spinal cord). It typically affects people in the 20-50 age range (mean onset around 28 years), is more common in female than males (ratio of 3:1), and is a very common cause of disability in the young adult population. The clinical course is often relapsing remitting type (in 80-85% of patients at onset), and many of these patients will turn into a secondary progressive type of MS after 15-20 years. A small percentage of patients (10-15%) have primary progressive multiple sclerosis. It is believed that 15-20% of multiple sclerosis may be benign i.e. relapsing remitting type of MS that never progresses.

Although the exact cause of MS is unknown, it is likely that a combination of nature (genes) and nurture (environment).

There clearly is a genetic predisposition as demonstrated by numerous epidemiological and genetic studies. For example first degree relatives are at 15 to 35 times greater risk of developing MS than the general population. This risk correlates with the degree of kinship, that is, the amount of shared DNA by descent. The highest risk occurs in identical or monozygotic twins, where the concordance rate is about 30%. Most of the genes are found on the major human histocompatibility system (HLA), a region on chromosome 6, which exerts the strongest genetic effect in MS. Over the years, many more genes have been identified. Most recent research has confirmed the previously known 23 genes known to predispose to MS, and added 29 further genes as being contributory. These genes have a pivotal role in the workings of the immune system of the body. (Steven Sawcer et al. A Genetic Risk and a Primary Ru1l for Cell-mediated Immune Mechanisms in Multiple Sclerosis. Nature 2011; 476(7359):204)

Genetic predisposition is only part of the story. If MS were a purely genetic disease, then the concordance rate in identical twins would be 100%. Such is not the case, and for this reason (and many others) there are clearly environmental factors at play. These include:

• There is a significant "latitude gradient" in the prevalence of this disease. MS prevalence increases as one moves away from the equator. Furthermore, migration studies have shown that people born in an area of the world with high risk of MS who then move to an area with a lower risk before the age of 15, acquire the risk of there new area (and vise versa). Potential explanations for this "latitude gradient" include:
  • Possibly an infectious agent that occurs in childhood or adolescence that then primes the immune system which years to decades later starts to go awry and causes symptoms and sign of multiple sclerosis.
  • Others have argued that the latitude effect is mostly on ethnic grounds. MS is primarily a Caucasian disease and as such seen mostly in Northwest Europe and in those parts of the world where Europeans migrated to (Canada, United States, South Africa, Australia and New Zealand).
  • In recent years, many studies have implicated vitamin D deficiency as one of the causes of MS. In fact vitamin D deficiency can clearly explain the latitude gradient as well i.e. people living around the equator are exposed to a lot of sun and therefore manufacture lots of vitamin D where as populations in the temperate climates do not get as much sun and are generally vitamin D deficient. A prospective cohort study found that taking vitamin D supplementation was associated with an approximate 40% reduction in the risk of developing MS. Another study showed that in whites, the risk of developing MS decreased significantly with the increasing levels of vitamin D (Munger K.L. et al JAMA 2006;296(23):2832-8.
• Another environmental factor that has always been in contention is infection (virus, bacteria and other microbs like chlamydia). In the literature, the strongest evidence is for the Epstein-Barr virus (EBV). In 2003, a study published in the Journal of the American Medical Association (JAMA) suggested that increased levels of anti-EBV antibodies was associated with an increased risk of developing MS. The corollary to this observation is that MS is very uncommon in adults who were never infected with EBV (the relative risks is very low with an odds ratio of 0.06). It also seems that the levels of EBV antibody are also important. People with high titers of anti-EBV antibodies have a higher risk of developing MS as compared with subject with low titers (Levin, LI, Munger KL, Rubertone MV, et al Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis. JAMA 2005;293(20):2496-500). Many other studies have confirmed higher risk of development of multiple sclerosis with those with a remote infection with EBV.
• Smoking is another risk factor that is gaining recent attention. A recent retrospective meta analysis gave a pool relative risk estimate for developing MS of about 1.51 for ever verses never smoking (paper attached). Furthermore, there are studies that smoking is a risk factor for faster progression in multiple sclerosis.
• In the past two years, there has been a flurry of reports (mostly in the lay media) on the so-called "chronic cerebrospinal venous insufficiency". This was first described by Dr. Zamboni (an Italian vascular surgeon) who contends that MS may be caused from problems with venous drainage of blood from the brain (because of narrowing or occlusion of veins in the neck). This then leads to back flow and iron deposition in the brain which then sets up the immunological insult. However, numerous studies since the original paper by Zamboni have failed to confirm his findings. Although more research is underway, it is unlikely that venous insufficiency is the cause of multiple sclerosis.

Many of the environmental factor listed above, interact in some way to affect or alter the immune system. Normally ones immune system recognizes one's own tissue and does not mount an attack against it. In MS, possibly because of the genetic predisposition and environmental factors cited above, the immune system goes awry and years to decades later starts attacking myelin (insulation of the nerves) and axons (actual nerve fibers). This then lead to inflammation, demyelination and axonal loss (known pathology of multiple sclerosis) which in turn causes the symptoms of MS.

The associated risk factors for MS seem to delineate a putative causal cascade. Factors largely defined from birth (i.e. gender, HLA antigen status, place of birth) need inciting environmental factors (vitamin D deficiency, late Epstein Barr Virus exposure, cigarette smoking and other as yet unknown factors) to develop the abnormalities required (mainly in the immune system) which subsequently can lead to multiple sclerosis. It is not yet clear as to whether MS susceptibility is a result of a chain of adverse factors that need to occur in a specific order and are dependent on one another (i.e. a domino effect) or whether risk factors are independent of each other but each acting in either additive/multiplicative manner to push an individual closer to the threshold of developing multiple sclerosis.

For an up-to-date authoritative discussion on the epidemiology multiple sclerosis, attached are two chapters on this topic published in "Neurology Clinics" May 2011, volume 29. Number 2.

As you can see in these chapters which sum up literature on the environmental factors in MS, stress is barely mentioned, mainly because the studies are inconclusive.

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2. What are the known effects of post-traumatic stress disorder on multiple sclerosis:

Stress and multiple sclerosis:

In essence, there are a variety of studies of varying quality (mostly poor quality) that have tried to address the issue. There are numerous reasons as to why this is such a difficult area of research: a) How does one define stress? b) There are acute stressful situations and chronic persistent stress. c) There are the degrees of stress and no one really can define what mild, moderate or severe stress is. d) There are different types of stress and finally e) there are different responses that different individuals have to stress. To compound this research further, multiple sclerosis in itself is a complex disease (different phenotypes, different clinical course, gender differences). Furthermore, MS relapses and progression are known to be affected by other environmental factors specifically viral infections, smoking, obesity, presents of other comorbidities (hypertension, diabetes, obesity) etc. Retrospective studies are profoundly affected by the so called "recall bias". Prospective studies are extremely tedious to do, but if done in a controlled blinded manner, would be ideal. However, such a study does not (and likely will not) exist.

These caveats aside, following is a summary of the relevant research in this area:

The paper entitled "Association Between Stressful Life Events and Exacerbation in Multiple Sclerosis: A meta-analysis" by David C. Mohr et al. in BMJ 2004 summarizes some of the relevant literature until that period. You already have a copy of this paper in your file, but I am attaching a copy for you anyway. These authors identified 20 studies and of these 14 were included for the meta-analysis. Basically they showed a statistically significant increase in the risk of exacerbation (relapse) in multiple sclerosis after stressful life events. Authors concluded, "there is a consistent associated between stressful life events and subsequent exacerbation in multiple sclerosis. However, this data does not allow the linking of specific stressors to exacerbations nor should they be used to infer that patients are responsible for their exacerbations". Included in this meta-analysis is a study from Nisipeanu in 1993 Neurology. This study clearly showed the opposite i.e that during prolonged periods of combat stress, the risk of multiple sclerosis relapses significantly was reduced.

Same author (DC Mohr) with different co-authors showed the increased conflict and disruption in routine was followed by slightly increased risk of developing new gadolinium enhancing lesions in the brain eight weeks later. However, there was no strong evidence of a relationship between psychological stress or distress and a clinical exacerbation (a relapse). Also in 2004 in the journal Neurology, a nationwide cohort study in Denmark, showed that parents that lost a child had 1.4 times the risk for developing multiple sclerosis and parents who lost a child unexpectedly had twice the risk as opposed to other bereaved parents. This study speaks to an unusual type of stress for a long period of time may have an association with MS prevalence. Another paper by Brown, RF et al in Multiple Sclerosis 2006 August (paper is attached), showed that life event stress impacts to a small degree on MS relapse. The number and not the severity of acute stressors are most important; chronic stressors do not predict later relapse. Males and those with early stage disease are also at greater risk of a relapse. The main message from this study is that chronic or persistent stress was not related to relapses (contrary to the above studies).

The most recent study is from T. Riise et al (interestingly the co-authors are mostly those that have authored the previous studies cited above!). This paper was published in Neurology earlier this year (copy attached). This is a very large study involving two cohorts of female nurses: one from the nurses health study (NHS) involving 121,700 female nurses from 1976 and the nurses health study 2 (NSH2) involving 116,671 followed from 1989. The risk of MS after self reported general stress at home and at work in the NHS in 1982 was studied and similarly the effect of physical and sexual abuse in childhood and adolescents collected in the NHS2 2001 was correlated with MS risk. Basically they found no risk of MS associated with severe stress at home in the NHS group. Similarly there was no significant increased risk in MS found among those that reported severe physical abuse in childhood or those who had been repeatedly forced into sexual activity during childhood or adolescents. Their conclusion: "these results do not support a major role of stress in the development of disease, but repeated and more focused measure of stress are needed to firmly exclude stress as a potential risk factor for MS."

In the Neurology Clinics Devoted to Multiple Sclerosis (May 2011 issue), there are two chapters (attached) related to environmental factors affecting multiple sclerosis and stress is barely mentioned. The focus again is on vitamin D deficiency, Epstein-Barr virus antibodies, cigarette smoking where the evidence is stronger. Stress is not mentioned in detail, as the studies are all poorly done and show conflicting results.

In conclusion, studies in the literature on "stress and MS" are poorly done and all have some flaws. A properly done perspective study does not exist and one can safely say that such a study is impossible and therefore there will never a definitive answer to this question. The data from the current literature (as cited above), swings back and forth from some studies showing that stress can trigger relapses and others where such is not the case. The most recent and comprehensive study (T. Riise et al) suggests no relationship between stress and Multiple sclerosis.

Therefore, on the issue of as to whether stress causes or is associated with onset of multiple sclerosis, my answer is no.

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3. Were the symptoms experienced by the Appellant in 1998 an early manifestation of his multiple sclerosis?

From August 1998, the Appellant started having a multitude of symptoms including profound fatigue, diffused musculoskeletal aches and pains, chills and night sweats, nausea, cough with some sputum, abdominal pain, major sleep disturbance and mood changes. Apart from fatigue which is a fairly common symptom in multiple sclerosis, none of the other symptoms would lead us to think about a diagnosis of multiple sclerosis. Fatigue in itself is a non-specific symptom and can occur in a number of entities including viral illness, fibromyalgia, sleep disturbance of any kind, depression/anxiety etc. In the Appellant's case, it is safe to say that the fatigue could easily be explained by whatever illness he had at that time, and that it was not an indicator of multiple sclerosis.

In one assessment (by a rheumatologist) mention is made of impaired vibration sense distal to the ankle. Based on this the rheumatologist wondered about the possibility of a peripheral neuropathy and as such EMG studies were requested. Apart from peripheral neuropathy, vibration sense can often be impaired in multiple sclerosis as well. However, I am reluctant to put much emphasis on this one finding detected on one occasion by one person only. Several other consultations have mentioned a "normal neurological examination". More importantly, Dr. llse, a neurologist, did perform a neurological examination at the time of the EMG and reported it as normal. In absence of any other corroborative evidence, I am reluctant to say that this vibration sense impairment was indeed a first physical sign of multiple sclerosis.

In conclusion, I do not feel that the clinical features (symptoms and findings) from August 1998 until June 2000 were an early manifestation of multiple sclerosis.

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4. Whether the symptoms or effects of the Appellant's psychiatric disability of post-traumatic stress disorder could have caused the onset of the Appellant's multiple sclerosis, or caused a permanent or chronic worsening of the nature or extent of his symptoms from multiple sclerosis?

From a review of the literature and my own clinical experience, there is no indication that post traumatic stress disorder can cause the onset of multiple sclerosis. Nor is there any suggestion that PTSD can cause a permanent or chronic worsening of multiple sclerosis (in terms of having more relapses, disability progression, more lesions on MRI etc.).

If one looks at any of the reviews into the etiology of multiple sclerosis (as cited above), the factors with strongest evidence are Caucasian race, place of birth (Canada has one of the highest rates), gender (females more than males), genetic profile (by this I mean the HLA genotyping and it should be emphasized that many of the associated genes can be present without any family history of multiple sclerosis), vitamin D deficiency (especially in gestation or in childhood), high titers of blood Epstein-Barr virus antibodies and smoking. Toxin exposure, vaccination. physical trauma and emotional stress have very weak or conflicting evidence in their favor as putative causative agents.

In the Appellant's case, it is the combination of Caucasian race, born and raised in Canada, high titer of Epstein-Barr virus antibodies in the serum and smoking that (in combination) would be the lead environmental causative agents. Almost certainly he has genetic predisposition (as most patients do), even though there is no family history of MS. As such I conclude that post-traumatic stress disorder or stress otherwise would be a highly unlikely factor in the causation of the Appellant's multiple sclerosis.

Similarly if one looks at the factors that are associated with permanent or chronic worsening of multiple sclerosis, these include male gender, older age onset (over 40), presents of comorbidities (smoking) and high number of relapses in the first one to two years (it seems that he had four to five relapses within a year).

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5. Whether the symptoms or effects of the Appellant's psychiatric disability of post-traumatic stress disorder could have contributed the onset of the Appellant's multiple sclerosis, or contributed a permanent or chronic worsening of the nature or extent of his symptoms from multiple sclerosis?

Once again as to PTSD or stress of any kind contributing to the onset of multiple sclerosis, I would have to say that this would be a minor possible contributing factor (as evidence by the literature above). There are more likely factors operational here - as cited above.

As to stress of PTSD contributing to permanent or chronic worsening of the nature of multiple sclerosis, the answer is still the same i.e. possibly a very minor contributory role. However, when one considers some of the symptoms of multiple sclerosis, I do feel that stress, PTSD, and multiple sclerosis can all cause "some similar symptoms" and this is discussed in detail below (under question 6)

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6. Whether current medical consensus could support the conclusion that there is a co-morbid relationship or other form of medical relationship between multiple sclerosis and the psychiatric symptoms or effects which are part of the Appellant's post-traumatic stress disorder diagnosis, and if so what is the nature of that relationship?

This is the area where I see significant amount of overlap between some multiple sclerosis symptoms, PTSD symptoms, depression/anxiety and perhaps even fibromyalgia (if that diagnosis has indeed been confirmed and is ongoing). The main reason for this is the "overlap of some symptoms" that occurs in these entities. In other words, both MS and PTSD independently can cause depression, anxiety, fatigue and cognitive dysfunction. For example, the lifetime prevalence of depression in multiple sclerosis is well over 50% and depression can certainly be a part of post-traumatic stress disorder. Anxiety (particularly social anxiety) is also very common in multiple sclerosis and again part of PTSD.

Fatigue is extremely common in multiple sclerosis (over 90% of patients have it). It can also be present in depression/anxiety, PTSD, stress, non-restorative sleep pattern (seen in fibromyalgia). The one study that addressed the relationship between PTSD and multiple sclerosis alludes to the same finding i.e. more of the PTSD patients had depression and anxiety.

Cognitive impairment occurs in 30 to 70% of patients with multiple sclerosis. Presence of depression and post-traumatic stress disorder can seemingly aggravate cognitive dysfunction. For example, worsening of PTSD symptoms (including poor attention span, thought intrusions, decreased motivation, depression and fatigue) can impair cognitive function. Yet, when the PTSD symptoms are under better control, the person can perform the same cognitive tasks with ease. Thus PTSD can transiently aggravate cognitive dysfunction. Similarly, when a person's MS symptoms are worse (physical or cognitive), it is likely to worsen the PTSD symptoms. As one can see there is interplay and as such overlap of these particular symptoms.

Given the known neurobiology and pathogenesis of MS (where lesions can affect various parts of the brain), it is clear that MS can cause many of the symptoms that are seen in PTSD. However, PTSD by itself, does not cause the symptoms of MS.

As you can see, the "neuropsychiatric symptoms" as described above, are likely to be more prevalent and more severe in this gentleman. It will be very difficult for the Appellant and his caregivers (neurologists, psychologists, psychiatrists and others) to tease out the contributing factors for these particular symptoms. For example if the issue is cognitive impairment, is it mostly based on poor attention span, thought intrusions, severe mood changes and therefore the major contributing factor would be PTSD or is it mainly driven by actual multiple sclerosis pathology (lesions) affecting areas of the brain that control mood, anxiety, attention span and memory. Sometimes neuropsychological testing may be necessary to get a better understanding of these issues. I suspect that he will need ongoing assessments and follow up with psychologist, perhaps even a psychiatrist and finally the neurologist as well. To avoid miscommunications the family doctor should be kept informed of all the therapeutic plans as implemented by various consultants.

It is also important to discuss the prognosis of multiple sclerosis with the Appellant, as seen in the "post disease modifying therapies era". What he found out (by reading the letter from his family physician/Dr. Melanson), pertains to prognosis in multiple sclerosis prior to advent of disease modifying therapies. Thus the fact that most patients are wheelchair bound by 20 years may not be accurate in the current context. There are several observational studies that confirm this and I am attaching one for your perusal. His neurologist should have a detailed, open and yet balanced discussion about prognosis of multiple sclerosis in general and his prognosis in particular. Some of the negativity comes from his perception of his prognosis with statements like "my future as I see is over."

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I have tried to be as objective as possible in rendering the above opinions. Unfortunately in a disease like multiple sclerosis and especially in the area of "stress and MS", where the literature is conflicting, it is very difficult to offer absolutely conclusive statements.

In case of any clarification or further questions regarding this report, please do not hesitate to get in touch with me.