LDN has 2 primary functions in the possible benefit for those suffering from HT/HE.

1.  LDN works by blocking opioid receptors, (example seen in the picture 2 where it has accepted opioids into the receptors) which in turn release a bunch of endorphins.  But in diseases like HE and HT that have shown no evidence of a lack of endorphins, endorphins just make you feel good.  Picture 1 just kinda gives you a better view of the brain.  So LDN would kinda be like a placebo effect if it were not (possibly) for number two…

2. LDN blocks ‘toll-like receptor 4 (TLR4)’ on microglia.  See picture 3.  First of all, normally microglia are the first and the main form of active immune defense in the CNS.  They’re like the soldiers on the front line.  Glial cells form myelin, supply nutrients and oxygen to neurons and modulate neurotransmission.  It has been shown that dysfunctional microglia play a big role in neurodegenerative disorders.  See the right side of picture 3.

Ok, I hope this clears things up a little better for people.  The primary benefit, I believe is the blockage of the TLR4 receptor so the microglia can’t become messed up and cause neurodegeneration.

Here’s a video someone posted:  (skip past the middle about 42:45 for the LDN brain stuff)

I looked up every pub med study I could (in 4-5 hours) in order to find the typical dosage of IVIG.

The typical “loading dose” is 400mg/kg body weight per day for 5 days.  So that ends up being a TOTAL of 2g/kg.

I only found one study that deviated by administering 1000mg/kg, but it didn’t tell over how many days, so it was useless to determine a typical dose.

The maintenance dose is also 400mg/kg/day for 1 day.  However I found this varied in frequency.  Some never got a maintenance dose, some every 4 weeks, some every 6 weeks…  I think every 4 weeks is more typical.

So there’s the typical dosing, based on pub med studies.  Below is the data.

• 2004 Review of case report from 1987 woman with HE
  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1739535/pdf/v076p00455.pdf
  400mg/kg daily as initial 5 day dose
• 2005 Review of case report of 2 year old boy with acute encephalopathy
  http://www.ajnr.org/cgi/content/full/26/9/2311
  Prolongation of the infectious encephalopathy condition was suspected, and high-dose (1000 mg/kg) intravenous immunoglobulin therapy was administered in the hope of improving the neurologic symptoms. The patient showed no clinical symptoms during and after infusion, but disturbed consciousness and weakness of limbs appeared later that evening.
  Low-dose (100–200 mg/kg) intravenous immunoglobulin is used as a replacement therapy for antibody deficiencies and high-dose (400–1000 mg/kg) intravenous immunoglobulin is used as an immunomodulatory agent in many immune and inflammatory disorders.
• Review of 10 case reports on limbic encephalitis
  http://brain.oxfordjournals.org/cgi/reprint/127/3/701
  case 1: IvIg; 2g/kg divided into five daily doses
  Case 4: IvIg; 2g/kg divided into five daily doses (improvement within 1 week, normal within 3 months)
  Case 8: IvIg; 2g/kg divided into five daily doses (worsened, then plasma exchange, no change then improved with steroids)
• 2001 Review of 10 cases with OMS
  http://brain.oxfordjournals.org/cgi/reprint/124/2/437
  3 cases: 0.4g/kg over 5 days (all recovered in <3 months)
• Review of 55 year old woman with Guillain-Barre
  IVIG 0.4g/kg per day was started
• 10 year review of MS patients receiving IVIG
  http://informahealthcare.com/doi/abs/10.1080/08916930600825867
  initial loading dose of 0.4g/kg body weight/day for 5 days
  booster maintenance dose of 0.4 g/kg every 6 weeks.

This post addresses the link between Levothyroxine, used to treat hypothyroidism, and its benefit on HE.

Mary Shomon, well known thyroid patient advocate, wrote an article “Do You Need Preventative Thyroid Treatment: Treating Antibodies When TSH is Normal“.  A lot of us HE patients fall into the category of having high anti-TPO antibodies but “normal” TSH, T3 and T4 thyroid levels.  A lot of us later develop hypothyroid symptoms, then it takes even longer to be diagnosed with hypothyroidism and finally receive treatment.

Recent studies show, preventative treatment could slow or even stop the development of hypothyroidism, and reduce the antibodies.  However, at this point, most endocrinologists will dismiss you if you talk about preventative treatment.  I have been dismissed many times by many endos, and now have developed almost all of the classic symptoms of hypothyroidism.  This possibly could have been prevented.

She notes a recent study (that I currently can’t find a link to):

En-Ting Chang, Du-An Wu, Dee Pei, Shi-Wen Kuo, Ming-Chen Hsieh. [P2-552] Influence of L-Thyroxine Administration in Patients with Euthyroid Hashimoto’s Thyroiditis. Endocrine Society Endo 2005 Abstracts

In this study on HT patients with normal range TSH, but high antibodies, half were given levothyroxine and half were not treated.  “Those receiving levothyroxine had substantially decreased auto-antibody levels; levels actually increased in some among the untreated group. TSH levels also decreased in the treated group, averaging 0.5 vs 2.5 in the untreated group. The researchers concluded that early prophylactic (preventative) levothyroxine treatment might be useful to help slow down the progression of the autoimmunity of Hashimoto’s Thyroiditis.”

Euthyroidism (patients having normal TSH levels):

In the study “One-Year Prophylactic Treatment of Euthyroid Hashimoto’s Thyroiditis Patients with Levothyroxine: Is There a Benefit?“, euthyroid HT patients were given levothyroxine as a prophylactic to see if it would benefit the autoimmune process.  Half of the patients were treated with levothyroxine, the other half were not treated.  The study states, “After 1 year of therapy with LT₄, TPO-Abs and B lymphocytes decreased significantly only in the treated group of euthyroid patients with HT (p < 0.05). In contrast, TPO-Abs levels did not change or even increased in untreated euthyroid patients with HT.”

The study also states, “Prophylactic treatment of euthyroid patients with HT reduced both serological and cellular markers of autoimmune thyroiditis. Therefore, prophylactic LT₄ treatment might be useful to stop the progression or even manifestation of the disease.”

The purpose of the 2008 study, “Long-Term Follow-Up of Antithyroid Peroxidase Antibodies in Patients with Chronic Autoimmune Thyroiditis (Hashimoto’s Thyroiditis) Treated with Levothyroxine” was to see if patients treated with levothyroxine for HT reached the point where their TPO-Ab levels became within normal range (negative).

In the study, 92% of patients had a decrease in their TPO-Ab levels.  “The mean decrease after 3 months was 8%, and after 1 year it was 45%. Five years after the first value, TPO-Ab levels were 1456 ± 1219 IU/mL, a decrease of 70%. TPO-Ab levels became negative, < 100 IU/mL, in only six patients, a normalization percentage of 16%.”

The conclusion of the study was “Serum TPO-Ab levels decline in most patients with Hashimoto’s thyroiditis who are taking levothyroxine, but after a mean of 50 months, TPO-Ab became negative in only a minority of patients.”

The aim of the 2008 study “Effects of Prophylactic Thyroid Hormone Replacement in Euthyroid Hashimoto’s Thyroiditis” was “to evaluate the effects of prophylactic L-thyroxine treatment on clinical and laboratory findings of patients who were euthyroid at the time of diagnosis.”  The study states, “After 15 months of L-thyroxine treatment, there was a significant increase in free T₄ and a significant decrease in TSH and anti-thyroglobulin antibody anti-thyroid peroxidase antibody levels.”  “In conclusion, prophylactic thyroid hormone therapy can be used in patients with Hashimoto’s thyroiditis even if they are euthyroid.”

The study goes on to conclude, “Early treatment of Hashimoto’s Thyroiditis with L-thyroxine may slow down not only the disease process itself but through its immune modulating events it may also affect the course of other autoimmune diseases which accompany.”

This would relate to HE and the HE patient would benefit from the lowering of the antibodies as well, with less side effects from levothyroxine than steroids. 

Subclinical Hypothyroidism (borderline levels):

A 2008 study, “Diagnostic strategies for subclinical hypothyroidism” notes “45 of the 61 subclinical hypothyroid patients had elevated anti-TPO levels (73%). This is an important finding suggesting an autoimmune etiology for subclinical thyroid dysfunction with a higher risk of developing overt hypothyroidism.”  This study states that the antibodies should be considered in order to treat subclinical hypothyroidism.

A 2006 study “Subclinical Hypothyroidism“, notes “the titer of anti-thyroid peroxidase (TPO) antibodies is proportional to the degree of lymphocytic infiltration and inflammation within the gland. Thus, hypothyroidism in patients with high titers of anti-TPO antibodies is more likely to progress from subclinical to overt disease.”   “Without treatment, progression to overt hypothyroidism is likely”.  He also states, “Endocrinologists also disagree about the normal range for serum TSH levels. Although many laboratories have traditionally used 4 to 6 mIU/L as the upper limit of normal, the data used to calculate reference ranges have frequently included measurements in patients who had positive results on anti-TPO antibody tests or other evidence of early thyroid dysfunction. Careful analysis suggests that the true upper limit of normal for serum TSH concentration is closer to 2.5 mIU/L.”

Spontaneous Remission or Levothyroxine?

One patient in the case study “An 85-year-old Case with Hashimoto’s Encephalopathy, Showing Spontaneous Complete Remission” was taking thyroxine treatment at the time of his remission.

The case study, “Long-Term Treatment of Hashimoto’s Encephalopathy” states “35% of cases had subclinical hypothyroidism; 22% were euthyroid not on levothyroxine; 20% had overt hypothyroidism; and 8% were euthyroid on levothyroxine (as were our two cases); 7% had hyperthyroidism (5% overt, 2% subclinical); 6% had unknown thyroid status; and 1% did not have thyroid disease. A goiter was present in 62% of cases (see Table 2). Of the above cases with subclinical or overt hypothyroidism, 17% improved following treatment with levothyroxine alone, while 40% improved following combined treatment with levothyroxine and steroids.² It is somewhat surprising that some cases improved with levothyroxine treatment alone. However, it may be that those cases were destined to improve spontaneously.“

The study summarized the treatment efficacy of reviewed literature, reporting “improvement in 98% of cases treated with steroids, 92% treated with steroids and levothyroxine, and 67% treated with levothyroxine, while 9% of cases did not improve with any of the above combinations.”

The study notes that it is interesting that some cases responded with levothyroxine treatment alone, and they hypothesize that these patients may have been destined to improve spontaneously.  Perhaps the levothyroxine reduced the antibody levels enough to improve the HE symptoms.  After all, we still don’t know the exact pathology of the link between the antibodies and the encephalopathy.  But we do know there is a link.

My ending thoughts on this post:

Considering most HE patients eventually develop hypothyroidism, those with hypothyroid symptoms (regardless of the “normal” level of their TSH) should be treated with levothyroxine and monitored regularly for further thyroid problems.  The side effects of levothyroxine are minimal and it has been shown to improve HE symptoms in some case studies, even leading to remission. 

Rather than just steroids, perhaps a combination of steroids and levothyroxine should be considered as a primary treatment for HE.

I sent out an email to the HELPS forum requesting what vitamin deficiencies we have.  Of the 8 people who responded (including myself), 7 reported vitamin D deficiency.  The 8th person reported multiple deficiencies, but did not explicitly report vitamin D deficiency.  There are also other vitamin deficiencies noted in the below table.

I found many case studies linking vitamin D deficiency to autoimmune diseases such as MS, Grave’s Disease, Hashimoto’s Thyroiditis, arthritis and diabetes.  First, I’ll start with the case studies on vitamin D deficiency with cognitive impairment.  This seems like it could be related to HE. 

• Vitamin D Impact on Cognitive Impairment

The 2010 case study, 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services, sought to examine the association between vitamin D status, dementia, and cranial MRI indicators of cerebrovascular disease (CVD).  There were 318 participants with a mean age of 73.5, mostly women.  There was a higher prevalence of dementia among patients with 25(OH)D insufficiency (<20 ng/mL).  The conclusion was that a vitamin D insufficiency was associated with more than twice the odds of all-cause dementia, Alzheimer disease, stroke, and MRI indicators of CVD.  “These findings suggest a potential vasculoprotective role of vitamin D.” 

The 2010 case study, Association of vitamin D deficiency with cognitive impairment in older women, sought to  examine the association between serum 25(OH)D (25-HydroxyvitaminD) deficiency and cognitive impairment while taking confounders (like age, body, chronic disease, physical activity, etc.) into account.  The groups of women (752 subjects over age 75) were divided according to their serum 25(OH)D concentrations either being deficient (<10 ng/mL) or non-deficient (>10 ng/mL).  The conclusions found that 25-Hydroxyvitamin D deficiency was associated with cognitive impairment in these subjects. 

• Vitamin D Impact on Multiple Sclerosis

The 2004 case study, Vitamin D intake and the incidence of multiple sclerosis, sought to indicate a protective effect of vitamin D on the risk of MS.  The study compared women at relative risk for developing MS.  Intake of vitamin D supplements was inversely associated with the risk of MS, compared to no supplemental intake.  Although purely statistical, ”these results support a protective effect of vitamin D intake on risk of developing MS.” 

In the 2004 paper, Vitamin D supplementation in the Fight Against Multiple Sclerosis,  indicates “In summary, vitamin D hormone has numerous effects on the immune system and acts within the CNS. All of these effects have the combined result of significantly reducing inflammatory autoimmune reactions from occurring and they readily explain the impressive correlation between MS prevalence and vitamin D supply and why vitamin D hormone is so effective in suppressing a variety of animal autoimmune diseases including EAE (animal MS).”

Other research has shown that the levels of vitamin D in the body can predict periods of low or high MS disease activity, so the higher the vitamin D, the lower the disease activity.

• Vitamin D and Graves’ Disease and Hashimoto’s Thyroiditis

The 2002 study, A Polymorphism with the Vitamin d-Binding Protein Gene Is Associated with Graves’ Disease nut Not with Hashimoto’s Thyroiditis, investigated the polymorphic vitamin D-binding protein (DBP) gene, which greatly facilitates vitamin D actions, with association with thyroid autoimmunity.  They found, “allelic variants of the DBP gene confer susceptibility to Graves’ disease but not to Hashimoto’s thyroiditis in our population. These findings support a role of the vitamin D endocrine system in thyroid autoimmunity.”

Their study also indicated, “There is evidence for a role of the vitamin D endocrine system in the pathogenesis of thyroid autoimmunity. 1,25(OH)₂ D₃ prevents autoimmune thyroiditis in animal models. In humans, serum levels of 1,25(OH)₂ D₃ were found to be significantly lower in autoimmune than in nonautoimmune hyperthyroidism.”

 A 2006 study, Vitamin D receptor gene polymorphisms are associated with risk of Hashimoto’s thyroiditis in Chinese patients in Taiwan, investigate if single nucleotide polymorphisms (SNPs) of the Vitamin D receptor (VDR) are associated with HE patients.  “The results revealed a significant difference between HT patients and normal controls in VDR SNP and a statistic correlation between VDR-FokI polymorphisms and HT formation. It could be concluded that patients who carry the C/C homozygote of the VDR-FokI gene polymorphism in exon 2 may have a higher risk of developing HT in Chinese patients in Taiwan.”

• Vitamin D and Environmental Factors

The 2000 case study, Vitamin D and Autoimmunity:  Is Vitamin D Status an Environmental Factor Affecting Autoimmune Disease Prevalence?, indicates “Geographical areas with low supplies of vitamin D (for example Scandinavia) correlate with regions with high incidences of multiple sclerosis, arthritis, and diabetes. The active form of vitamin D has been shown to suppress the development of autoimmunity in experimental animal models. Furthermore, vitamin D deficiency increases the severity of at least experimental autoimmune encephalomyelitis (mouse multiple sclerosis).”

• Lack of Vitamin D and Aggravating Immune Response

A 2009 article, Vitamin D Deficiency Related To Increased Inflammation In Healthy Women, indicates “The findings reveal that low vitamin D levels negatively impact inflammation and immune response, even in healthy women,” said Catherine Peterson, assistant professor in the MU College of Human Environmental Sciences. “Increased inflammation normally is found in people with obesity or chronic diseases; a small decrease in vitamin D levels may aggravate symptoms in people who are sick.”

Ending thoughts on this post:

Although I couldn’t find any published information directly linking Vitamin D deficiency to HE, it is clear that it plays a role in many other autoimmune diseases.  One question is what role the deficiency plays in the cause or result of the disease. 

The case studies have shown from a symptomatic level that Vitamin D deficiency is linked to cognitive impairment and inflammatory responses.  Increasing /supplementing Vitamin D in the patient has been shown to help reduce and alleviate symptoms, and in animals has even been shown to suppress the development of autoimmunity.

Out of the 8 people who responded in the HELPS group, 7 had confirmed Vitamin D deficiency (the 8th is unconfirmed).  Although it would have been nice for more to respond, I think it is clear Vitamin D deficiency is playing a role in our disease.

Anyone who is Vitamin D deficient, should consult their doctor to be put on supplementation.

**After reading this post over, I realized this post is truly a stream of consciousness.  I’m not sure it will make sense to anyone but me.  So, sorry if this makes no sense.

Prednisone works from 2 possible directions:  it suppresses the production of antibodies, and it reduces inflammation.

There is a lot of debate about what the antibodies are doing to cause the neurological problems.  Are the antibodies themselves causing the HE or is the body’s response to the existing antibodies causing the HE?

In my case, I showed no signs of inflammation even in the most acute stages of my illness (in blood and scans).  I find this to be strange.  Swelling is the body’s natural response to damage after all.  However, most people diagnosed with HE do not show signs of inflammation.  Maybe the body doesn’t realize it is being damaged in a way that it would normally respond with inflammation.

So if there is no sign of an inflammatory process in most people, then is it really that reasonable to conclude that the neurological symptoms are a result of the body’s inflammatory response to the existence of the antibodies?

Wouldn’t it seem more likely that the antibodies themselves are actually attacking the brain, causing the neurological problems?

In the study, Anti-thyroperoxidase antibodies from patients with Hashimoto’s encephalopathy bind to cerebellar astrocytes, states “In immunofluorescence assays on monkey brain cerebellum sections, both HE patients’ sera and anti-TPO monoclonal antibodies (mAb) were able to bind cerebellar cells expressing glial fibrillary acid protein. Normal human astrocytes from primary cultures also reacted with anti-TPO mAb. Specific astrocyte binding of anti-TPO aAb suggests a role of these aAb in the HE pathogenesis.”

The glial fibrillary acid protein (GFAP) has a role in the functioning of the blood brain barrier.  Disease related to GFAP is thought to interfere in astrocyte interactions with other cells as well as a possible inability to maintain the blood brain barrier.

So if the anti-TPO antibodies are binding to the cerebellar cells expressing GFAP, those cells might be interacting unusually with other cells and compromising the BBB.

Possible pathogenesis:

HT -> results in overproduction of anti-thyroid antibodies -> intrathecal synthesis of autoantibodies into CSF -> anti-TPO antibodies bind to cerebellar cells -> possibly causing neurological symptoms

It appears that the antibodies are possibly directly responsible for neurological symptoms of HE.  If true, this would serve to confirm that HE is a specific disease.

The question is what is allowing the antibodies through the BBB into the CSF so they can wreak havoc on our brains?  In recent research it seems that although there is high prevalence of anti-thyroid antibodies in the serum of the normal population, those antibodies do not normally appear in the CSF of the normal population.

It appears that the process could be cyclic, that once the anti-TPO antibodies bind to the cells expressing GFAP it compromises the BBB.  So the more antibodies that are binding would further compromise the BBB, possibly allowing more antibodies through the BBB.  This would indicate that there should be a link between the level of the antibodies in the CSF and the severity of the symptoms.

If the antibodies are causing the problems, the Prednisone (or other steroids) would be working to suppress the production of these antibodies.  This would be the primary benefit of the treatment.

Ending thoughts on this post:

This post was really a stream of consciousness.  I made a lot of assumptions in order to make my conclusions.  To me, this possible pathogenesis makes sense (and is based on a small number of recent studies).  For someone with HE, the body’s autoimmune response creates an abundance of anti-thyroid antibodies (HT).  These antibodies migrate into the CSF where they get to the brain and bind to the cells that regulate the BBB.  Once these cells are compromised, they interfere with other cells, likely causing unusual neurological symptoms.

At this point, none of that is proven to be true.  However, considering the efficacy of steroids in reducing the antibodies and thereby reducing symptoms, we should continue to search for a link between antibody levels in the CSF and the severity of the symptoms.  This would be helpful in monitoring the treatment (for example when it would be safe to taper down the steroids).  We should continue to develop safer treatments for reducing antibody levels in the CSF.

The case study from 1985, Antithyroid antibodies in depressed patients, states ” The presence of antithyroid (antimicrosomal and antithyroglobulin) antibodies was assessed in 45 psychiatric inpatients with prominent depressive symptoms (28 with DSM-III major depression). Nine patients (20%) had detectable titers of antithyroid antibodies, a rate considerably higher than the 5%-10% observed in the normal population.”

Another research article, The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future, indicates “individuals in the community with thyroid autoimmunity may be at high risk for mood and anxiety disorders.” The results of the study were that 16% of the overall sample had an anti-TPO value above the normal cut-off. Subjects with at least one diagnosis of anxiety disorders or mood disorders were positive for serum anti-TPO more frequently than subjects without mood or anxiety disorders.

Those patients with high antibody levels who do have a mood disorder being treated by lithium should be monitored.  The case study, Lithium-induced Hashimoto’s encephalopathy: a case report, indicates “RESULTS: Lithium clearly relieved the patient’s depressive symptoms, but after 40 days encephalopathy developed. Thyrotoxicosis was ruled out, and serum antithyroid antibody titers were elevated. In the cerebrospinal fluid, protein content was substantially elevated and antithyroid antibodies were detected. Encephalopathy resolved dramatically after course of intravenous pulse therapy with methylprednisolone. CONCLUSIONS: We believe that autoantibodies against antigens shared by the thyroid gland and the brain were induced by exposure to lithium, causing the patient to develop Hashimoto’s encephalopathy.”

My ending thoughts on this post:

This research on the link between high anti-thyroid antibodies and mood disorders appears to have been well documented since the 80′s at the latest. Anxiety and depression can cause symptoms similar to HE symptoms. When doctors are evaluating HE patients after treatment, anxiety or depression symptoms could be masking the true effectiveness of the treatment of HE. Considering the link between anti-thyroid antibodies and mood disorders and the finding that HE patients are at high risk for developing depression and anxiety, each HE patient exhibiting anxiety or depression symptoms should be seen by a psychiatrist to screen for depression or anxiety.

In the case study, Steroid-responsive encephalopathy associated with autoimmune thyroiditis, the patient’s blood was checked for the antibody titers and the CSF was checked for other signs of disease. The CSF IgG index was normal in all tested. However, “The protein level was elevated in 17 patients (85%) (range, 55-680 mg/dL [0.055-0.68 g/dL]; referencerange, <45 mg/dL [<0.045 g/dL]).”

This case study also states, “The levels of thyroid antibodies were variable. All patients were encephalopathic, but antibody levels did not correspond to the severity of the clinical deficits. The presence of thyroid antibodies in serum, not the level, was the clinically relevant issue, indicating that SREAT should be considered in patients with encephalopathy even if thyroid antibody levels are only mildly elevated.”

The 2003 published case study, Antithyroid antibodies in the CSF: Their role in the pathogenesis of Hashimoto’s encephalopathy, compares the antibody levels found in the serum to those found in the CSF. The below table is copied from the study.

Table 2 Laboratory findings in patients with HE

When you examine the serum TPOAb and the CSF TPOAb level changes from the 5 patients with before/after data (I colored in blue) all patients except Patient 6 experienced a greater percentage decrease in the CSF antibody levels compared to the serum antibody levels.

Ignoring Patient 1 (who was lost to follow-up), all patients except patient 3 were treated with steroids. Patient 3 experienced a spontaneous recovery. Although her TPO antibodies in her blood did not decrease much, the TPO antibodies in her CSF decreased to 0 after her recovery. Patient 2 experienced dramatic recovery and a significant decrease in the antibodies. On the contrary, Patient 6 had clinical recovery in spite of his CSF TPO antibodies only slightly decreasing and still remaining high above normal. Patients 4 and 5 did experience decrease in TPO antibodies however did not experience clinical recovery. In reading their symptoms and history, it is possible Patients 4 and 5 have the more progressive type of HE (as opposed to the stroke-like relapsing type) which has been noted as having more difficulty responding to steroids and treatments.

Based on this data, there is no apparent correlation between the levels of the TPO autoantibodies in the blood or CSF with the symptoms of HE.

When you examine the serum TGAb and the CSF TGAb level changes from the 5 patients with before/after data (I colored in green) the data much better supports the possibility of a correlation of antibody level to symptoms. All patients that experienced a recovery experienced a significant decrease in the CSF of the TGAb. Patient 4 was the only patient who did not experience a significant decrease in the TGAb level, and this patient did not experience clinical improvement. Although Patient 5 experienced more than 50% decrease of the TGAb, the CSF level still remained very high (more than 7 times the levels of the other patients). Patient 5 did not experience clinical recovery, possibly because the TGAb remained so high.

The levels of the TGAB in the CSF better support correlation to symptoms compared to the levels in the blood. Just look at patient 6 who experienced recovery with TGAb levels drastically decreasing in the CSF, but actually increasing in the serum.

Another case study supports the correlation of TGAb levels with clinical symptoms and recovery, An 85-year-old Case with Hashimoto’s Encephalopathy, Showing Spontaneous Complete Remission. Note: The autoantibody against the amino (NH₂) terminal region of α-enolase was positive in the serum of this patient. “Thyroidperoxidase antibody was within normal limits (1.8 IU/ml, normal value less than 10.0 IU/ml), but anti-thyroglobulin antibody (TGAb) was markedly elevated (29,043 IU/ml, normal value less than 10.0 IU/ml).”

The patient’s symptoms improved without steroid treatment. He was continuing to receive thyroxine treatment for a previous thyroid problem. ” TSH showed no obvious alterations and TGAb in serum increased after admission, while TGAb in CSF clearly decreased in conjunction with the disappearance of neuropsychological symptoms.”

The article also confirmed the benefits of testing the CSF for the antibodies because although anti-thyroid antibodies commonly appear in the serum of healthy individuals, “anti-thyroid autoantibodies in CSF, including TGAb, are considered to play an important role in manifesting CNS symptoms because these antibodies are undetectable in patients with autoimmune thyroiditis or other neurological disorders.”

According to the study, Long-term Treatment of Hashimoto’s Encephalopathy, 100% of HE patients studied had elevated anti-TPO antibodies in their serum and 73% had elevated anti-TG antibodies in their serum. There was no mention of the CSF levels.

This study also noted the possibility of intrathecal synthesis of the antibodies.

My ending thoughts on this post:

Elevated antithyroid antibodies has been one important factor in diagnosing HE.  Elevated anti-TPO antibodies (TPOAb) being the most common among HE patients, with elevated antithyroglobulin antibodies (TGAb) also being a very common marker for diagnosing HE.

In the case studies prior to 2005 it appears the antibody levels were examined primarily in the serum.  More recent studies have indicated it may be more useful to examine the antibody levels in the CSF.

Recent case studies have shown a possible correlation with the level of TGAb in the CSF and the acuteness of the HE symptoms.  If this correlation proves to be true, it would be a very good indicator of when treatment has been successful and when tapering off steroids or changing other treatments would be safer.

If a patient is presenting with acute symptoms of HE, the CSF should be examined before and after treatment for levels of antithyroid antibodies, specifically TGAb.

However, I have read many other case studies indicating that there are so many healthy people with elevated TPO antibodies (up to 20% of the pop.) that this may not be the best way of diagnosing HE.

I even have a friend who was experiencing chronic pain for 2.5 years and personality changes. All neurological tests were negative. His blood was checked and he had elevated TPO antibodies. He was diagnosed with HE and was shortly after admitted to the hospital for high dose IV steroid therapy (we were in the hospital getting the IV steroids at the same time). His pain and personality changes did not respond to steroids at all. He was discharged on 60 mg prednisone per day. After 1 week there was still no positive response. He was experiencing the typical (and crappy) side effects to the steroids.

My question to his diagnosis is does he really have HE? Is he being treated for an autoimmune response that he isn’t really having? And subsequently is he being subjected to some pretty bad side effects for nothing? Maybe he is one of those people with elevated TPO antibodies in his blood and they are not hurting him (or at least not causing his pain). Since the steroid treatment, he has begun treatment for fibromyalgia (he hasn’t been diagnosed with fibromyalgia yet). I’m interested to see how he does and what diagnosis ends up sticking.

In a case study from 2007, Hashimoto’s encephalopathy presenting with progressive cerebellar ataxia, it indicates the serum autoantibodies against the amino (NH₂) terminal region of α enolase (NAE) as a useful diagnostic marker of Hashimoto’s encephalopathy. The patient in the study had the anti-NAE antibodies as well as the antithyroid antibodies in her blood. Unfortunately, the full text was not available for free, so I do not know how her treatment worked out. However, the anti-NAE antibody indicator may be a better indicator of HE than the anti-TPO antibodies.

The article states, “The detection of antithyroid antibodies in patient sera is helpful but not sufficient for the diagnosis of Hashimoto’s encephalopathy because of the high prevalence of antibodies in the normal population.”

In a 2008 case study, Case report of a patient with Hashimoto’s encephalopathy associated with Basedow’s disease mimicking Creutzfeldt-Jakob disease, the patient had increased titer of anti-TPO antibody, anti-Tg antibody, and anti-NH2 terminal of alpha-enolase (NAE) antibody. Again, here’s this mention of the anti-NAE antibody that I haven’t seen mentioned in too many of the older case studies. In this case, the high dose IV steroid therapy alleviated her symptoms.

A very interesting 2009 case study in Japan had more data on the Anti-NAE antibodies, Anti-NAE autoantibodies and clinical spectrum in Hashimoto’s encephalopathy. The article states, “Recently, we discovered serum autoantibodies against the NH2-terminal of a-enolase (NAE) as a specific diagnostic marker for HE. We analyzed these serum anti-NAE autoantibodies and the clinical features in 84 cases of HE. The 84 patients consisted of 26 men and 58 women, from many institutions throughout Japan and other countries. A total of 37 patients carried anti-NAE antibodies (44%).”

More interestingly, the article states “The patients with anti-NAE antibodies tended to exhibit acute encephalopathy.” Perhaps the level of these anti-NAE antibodies can indicate how acute the symptoms are. If that proves to be even somewhat true, we could more easily monitor our health by periodically checking our anti-NAE antibody levels. We could be more proactive in monitoring for relapses. However, there are currently conflicting studies indicating whether or not the level of antibodies correlates to the severity of the symptoms. In some cases they do, in some cases they don’t. This is something I am particularly interested in studying.

Thyroidmanager.org states, “Recently, autoantibodies against the amino (NH2)-terminal of α-enolase (referred to as NAE) were reported to be highly specific in sera from a limited number of HE patients (68-83% with HE; 11%, 2 of 17 with HT without any neuropsychiatric features; none of controls [50 individuals] including those with other neurological or immunological conditions involving encephalopathy [25 individuals])”

A 2006 case study, Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis, states “The putative role of thyroid autoimmunity in the pathogenesis of Hashimoto encephalopathy is complicated by the fact that serum TPO levels are elevated in approximately 10% of healthy adults, and the prevalence of individuals with elevated TPO levels increases with increasing age.”

The study had used elevated anti-TPO antibodies as one of the criteria for the study.  Another criteria for the study was responsiveness to steroids.  The data indicated that many of the patients who did not respond to steroids (those that were taken out of the initial study) ended up being diagnosed with other disorders (they did not have HE).

The study states, “We hypothesize that patients with an encephalopathy associated with thyroid antibodies who do not markedly improve with corticosteroids represent those with a nonautoimmune or noninflammatory disorder, and our 4 patients who underwent autopsy and who did not respond to high-dose corticosteroids support this contention. We suspect that most of the other nonresponders in Table 5, and most others who do not respond to corticosteroids,have an underlying neurodegenerative or prion disorder.”

My ending thoughts on this post:

Considering the high incidence of elevated anti-TPO antibodies in the healthy population, the anti-NAE antibodies should be checked as an indicator of HE.  The anti-NAE antibodies also appear to indicate acute encephalopathy.  Anti-NAE antibodies should also be checked when a patient is exhibiting HE like symptoms.

When TPO antibodies are used as a major criteria for diagnosing HE, it is possible another neurodegenerative disorder may be going undiagnosed.  However, considering how treatable HE is, it might still be useful to try steroids as an initial therapy.  If there is no positive response to the steroids, another diagnosis should be considered before continuing to subject the patient to the side effects of the steroids.