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Year : 2007  |  Volume : 10  |  Issue : 4  |  Page : 198-213

A neurotropic virus (chikungunya) and a neuropathic aminoacid (homocysteine)

Dept. of Medicine, Ruby Hall, Clinic, Pune and Poona Medical Research Foundation, Pune, India

Correspondence Address:
R S Wadia
Ruby Hall, Clinic, Pune and Poona Medical Research Foundation, Pune
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Wadia R S. A neurotropic virus (chikungunya) and a neuropathic aminoacid (homocysteine). Ann Indian Acad Neurol 2007;10:198-213

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Wadia R S. A neurotropic virus (chikungunya) and a neuropathic aminoacid (homocysteine). Ann Indian Acad Neurol [serial online] 2007 [cited 2022 Nov 29];10:198-213. Available from:

When a person is elected as the Vice President of the IAN the first problem that he/she comes across is what shall be the Presidential Oration. I had a number of possibilities to choose from starting with our work on the Neurology of Organophosphate poisoning. [1],[2],[3],[4],[5],[6],[7],[8] As I wished to be topical my choice was between two studies we were pursuing in the 21 st century viz Vit B12 deficiency and Hyperhomocysteinaemia, and Chikungunya Virus Neurology. I could not make up mind between these two topics; hence I decided to include both and I decided the Presidential address would be "A neurotropic virus (Chikungunya) and a neuropathic aminoacid (Homocysteine)." This implies two topics in one oration; however, in the previous year, nearly half a dozen different topics that were related only by sex were included. They both cause encephalopathy, myelopathy and neuropathy and may affect the muscles and eyes and show teratogenicity. Moreover, there is one more connection: the vector for Chikungunya is Aedes aegypti and the host immunity and genetics are defenitely the major factors in the infection. Similarly, the vector causing hyperhomocysteinemia can be said to be B12 and folate deficiencies and the host genetic factors are known (MTHFR mutations TT genotype), and this leads to raised homocysteine. The treatment of both is to tackle the vector Aedes aegypti and B12, folate and pyridoxine deficiencies.

   The Chikungunya virus and the Indian Epidemic Top

Chikungunya (CHIK) fever is a relatively rare viral infection. The virus belongs to family Togaviridae and the genus alpha virus. It spreads by bite of an infected Aedes aegypti mosquito. The disease was first detected in 1952 in Africa, [9] and the name is derived from the Makonde word that means "that which bends up" in reference to the stooped posture developed as a result of the arthritic symptoms of the disease.

The outbreaks of Chikungunya occurred in India between 1963 [10] (Kolkata) to 1973 (Maharashtra). [11] The virus then disappeared. It suddenly reappeared in India after 32 years. In 2005, an outbreak was recorded in the southern Indian Ocean Islands of Comoros, French Rιunion, Mauritius, Madagascar, Mayotte and Seychelles. The epidemic in the French Reunion islands is the best documented one thus far. [12],[13] Since Dec 2005, several cases have been found in India. These cases were reported from 12 states, including Andhra Pradesh, Tamil Nadu, Kerala, Karnataka Orissa, Goa, Maharashtra, MP, Gujarat and Rajasthan, and approximately 15,00,000 cases have been estimated to be present in India in 2006. [14]

A recent study has shown that the current epidemic is caused by Central/East African genotype of CHIKV and not by the Asian genotype that caused previous epidemics in India. Since this is a new strain, the lack of immunity may be a factor for this massive epidemic and it has been shown that the virus has mutated (E1 protein) to become more virulent. [15]

Clinical Features - The clinical picture is fever, malaise, rash, headache, nausea, body ache and joint pains. The fever lasts for 3ş6 days only but arthropathy and body aches are severe and persisting. The illness is a self-limiting one; however, the arthropathy may last 3-6 months and occasionally longer, and this is an exception to the general rule that viral arthritis lasts for less than 8 weeks. Neurological manifestations are not described in textbooks.

A recent review of the disease in India does not mention the neurological manifestations. [16]

There are however rare reports of possible neurologic affection in Chikungunya, but the best examples were in the Reunion Island epidemic where meningoencephalitis and myelopathy and teratogenicity were described. [13],[15]

Neurology of Chikungunya - In the 2006 epidemic, we saw patients suffering from Chikungunya infection and having neurological manifestations. These patients were subjected to serum and CSF IgM antibody testing against Chikungunya. Those in whom the antibodies were found in CSF and serum were included in the study and a report of 50 cases was presented by us from Pune at the IAN Conference 2006; [8] 24 cases were observed subsequently. Thus, this report covers 74 cases.

General Features - The age and sex distribution of our cases was 57 males to 17 females. Ten out of these cases had carpal tunnel syndrome, which was observed in 7 females and 3 males. If these are excluded the male female ratio is 54:10 (5.4:1)

[Table - 1] shows the neurological features.

Encephalopathy: Encephalopathy was observed in 35 cases (47.2%) and was the isolated neurologic finding in 11 cases (14.9%) and the most prominent feature in 33.

Encephalopathy was observed in the first few days after fever with headache, altered sensorium and with fits in 5 patients (14.7%). Transient focal signs were rare: ataxia in 4, focal rigidity in 1 and opsoclonus in 2. Death occurred in 10 - 3 died with isolated encephalopathy - after coma, etc. Other deaths occurred after the development of limb paralysis.

The remaining 25 cases recovered gradually frequently developing myelopathy/neuropathy, subsequently. The CSF showed raised proteins and cells in all with the predominant cell lymphocytes. MRI was normal at times, but often showed a rather unique finding. There were multiple hyperintense dots on diffusion weighted (DW) images [Figure - 1] that were considerably marked in comparison to that in T2 and flair. Rarely, the T1 view showed the dots to be hypodense.

Multiple white dots have been described before in other encephalitides, e.g., Nipah virus encephalopathy, Rocky mountain spotted fever and Lyme disease. [17] In the last two cases, vasculitis in the brain is demonstrated. Similar dots may also be rarely observed in cryptococcal meningitis and have been described in cerebral malaria, although we have never observed these. Lim et al . [17] described the dots in Nipah virus encephalitis. They pointed out that the lesions were clearly observed in T2 and they were considerably fewer in Diffusion and they enhance on diffusion. This was not observed in our cases, where lesions were observed to be clearer on Diffusion then in T2 [Figure - 2]. Occasionally, the first scan did not show the lesion whereas the second scan did [Figure - 3].

Myelopathy : Thirty-three (44.6%) of our patients had signs of myelopathy in which 16 (21.6%) had myelopathy as a predominant feature and 4 had isolated myelopathy. It started a few days after fever. Patient often first developed retention of urine and then showed paraparesis. Usually, the upper limbs were more or less not involved . The CSF showed raised proteins and lymphocytic pleocytosis in all . The MRI rarely showed cord changes (only 2/23); however, the CSF was abnormal in all cases. Some improved in hospital and others gradually improved over months after discharge.

Neuropathy : We found two types of neuropathy.

Early neuropathy was observed in 32 (43.2%) cases. These presented within few days of the onset of fever. These patients had additional encephalopathy or myelopathy in 27 cases.

Late neuropathy occurred in 11 cases and presented few weeks after the onset of fever. These were often with a "pure" syndrome . They improved with treatment (steroid/plasmapheresis). In early neuropathy, the patient rapidly developed quadriparesis and many of them had facial weakness and required a ventilator.

The NCV in these cases showed axonal sensory motor neuropathy. The CSF shows raised proteins and lymphocytic pleocytosis. Cells varied from nil to 12/cmm . Neuropathy often did not improve well with IVIg or plasmapheresis.

In this early neuropathy, the features that were found to be different from typical Guillain-Barre Syndrome were

  1. Almost always axonal
  2. CSF pleocytosis
  3. Additional signs in many of myelopathy/encephalopathy
  4. Response to plasmapheresis - IVIg infrequent .

   Carpal Tunnel Syndrome Top

This was not recorded by us in our first report. [8]

Since then we have come across 10 cases. These appeared several weeks after Chikungunya. In these cases, the wrist synovitis was ++ with severe pain in hand that was considerably severe than usual, and in 7 cases, the pain was bilateral. Median nerve territory weakness was noted in all cases.

Further, during early neuropathy, we often noted that the median nerve findings of motor amplitude and distal latency were considerably worse than in the ulnar (however, this may be observed in other acute axonal neuropathies).

An ultrasound of the carpal tunnel was done in one case and showed the clinically noted excess of synovial fluid and swelling that was severe in comparison to the usual carpal tunnel syndrome patients. Apparently, carpal tunnel syndrome does not imply entry of virus into the nervous system and it was secondary to synovitis.

CSF Studies : This was carried out in all cases except for those with carpal tunnel syndrome (64 cases).

It was normal in two (3.1%) patients. In the remaining patients, the abnormalities were raised proteins 59 cases (92.1%), and pleocytosis was found in 53 cases (82.8%). Cells were predominantly lymphocytes in all the patients. Typical albuminocytological dissociation was observed in 5 patients with neuropathy. They had late neuropathy, axonal on NCV and improved with plasmapheresis (like AMSAN). Such cases were also found later; hence, the absence of cells may be due to the CSF examination that was performed later in the course.

   Viral Isolation Top

A 65-year-old female was admitted with encephalopathy and axonal neuropathy.

The MRI showed lesions in diffusion weighted scans (DW) as described before. The CSF was taken to NIV on the second day of the presentation of the neurologic disease, and the virus was isolated from her CSF. The genome of the isolated virus matched with the new strain of Central/East African Chikungunya virus and not the original Indian genome, as observed in viruses stored at the NIV (Pune) since the 1970s.

This is the first case where virus is isolated from CSF in life.

   Treatment and Prognosis Top

We were uncertain regarding how to treat our cases: 18 received methylprednisolone: 7 improved and 3 died; 11 received plasma exchange: 9 improved and 2 died; 8 received plasma exchange and steroids: 5 improved and 1 died; and 4 received IVIg: out of these, only 1 improved.

From the remaining who received only supportive care, 4 died. Apparently, the 10 cases with Carpal tunnel syndrome did not receive steroids, plasmapheresis or IVIg.

   Chikungunya and the Fetus Top

In the Reunion epidemic, 84 pregnant women had acute Chikungunya infection. [18] When infection was distant from the delivery date (74 cases), the fetus was normal. 10 cases were infected intrapartum: 4 fetuses showed meningoencephalitis; 1, intravascular coagulation; and 1, cerebral hemorrhage with thrombocytopenia. The risk to fetus was 48% at birth if mother was viremic at the time. In another report, [19] 7 fetal deaths occurred when the mother was infected at 12-18 weeks of pregnancy. In 3 out of these 7 cases, the fetus was infected. All the 3 expelled macerated fetus without malformation. The RT PCR for Chikungunya was +ve in the amniotic fluid and from the fetus including fetal brain. (Herpes, CMV and parvovirus were excluded). Clearly, neurotropism was proven in these cases.

   Chikungunya and the Eye Top

Some of the cases of early neuropathy showed delayed VER bilaterally. This was observed in 3/6 tested cases.

Two other cases were found to be interesting. T N aged 10 was admitted with encephalopathy and myelopathy; later, we noted visual failure. Fundoscopy revealed severe bilateral retinal hemorrhage. The ANA and dsDNA antibodies were +ve and the child was felt to be suffering from SLE. Later, the IgM antibody for Chikungunya was +ve in the CSF and blood. With recovery, ANA and dsDNA have become -ve. Now, we believe that child had Chikungunya infection. The vision is still decreased but no new features (10 months of followup) have appeared though steroids are long omitted.

[Figure - 4] shows the retinal photographs of the two eyes showing disc hemorrhage, exudates and exudates along the vessels. These pictures were not taken in the acute phase but 3-4 weeks later.

A second case was observed 3-4 weeks after Chikungunya. He had developed vision failure. The fundus showed arterial branch occlusion. Intravitreal steroid was given. Occlusion cleared, and the vision improved to 6/6-6/9. The suspicion in both the cases was that there was inflammatory vasculitis.

Optic nerve involvement has been recently described from South India. Mittal et al . [20] described 14 cases with recent Chikungunya infection who had optic nerve involvement. In these cases, 19 eyes were affected, 8 showed papillitis, 4 showed retrobulbar neuritis, 4 showed retrochiasmal optic neuritis and 3 showed neuroretinitis with incomplete macular star. In five cases, the visual problem appeared with the initial illness and in the rest after a mean of 11.0 days after they were symptom-free from the initial fever. CT and MRI were normal in all the cases; 10 patients improved with methylprednisolone.

There is one more reason to suspect vasculitis as a feature of these cases. Several of our cases had albuminuria reaching the nephrotic range of 2.5 gm and more than this range per day in the early stages. In some of them, it regressed; however, several went on to renal failure, and out of the 10 patients who died, 7 had renal impairment and 4 were on dialysis. The suspicion was glomerular injury. In the best biopsy performed, 7 glomeruli that were observed in the section 1 was completely hyalinized and others showed a mild infiltrate.

   Death in Chikungunya Neurology Top

There were 10 deaths (13.5%) All had severe encephalopathy at onset. Additional features of myelopathy and neuropathy were found in 5 (50%) and 6 (60%), respectively. All were >55 years of age; seven (70%) had additional renal impairment. MRI was carried out in 7 cases. Out of these, 5 (71%) were found to have DW lesions. Four patients were treated with steroids and 7 patients were treated with plasmapheresis. Unfortunately, we had no post mortem. From Jaslok Hospital, post mortem was reported for 1 case. The findings were found to be equivocal. [21]

The important question is whether the neurologic manifestation is infectious or an immune-mediated postinfectious phenomenon. We believe they are likely to be infectious because of the following reasons:

  1. Neurological features arise with febrile illness.
  2. Lesions observed on MRI are certainly not similar to any cases of acute disseminated encephalitis as described.
  3. IgM antibodies to Chikungunya are found in CSF. Pleocytosis was present in CSF.
  4. Virus was isolated from CSF in one case.

Late neuropathy may represent postinfectious neuropathy. Even here, 3/6 had CSF pleocytosis.

   Other Indian reports till October 2007 Top

We are aware of 4 other reports of Neurologic manifestations of Chikungunya in India described since our initial report. The first was from Nadgir, Hubli [22] (50 cases) and three more cases appeared in the abstracts of the 2007 IAN Conference: Gajre et al. [23] (88 cases), Jawatkar et al. [24] (83 cases) and Shah et al. from Ahmedabad (58 cases). These four series along with ours gives a total of 359 cases. [Table - 2] gives the summated findings in these 359 cases with 35 deaths (9.7%). In addition, a report from the Andaman Islands reported 17 cases of Chikungunya infection from which four had areflexic quadriplegia; [25] this report is not further described and not included in above mentioned 359 cases.

It may be mentioned that although there are only 35 deaths recorded here, Mavlankar et al. (IIM Ahmedabad health management) compared the mortality in Ahmedabad city between July-November 2006 and the same period in previous 4 years (2002-2005). [26]

Total excess mortality for 2006 vs 2002-2005 was recorded [Table - 3]

No other recognized factor was noted to be different between July and November, and he found a total of 3112 extra deaths in July-November 2006 in comparison to July-November of the four previous years. He considers Chikungunya as a silent killer. Perhaps, Chikungunya is not recorded or recognized as a cause of death in cases with comorbiditie s, Chikungunya infection may tip the balance into mortality.

   Conclusions Top

  1. It appears that Chikungunya is a new neurotropic virus (African strain).
  2. The virus can cause encephalitis, myelopathy and neuropathy (such as HSV, VZV and CMV) and combinations thereof. It also affects the fetus and occasionally the eye.
  3. The reported cases of neurology with Chikungunya in India up to October 2007 are 359 cases with mortality in 35 cases (9.7%). It is certain that several others who had neurologic manifestation died but were not recorded.

   Homocystein: A neurotoxic amino acid Top

This part is named as neurotoxic aminoacid. One may ask is the aminoacid, i.e., homocysteine, the neurotoxic factor or is the deficiency of B12 /folate important for the neurologic manifestation?

In fact, raised homocysteine levels are the basis of vascular disease, stroke, venous thrombosis, IHD and peripheral vascular disease. A raised level of homocysteine may lead to the following:It is the basis of vascular (and other) dementias and is toxic to the hippocampus and amyloid precursor protein. [27] It is toxic to neural cells in the basal ganglia and may cause dystonia and DOPA-induced dyskinesia. It interferes with the cross-linking of the collagen, increases the osteoclastic function, reduces osteoblastic activity and predisposes to fractures in patients with and without stroke.

In neuronal cultures, the culture dies if we [27]

a. Cause deficiencies of methionine/folic acid

b. Add amyloid beta peptide

c. Add homocysteine [27]

d. A combination of the above. In such case, homocysteine is defenitely toxic to the nervous tissues.

What then are the causes of raised serum homocysteine? [Table - 4] gives the important causes; however, it must be noted that the most important are the deficiencies of Vitamins B12, folate and pyridoxine, which between them causes 2/3 of the cases of hyperhomocysteinemia.

Incidence of Hyperhomocysteinemia in India: The normal level of homocysteine is 5-15 umol/L We now know that even the upper part of this level is not a desirable level; the lower the level, the better it is. To study the frequency of hyperhomocysteinemia we did a study at Ruby Hall in the clinic population. We examined ward patients who had no evidence of B12 deficiency and did not have stroke, IHD or were suffering from renal disease, hypothyroidism or malignancy. [Table - 5] shows the result of our study with 36.5% having a raised homocysteine level and 35.9% having a B12 level lower than 200 pg/ml. Only 9.4% had low folate (serum level < 4 ng/ml). The table shows that hyperhomocysteinemia and Vitamin B12 deficiencies were considerably higher in vegetarians than those who consumed nonvegetarian food frequently. Those who consumed nonvegetarian food occasionally were not significantly protected.

Yagnik et al . [28] recently reported a population-based study in and around Pune that included only males. In 149 males in rural areas, 48% had raised homocysteine (Hcy) and 68% had low B12 (< 150 pg/ml). In slums, the figures were 47% and 61% and in urban Pune, Hcy was high in 79% (with mean Hcy as 23 Ámol/L) and B12 was low in 89%. Overall, raised Hcy was observed in 58% of 441 men and serum Vitamin B12 was low in 67%.

They measured RBC folate and found it to be low in 5.12% in the three groups. They found the vegetarian risk for low B12 was 4.4 times the high nonvegetarian group and the risk of high Hcy was 4.3 times more. The reason for this is that no vegetarian food contains significant amount of Vitamin B12. Vegetables grown in a field using fecal material as manure may have a certain amount of Vitamin B12. Milk contains B12; however, in studies performed at Ruby Hall, if we use boiled and pasteurized milk, as most of us do, one has to take 600-700 cc of milk to obtain what is the daily requirement of Vitamin B12 according to US standards.

What is the age at which raised Hcy levels and low B12 levels noticeable in India? At RHC we conducted a study on the toddlers who were 1-3 years of age from a low socioeconomic group. [29] Out of the 51 children in this study, 4 had low levels of B12 (< 200 pg/ml) and 9 had marginal levels of B12 (200-250 pg/ml) and Hcy was > 15 Ámol/L in 6 of them (11.7%) and 13-15 Ámol/L in 7 children (13.72%). Thus, one out of four children by the age of 3 has the Hcy levels greater than what is considered to be desirable in adults. In a Dutch study of children between 2-5 years, the mean Hcy was 4.6 umol/L (95% C.I. 4.2-5.1). [30] In Pune, the mean was 10.6 + 0.7 Ámol/L and the median was 9.4 Ámol/L. Our study considered the low socioeconomic group; however, the study by Yagnik showed that the Hcy levels were higher in Urban Pune in comparison to those in slums. [28] The possible reason is that B12 comes from bacteria and a very hygienic vegetarian is likely to have less serum B12 than one from the slums.

Neurology of B12 Deficiency - For long, it was believed that as pernicious anemia is uncommon in India. B12 deficiency is also uncommon. Thus, in 1972, Dastur et al . [31] made a 4-5 years study on the nutritional disorders of the CNS and found only five cases of B12 deficiency during these 5 years at a large public hospital in Bombay. Jeejebhoy et al . [32] reported 8 cases, all of which were due to malabsorbtion. However, Desai and Antia had described seven cases of subacute combined degeneration in 16 cases of B12 deficiency. These they ascribed to intrinsic factor antibody. [33] In 1998, we reported our study and collected 99 cases of B12 deficiency and 68 probable cases. [34] Since then, we continue to observe the cases, and [Table - 6] shows our experience with regard to B12 deficiency manifestations between April 2001 and 30 September 2007 (6Ż years) and shows how frequent the disease really is.

Neuropathy of B12 deficiency - If stroke is not included (see later), neuropathy is the commonest manifestation of B12 deficiency. We had 90 cases of B12 deficiency neuropathy and out of these 35.6% had sensory neuropathy alone and abnormality was frequently observed only in the lower limbs. On nerve conduction, there was suggestive evidence of axonal degeneration in 54% and mixed axonal degeneration and demyelination in 37%. From a long time , I have been teaching that if we encounter absent reflexes in a person when we are not expecting it, one must look for diabetes. At present, it is clear that the next disorder we must check for is B12 deficiency, and if the patient is vegetarian (or takes non vegetarian only occasionally < once a week), B12 deficiency is very likely. If the neuropathy is due to B12, symptomatic improvement will occur within 1 month of treatment, although the sensory action potentials may take a year to reach normality .

Myelopathy due to B12 deficiency

In the same period, we saw 53 cases of myelopathy. Thirty-three had myelopathy with neuropathy and were diagnosed as subacute combined degeneration. Nineteen had only myelopathy without neuropathy and one of them showed only Lhermitte's sign as the sole manifestation of myelopathy. In myelopathy, we had four cases, which I would call as upper limb posterior column myelopathy. They had ataxic upper limbs; joint sensation was lost in the hands, not in the toes, and the nerve conduction in the upper limbs was normal. They had the characteristic MRI of B12 deficiency [Figure - 5],[Figure - 6]. The sagittal section shows demyelination in the posterior part of the cord and the axial view shows a classic inverted V of demyelination, [35] affecting only from the posterior column to the upper limbs. When the posterior column fibres to the lower limbs are also affected, V gets filled up and we obtain a diffuse posterior hyperintensity [Figure - 7]. We have seen cases with the posterior hyperintensities on the sagittal view and the inverted V of demyelination, as shown in [Figure - 6], right down the cord from C2-T1. In myelopathy, it is believed that the posterior column loss preceds the pyramidal defect. In India, in subacute combined degeneration, intrinsic factor antibody was found in 45.8% of the cases studied by Diwate et al . [36] This would serve to increase the severity of B12 deficiency produced by a B12 deficient diet.

What is the mechanism of the neuropathy? The metabolic reactions of B12 are as follows:

i.e., homocysteine is converted to methionine by methylation. Methylenetetrahydrofolate reductase (MTHFR) is the donor and Vitamin B12 is the enzyme; therefore, B12 and Folate are both involved in this reaction.

Here, propionyl CoA is converted to methylmalonic CoA and this with the help of ADO B12 is converted to succinyl CoA. In the absence of B12 methylmalonic acid is formed. It is because of these two reactions that a raised serum homocysteine is the hall mark of deficiency of B12 or folate and a raised methylmalonic acid is the best guide for the deficiency of Vitamin B12.

3. Alpha leuceine ADO B12 Beta leuceine

The mechanism of B12 deficiency neuropathy is believed to be due to

  1. Homocysteine, is not converted to Methionine; therefore, S-adenosyl methionine is not formed

    This is required to form phosphatidyl choline, which is required for myelin.

  2. Methylmalonic CoA - Succinyl CoA (4C compound) is blocked by B12 deficiency.

Therefore, propionyl CoA (3 C compound) is formed. Fatty acid is formed by adding 2 C at a time to produce fatty acids with 15C and 17C carbon atoms instead of 16C and 18C compounds, and these compounds enter the nerve sheath and affect its functioning.

Therefore, B12 deficiency has two effects viz. high homocysteine and high methylmalonic acid and less production of methionine or succinyl CoA. The neuropathy is believed to be due to less methionine and succinyl CoA that is being formed. This however explains only demyelination. On nerve conduction and biopsy, the nerve lesion of B12 deficiency is usually an axonal degeneration neuropathy and raised homocysteine may still be playing some part.

Depression and Homocysteine: In 1980, Shorvan et al . [37] attempted to separate the effects of B12 and folate deficiency by examining the cases of pure B12 deficiency and pure folate deficiency. They noted that neuropathy was observed in 40% cases with B12 deficiency and 16% cases with folate deficienc y. Cognitive changes were equally observed in both cases. Subacute combined degeneration was observed in 16% of B12 deficient cases and none in folate deficiency, although subsequently subacute combined degeneration due to folate deficiency has been described and we have observed two such cases with normal Vitamin B12 and low folate levels. Depression was observed in 20% of B12 deficient cases and 56% of folate deficient cases. Fava et al. [38] studied 213 depressed patients - 19% had low folate levels (< 2.5 ng/ml), 12% had low B12 levels (< 200 pg/ml) and Hcy levels were found to be > 13.2 Ámol/L in 20% and > 16 Ámol/L in 9% cases. Low folate levels were associated with melancholic depression. The low folate cases were less likely to respond to treatment. Fluoxitane failure was noted in 35% of low folate cases and 20% of the normal folate group ( p < 0.005). The best data on the association of depression and homocysteine is from the Hordaland Homocysteine Study, [39] which is a population-based study. Here, two groups were studied: the age range of one group was between 46 and49 years and that of the other one was between 70 and 79 years. When the Hcy level was < 9 Ámol/L, depression was noted in 2.6% cases, and when it was between 9 and 11.9 Ámol/L, depression was noted in 5.4% cases. With a serum homocysteine level was between 12 and14.9 Ámol/L, depression was noted in 6.9% cases and with Hcy 15+ depression was noted in 7.3% . These findings were adjusted for age, sex, smoking and education. The OR for depression between the highest group and rest of the three groups was 1.9 times and statistically significant.

The Eyes in B12 deficiency: The optic nerve function is affected in B12 deficiency. We studied the VER in 20 cases of B12 deficiency and our findings are reported in [Table - 7]. It is clear that the more severe the neuropathy, the worse were the Hcy and B12 levels and the greater was the likelihood of optic nerve dysfunction. Misra et al . [40] also reported evoked potentials in B12 deficiency. They reported 17 cases over 3 years - 8 with B12 levels. The VER was done in 13 and it was delayed, bilaterally in 7 and unilaterally in 2.

Central motor conduction was performed in 12 patients. It was unrecordable in 2, delayed in 8. Sensory evoked potential was carried out in 15 and found to be unrecordable in 9 and delayed in 4.

These cases represent the subclinical optic nerve affection; however, I came across a case who presented with progressive deteriorating vision from 6/9-6/60 from Nov-May while being treated by three ophthalmologists who declared the eyes were normal and had an MRI brain done, which was normal.

While I examined him in the end of May, he mentioned that he experienced paresthesia in legs and clinically he had all findings of subacute combined degeneration. The Hcy level was raised the B12 level was low; and he was administered with Inj. B12 (he was a vegetarian). Vision improved from 6/60-6/9 from May to September

Subsequently, I have seen another case of clinically manifest optic neuritis due to B12 def. and one case who spontaneously remarked that his hearing had considerably improved since the treatment had started.

This reminds us of the observation by Strachen in prisoners of war who were severely nutritionally deprived. Besides neuropathy and myelopathy, there were several prisoners with clinical optic neuritis and deafness (Strachen's syndrome), B12 deficiency of hydroxycobalamin was also thought to play a part in alcohol-tobacco amblyopia, but a study by Wadia et al. seems to suggest that this is not significant. [41]

   Chorea and Dystonia and raised Homocysteine Top

In 2002, I was struck by a case report of progressive chorea over 7 months. [42] During this period, there was development of blepharospasm-type dystonia and mild neuropathy on testing.

MCV was 102-106, Vitamin B12 levels declined from 124 to 93 pg/ml and Hcy was 40.1 Ámol/L.

Other tests and CT Scan were normal. The response to B12 in high doses was complete after amantadine and tiapride had failed. The authors pointed out that homocysteine is the agonist of NMDA receptors. MTH Folate is agonist of Kainic acid receptor. Several other similar reports describe the association, and in a study of 24 cases of dystonia, [43] Hcy levels ranged from 8.4-37 Ámol (mean: 19.3 umol/L), while the control levels were 5.8-24 Ámol/L (mean: 13.9) (p < 0.008) There was a significant association of severity of dystonia and Hcy level but no association with the duration of dystonia.

In this viewpoint, I considered our cases of writer's cramp. Writer's cramp is usually very resistant to drug therapy, yet most of us have seen cases of writer's cramp improve with drug therapy quite significantly at times. I have checked homocysteine and B12 in cases with writer's cramp. In 19 cases, I have noted raised homocysteine and B12 deficiency. After administering B12, 12 cases did not improve significantly, but 7 were quite happy with their results and were able to sit for exams writing by themselves or by carrying out writing work that they could not do before. It may be mentioned that the results with botulinum toxin in writer's cramp is not really spectacular either.

   B12, Folate, Homocysteine and Pregnancy Top

The Hordaland Homocysteine Study [44] concluded that Folate deficiency in the mother was associated with risk of low birth weight and increased neural tube defects, and there was a moderate evidence of this leading to cognitive defects. This was confirmed in a WHO report in Dec 2006. [45] A Mexican study found that low folate in mother is associated with small head circumference in the baby reaching down to the 3rd percentile by 4 months and then improving with folate replacement.

Low maternal B12 causes [44],[45]

  1. Low neonatal Vitamin B12
  2. Decline of B12 in breast milk. (Folate does not reduce in breast milk with maternal deficiency)
  3. Greater incidence of IUGR O.R 1st/3rd tertile 2.81 at delivery.
  4. Children show delayed development in the first 2 years and this does not recover later so
  5. Children show lower IQ score in school. The WHO Consultation also claimed there was moderately convincing evidence that low maternal B12 status was associated with an increased risk of neural tube defects. [19]

In Mexico, a study on 18 children born from B12-deficient mothers showed low birth weight < 10 percentile in 14/18, length > 10 percentile in 10/18 and head circumference < 10 percentile in 10/18 and delayed development. The effect of raised homocysteine has also been studied. [46] A raised homocysteine level is associated with the increased incidence of preclampsia, prematurity, low birth weight, increased still birth, neural tube defect, pregnancy hypertension and placental abruption. Out of these, several ill effects were reduced by folate supplementation; however, the increase of preclampsia, still birth and placental abruption was not reduced by folate supplementation. The effect of folate in preventing neural tube defects is well known at present, and in the large study, from China [47] the use of folic acid 0.4 mg/daily from preconception to the end of the first trimester reduced the incidence of neural tube defects in the northern region of China from 4.8/1000 to 1/1000 (approximately 80% reduction). In Southern China, where the incidence of neural tube defect was initially lower, the fall was less marked (1 per 1000 to 0.6 per 1000). The effect of folate is mostly mediated by lowering homocysteine.

In Pune, Yagnik et al . has set up a maternal nutritional study (Pune MNS study). Here an entire rural area has been covered with 38000 population and 2675 eligible couples. The couples were examined pre-pregnancy and were evaluated in pregnancy at 16, 28, 34 weeks. The baby was examined at birth and several babies have now been followed up to the age of 9 years. They found that studying the MTHFR 677 polymorphism mothers with a CC genotype had plasma Hcy level of 8.4 Ámol/L in 28 weeks of pregnancy; the CT genotype had an Hcy level of 9.3 umol/L and TT genotype had an Hcy level of 10 umol/L in the same period. The mean birth weight of children in the three groups were 2.8, 2.8 and 2.52 kg, and the difference in the high Hcy group was significant ( p < 0.003). [48] In this study, the incidence of TT genotype around Pune was only 2.3%. As mentioned before, several children are now being followed up for 9 years in Pune - Maternal Nutrition study. The children born to mothers with low B12 in pregnancy still had low cognitive function at 6-9 years (attention and concentration tests). [49]

Perhaps, more significantly, they have noted that if maternal B12 is low and folate is high, the baby was adipose and showed evidence of insulin resistance. [50] This seems to imply the start of the metabolic syndrome produced by giving mothers with low B12, folate supplement in pregnancy and is a very important finding worth studying further.

Finally, in children in India, we have a unique syndrome called the infantile tremor syndrome. A syndrome of wide-spread tremor in infants, starting at the first year was first reported from India in the 1960s. Jadhav et al . reported Vitamin B12 deficiency in these cases, [51] and Garewal et al . [52] showed megaloblastic anemia in 20/23 and B12 below 100 pg/ml in 88%. Several improved with B12. Other reports found no such association and no improvement with B12. The meaning of this is unknown. It may be a subset of infantile tremor that is due to B12 deficiency. I am not convinced of this as the infantile tremor syndrome is now rare and the maternal B12 deficiency continues.

Epigenetics and Homocysteine: Lastly before we leave children let me introduce you to a new concept called epigenetics. Everyone knows that the environment influences your genetic makeup, i.e., if the genes suggest a certain action, e.g., aggressiveness in men with YY sex chromosome genotype, the environment that such men have may change that feature. Epigenetics, however, is the influence of embryonal environment on a person's genetic makeup. The most well known case is that of the yellow Agouti mouse. Transgenic Agouti mice fed with vitamin B12, folic acid, choline and betaine before, during and after pregnancy gave birth to thin brown pups. The control animals with identical genes had offspring who were fat and yellow. The changes produced were explained by DNA methylation in utero . There are many ways of causing epigenetic change, but the most widely studied method in animals is the methylation of the offspring DNA by methionine homocysteine reaction.

   Homocysteine and Stroke Top

Boushey et al . [53] reported a metanalysis of 27 studies of the association of stroke and homocysteine levels. The homocysteine levels above the 90 percentile control in comparison to the rest showed a risk ratio for coronary disease of 1.7 (95%, CI - 1.5-1.9). The risk ratios for cerebrovascular disease, peripheral vascular disease and venous thrombosis were 2.5 (2.0-3.0), 6.8 (2.9-15.8) and 2.95 (2.08-4.17), respectively. Homocysteine was shown to be an independent risk factor equivalent to smoking and hypercholesterolemia and another study suggested that a 5 umol rise in serum homocysteine increased the risk of stroke by 1.7 times.

Therefore, at Ruby Hall, we mounted a study of homocysteine in stroke and first reported our results at the IAN Conference 2001, which were published later. [54] That study of 163 cases of stroke (who had not received prior supplement and had no other cause for raised homocysteine) showed Hcy levels elevated above 16 umol/L in 109/135 continuous ischemic stroke patients (80.7%), 25 of 27 cases with young arterial stroke (< 45 years of age) and 21 out of 28 cases (75%) with venous infarction. As mentioned before in controls (with no strokes, IHD or obvious cause of raised Hcy, as noted in [Table - 4]) the Hcy levels was raised in 62/170 controls, 35.2% and p was significant for all 3 groups compared to controls . Homocysteine was the commonest risk factor noted in our stroke patients, and in the ICASS study of arterial stroke from 10 Indian centers (involving 2162 cases of stroke), no risk factor exceeds this figure with hypertension being the commonest recorded (63.6%) followed by diabetes 31.9%. [55] When divided by diet in our 65 vegetarian patients with stroke, 59 had B12 levels below 200 pg/ml and 5 had borderline levels, i.e.. B12 200-300 pg/ml and 3 had low folate, as seen by serum folate < 3 ng/ml. There were only 14 heavy nonvegetarians among the stroke cases; none had a B12 level below 200 Ámol/L and 7 were in the borderline B12 group.

Recently, we expanded this series to cover 461 cases of stroke. The results are seen in [Table - 8].

Thus, with 461 cases of stroke, the Hcy level was elevated above 15 umol/L in 80.2% cases. Out of these, 461 cases of stroke (46.1%) had serum Vitamin B12 below normal (< 200 pg/ml) and the serum Vitamin B12 level was borderline in 9.54% cases. If cases with raised Hcy levels were considered, B12 levels were low in 57.5%, borderline in 11.8% and folate was low in 14.8% (most of these 63 cases also had low B12 levels).

What is this discussion of borderline Vitamin B12 levels and probable B12 deficiency? As mentioned before, true metabolic deficiency of B12 produces raised serum homocysteine and methylmalonic acid. It has been noted that in cases with true metabolic B12 deficiency, 50% will have levels below 100 pg/ml, 40% will have levels between 100 and 200 pg/ml and 10% will have levels between 200 and 350 pg/ml. On the other hand, if methylmalonic acid or homocysteine is normal, a Vitamin B12 level of 150pg/ml is also normal. When we use terms probable and borderline B12 levels in this study, we mean raised Hcy and B12 levels, i.e., 200-300pg/ml (mostly below 250), all of which are the true metabolic B12 deficient cases. Similarly, cases with true folate deficiency may have serum folate up to 5 ng/ml. Unfortunately, we were not able to assay methylmalonic acid in our study.

It may be mentioned there are other Indian studies showing similar high homocysteine in stroke patients. Das and Borah [56] from Gauhati found Hcy levels raised in 59.1% of 110 ischemic strokes. Kalita et al. (Lucknow) found the Hcy levels to be above normal in 83% of 58 cases.

Refsum et al . [57] found that 77% of strokes had raised homocysteine, 47% had low cobalamine, 73% had raised MMA. In the 2007 IAN conference abstracts, Noone et al . [58] studied 30 cases of cerebral venous thrombosis and 64 controls and calculated that the risk for venous thrombosis with Hcy levels above the 90th percentile was 4 times those with a low level even after adjusting for Vitamin B12 status.

Mendelian Randomization studies : This is another way of checking if homocysteine is truly a risk factor for stroke, i.e., by observing the effects of Mendelian randomization. Cronin et al . [59] studied 22 good stroke series reporting stroke incidence with MTHFR 677 polymorphism. The CC genotype at this location causes a lower Hcy than the CT or TT Genotype. In 22 series covering 4740 cases with ischemic stroke and 7486 controls, they found if MTHFR 677 genotype CC risk from stroke was 1.0, the risks for CT genotype was 1.18 (CI - 1.09-12.9, p < 0.001) and for TT genotype was 1.48 (CI - 1.22-1.8, p < 0.001). TT genotype led to an Hcy level of 3 umol/L, which was greater than that for CC genotype. The difference was less if the folate replete patients were compared. Subsequently, Casas et al . [60] reported a large meta analysis of 81 trials, including 6312 strokes and 15635 controls; the OR TT to CC was 1.26 (CI - 1.14-1.4), even though Hcy difference between the two groups was only 1.93 Ámol/L. Casas et al. have also reported a similar difference in IHD cases involving 23920 subjects. The importance of Mendelian randomization is that one cannot say stroke caused the raised Hcy or that some other factor caused both raised Hcy and stroke because the patients for comparison were randomized at birth by genotype.

Before leaving the aspect of Homocysteine risk and stroke, one has to mention a landmark study on nutrition and stroke/IHD. Key et al . [61] published a meta analysis of five prospective studies of diet influence on disease that involved 76172 persons and 27808 vegetarians with a mean followup of 10.6 years. Mortality from IHD was less in vegetarians in comparison to non-vegetarians. When compared to regular meat eaters, it was 20% less in occasional meat eaters, 34% less in fish eaters who did not eat meat and 34% less in lacto vegans. The number of studies from different countries was as follows: 2 from UK, 2 from US, and 1 from Germany, where the diet is different and the need for supplements is well known. There was no difference in stroke (or colon cancer)

   Homocysteine and Dementia Top

Silent brain infarcts and white matter lesions are common in the elderly. This is associated with the risk of stroke and dementia. The Rotterdam Scan Study examined 1077 patients with stroke or dementia (age range: 60-99 years). [62]

They noted that if the group with levels of Hcy (5-8.5 umol) per liter had silent brain infarction incidence taken as 1, 2 nd quintile (8.6--9.8 umol/L) had 1.4, 3 rd quintile was 1.7, 4 th quintile 11.4-13.7 umol/L had 1.6 and the top quintile 13.8-45 umol/L. incidence was 2.5. Further, the white matter lesions in the five quintiles was 1, 1.9, 2.1, 2.0, and 2.3, and if both are counted together, the OR between 1 st and 5 th quintile (13.8 + Hcy) was 3.0. One thousand one hundred and fifteen participants of this group were followed for 3697 pt/years (3.6 years each). Thirty patients had developed dementia. For those who had silent brain infarcts (SBI), the risk of developing dementia was 2.26 times than those with no SBI and the SBI +ve showed a steeper decline in the global cognitive function than those with no SBI even if they did not develop dementia. If SBI was present at base line, the occurrence of developing dementia was restricted to those who got more SBI. Therefore, silent brain infarction is related to homocysteine and is related to the subsequent development of dementia and cognitive decline. A similar result was noted in the Framingham Cohort. [63] One thousand and ninety-two persons without dementia had a median followup of 8 years. Dementia developed in 111. Homocysteine levels at base line and 8 years before were available. The level of plasma homocysteine at baseline >14 umol/L had a RR of dementia as 1.9 times that of patients below that level and the risk for Alzheimer's also was 1.9 (95% c 1.2-3.0) The risk per quartile was as follows: 2nd quartile - 1.3, 3 rd quartile -1.3 and 4th quartile - 2.2. The findings were not changed by Vitamin B levels or APOE group

Dementia is a known finding in B12 Def (occ. with folate). In our series, the fall in MMSE < 27 was observed in 27 cases When MMSE was 20 or below recovery, was not seen with B12/Folate supplement. This may be because it is too late or the dementia led to poor intake Most striking recoveries were observed in M.C.I. Usually, at the first recheck, the patient was reported strikingly better.

[Figure - 8] shows the MRI of a 31-year-old, showing cognitive defect with B12 deficiency.

There was nil to suggest cerebrovascular disease . The symmetric changes seemed to more likely represent the metabolic abnormality. Recently, Narayan et al . [64] studied 167 demented patients serially each year with cognitive battery. The slope of decline of the speed of cognition and episodic memory showed an independent association with the Hcy levels: Speed of cognition - p < 0.008 and episodic memory - p < 0.001. Decline was noted to be independent of B12 and Folate levels and other confounding variables.

Other CNS effects of raised Homocysteine levels - Other CNS defects that have been described in which homocysteine may be playing a part are as follows:

a. Increased L-DOPA dyskinesia in Parkinson's disease

b. Methotrexate leucoencephalopathy

c. Increased risk of fractures in the cases of stroke and other patients has been reported. [65] Van Meurs et al . [65] noted that the fractures in the highest quintiles of Hcy was 1.9 times that in the lower quintiles, and Sato et al . [66] showed that administering B12/folate reduces the chances of fractures in stroke cases by 80% as compared to the placebo group. Homocysteine interferes with the cross linking of collagen, and fractures in these cases are not related to BMD.

Treatment : The treatment to lower homocysteine is well known, viz. folate and B12 and pyridoxine. In patients with hyperhomocysteinemia, folic acid alone reduces the Hcy level by 22%. B12 alone reduced the Hcy level by 11% and Folic acid + B12 reduced the Hcy level by 38.5%, Pyridoxine reduces the postmeal Hcy levels. Pyridoxine reduced post-methionine-load Hcy levels by 22%. The main question is that does the lowering of homocysteine levels really help in treatment? In cardiology, the Swiss heart study result was fairly clear. [67] Two hundred and five patients who had undergone angioplasty were randomized to homocysteine lowering vitamins (HLVs) or placebo for 6 months. The HLVs reduced the Hcy levels from 11.1 to 7.1 umol/L. In the HLV group, the rate of restenosis reduced from 37.5% to 19.6%. The need for reasularization reduced from 27.3 to 10.8% and at end the luminal diameters was significantly greater in the HLV group (1.72-1.44 mm). The FACIT trial examined the effect of homocysteine lowering on cognitive change. [68] They randomly selected people who were 50-70 years of age. In this study, those with a total of Hcy < 13 Ámol/L (73% of the total) and Hcy > 26 Ámol/L were eliminated; further, those with renal failure, hypothyroidism, B12 deficiency, mal-absorption and those on supplements were also eliminated from this study. One group received 800 Ág of folic acid and the other group was not administered with folic acid for 3 years. With supplements, serum folate levels increased from 12 to 76 Ámol/L, Hcy levels dropped from 13.0 to 10.3 umol/L. (In controls, it rose from 12.9 to 13.4 umol/L.). Careful higher function tests showed improvement in the memory ( p < 0.0001). The speed of information processing improved ( p < 0.005); sensory motor speed was the same. Delayed memory test showed improvements equal to the performance of a person who is younger than the patient by 6.9 years . Global cognitive function improved ( p < 0.033). The effect was not modified by the MTHFR status. If Hcy levels were higher at the onset, then the results were better. If B12 levels were high, then the effect was less.

In stroke patients, the results of homocysteine lowering were initially negative. Thus, the VISP trial [69] carried out in patients with prior stroke and vitamins failed to prevent recurrent stroke. One year later, the same authors reexamined their data. [70] They decided that possibly the low B12 group had malabsorbtion and those with high B12 had been given injection before entering the study. When these two groups were removed, the result was that B12 supplementation was beneficial. Another major negative study was the HOPE-2 study. [71] This study examined homocysteine lowering with Folic acid (2.5 mg), Vitamin B6 (50 mg) and B12 (1 mg) or placebo. Five thousand five hundred and twenty two patients with an age of 55 years or older were included in this study. Active treatment reduced the Hcy level by 2.4 mmol/L. The Hcy level of the placebo group increased up to 0.8 mmol/L. Their final conclusion (as published) was "Supplements did not reduce the risk of major cardiovascular events in patients with vascular disease."

What surprisingly was not mentioned in the conclusion was their own finding that active treatment did in fact reduce the risk of all strokes. The reduction was 0.75 (CI - 0.58-0.97, p < 0.03) and non fatal strokes were reduced by 28% ( p < 0.02), although the end point stroke, MI and death was not reduced. Careful evaluation of the study showed the following:

a. Seventy-two percent of the placebo group were receiving folic acid in their cereals, i.e., they were already being supplemented to a level that was considered to be adequate. Only 1540 did not receive supplements - 770 in each group . [64]

b. The mean Hcy level before supplements was 12.2 mmol/L. After 5 years, supplement Hcy dropped down to 9.7 mmol/L, i.e., a decrease of 2.5 mmol/L. Placebo rose to 12.9; the difference was 3.2 Ámol/L

c. Mean B12 level in the two groups was 436 and 426 pg/ml before the treatment.

Thus, in HOPE-2 study, the starting Hcy level was 12.2 and at 5 years, the difference between the 2 groups was 3.2 umol/L. At Ruby Hall, the normal control vegetarian group had a mean Hcy level of 27.7 Ámol/L, the mean B12 was 190 pg/ml and 55% had B12 deficiency to start with. In our studies on B12 Folate treatment in stroke, we have observed a drop in the Hcy level from a mean of 39.5-12.5 umol/L over 1Ż-5 years (i.e., a decrease of 68.3%). Defenitely, the results possible in India would be different from that in HOPE-2.

However, more recently, Wang et al . [72] published a metanalysis of all homocysteine-lowering trials in stroke prevention. They collected 8 trials, including VISP and HOPE-2, and concluded that folic acid supplementation significantly reduced the risk of stroke by 18% (RR - 0.82, 95%; CI - 0.68-1.0; p < 0.045). The greater benefit was observed when the trial was more than 36 months (RR - 0.7; CI - 0.57-0.87; p < 0.01), when the decrease in concentration of Hcy was more than 20% (RR - 0.77; CI -0.63-0.92; p < 0.012) and when the control population did not have fortification of cereals by folic acid (RR - 0.75; CI -0.62-0.91; p = 0.03) and when there was no prior stroke ( p < 0.002).

Even before the Wang metanalysis , the value of homocysteine-lowering treatment was strongly supported by a report on the result of folate fortification on stroke mortalities in US and Canada. [73] This was a report on the stroke mortalities in US and Canada between 1990 and 2002. Folate fortification became mandatory in 1998. The US stroke mortality was falling in 1990-1998 at a mean rate of 0.3% per year. From 1998-2002, the mean fall was 2.9% per year. Similarly, in Canada, the mortality in 1990-1998 was falling at a mean rate of 1% per year . However, between 1998 and 2002, a mean fall of 5.4% per year was recorded.

No such change in mortality was noted in Great Britain and Wales where no folate supplements were used. More importantly, the improvement in US was noted in all classes: males, females, Blacks, Hispanics, etc.

In the same period (1998-2002), authors studied the prevalence/changes in HT, diabetes, smoking and cholesterol reduction. Changes in these four cases actually predicted that there should be a 0.1% increase in the stroke mortality; instead, they found a reduction of 9.3%. New treatment could not be the explanation as no change was seen in England, Wales. The folate fortification of cereals in Canada caused a 48% reduction in the neural tube defects in 2005 in comparison to 1998. [74]

Let me conclude by giving you a thought for the day: at present, diabetes, hypertension and raised homocysteine levels are all known to be the risk factors for stroke. The relative frequencies and RRs are outlined in [Table - 9].

In 2007, a doctor who did not check and treat diabetes and HT in his stroke patient would of course be considered to be grossly negligent. Then, what would we consider regarding a doctor who has neither checked nor treated hyperhomocysteinemia in his stroke patients? I guess the word would be IGNORANT, especially as it is by far the easiest of the risk factors to control. We have noted that 10 injections of B12 can lower the homocysteine level from 50+ to 10 in 10 days and the oral supplement would take a little longer (30 days to bring it from 50+ to 25 in our study). A pill a day would keep the level normal in long term with virtually no need to check it repeatedly.

Finally, I will leave you with an interesting set of images.

[Figure - 9] shows the angiogram of a 28-year-old female with no HT, diabetes, smoking and normal lipids (Cholesterol - 133, TG - 64, LDL - 80, normal 2D-Echo and an MCA infarct in 2006). Her angiogram of February 2006 shows a left MCA stenosis (which our interventionist would love to stent ). She had a B12 of 125 umol/L and raised homocysteine level. We gave her B12 (with aspirin and statins). The angiogram of April 2007 [Figure - 10] shows a near total reversal of vasculopathy with Vitamin B12/Folate (and the lowering of homocysteine), and the reversal of atherosclerosis?

   Acknowledgement Top

The full text of the presidential oration delivered at the fifteenth annual meeting of the Indian Academy of Neurology in Mumbai in December 2007. The data above represents the work of Dr. R. Kulkarni (Deenath Hospital), Dr. S. Bandhishti and myself from Ruby Hall Clinic Pune. I wish to acknowledge the help of the Radiology Department, Ruby Hall Clinic, Dr. A. Atre and S. Nanivadekar and their staff. The viral studies were done at the National Institute of Virology, Pune, under the guidance of the director Dr. N. P. Mishra who gave valuable inputs into the study.

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  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10]

  [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8], [Table - 9]

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