Dr. Ron’s Research Review – February 3, 2016

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This week’s research review focuses on high-dose thiamine therapy by Dr. Costantini

In 2013 and 2014 Dr. Costantini published several case reports of successful treatment with high-dose thiamine therapy on a variety of diseases.
Several regimens were used, including intramuscular (100 mg every 3-5 days) oral (based on body weight 600 mg/day; 60 kg to 1,500 mg/day; 90 kg) and parenteral (100 mg/ml every four days).

Fatigue in multiple sclerosis. (Costantini et al., 2013c)
Initial treatment for Parkinson's disease (Costantini et al., 2013a) (Fancellu et al., 2015)
Fibromyalgia (Costantini et al., 2013d)
Friedreich's ataxia (Costantini et al., 2013d)
Spinocerebellar ataxia type 2 (Costantini et al., 2013b) (Fancellu et al., 2014)
Fatigue after stroke (Costantini et al., 2014)
Hashimoto's thyroiditis (Costantini and Pala, 2014)

In addition, two studies were published in the Journal of Alternative and Complement Medicine.

Twelve patients with inflammatory bowel diseases (8 with ulcerative colitis and 4 with Crohn's disease) received oral thiamin. Ten patients out of twelve showed complete regression of fatigue, while the remaining two patients showed nearly complete regression of fatigue compared to the chronic fatigue syndrome scale scores before therapy. (Costantini and Pala, 2013)

A second study included 50 patients with Parkinson Disease. Thiamine treatment (100 mg of thiamine intramuscular twice a week) led to significant improvement of motor and non-motor symptoms: mean UPDRS scores (parts I-IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10(-14), t test for paired data) within 3 months and remained stable over time; motor UPDRS part III score improved from 22.01 ± 8.57 to 9.92 ± 8.66 (p = 3.1 × 10(-22)). Some patients with a milder phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved from 53.00 ± 8.17 to 23.60 ± 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged from 95 to 831 days (mean, 291.6 ± 207.2 days). (Costantini et al., 2015)

In many cases, blood free thiamine and thiamine pyrophosphate levels were within the healthy reference range.
Costantini hypothesizes that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. The symptoms may be a manifestation of mild thiamine deficiency due to a dysfunction of intracellular transport of thiamine or to structural enzymatic abnormalities.

Dr. Ron


 

Articles

High dose thiamine improves fatigue in multiple sclerosis.
            (Costantini et al., 2013c) Download
The majority of the patients with multiple sclerosis (MS) experience fatigue. Some observations indicate that fatigue and related manifestations concomitant with MS could be associated with an intracellular mild thiamine deficiency. We recruited 15 patients with MS who also experience fatigue and assessed the severity of the fatigue using the Fatigue Severity Scale. Although blood thiamine and thiamine pyrophosphate levels were within normal limit in all the patients, high-dose thiamine therapy administered orally or parenterally led to an appreciable improvement of the fatigue. The absence of apparent decrease in blood thiamine despite the presence of symptoms referable to a mild thiamine deficiency suggests that these patients may have a dysfunction of the mechanisms of intracellular transport or structural enzymatic abnormalities. The administration of large quantities of thiamine was effective in reversing the fatigue in MS, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.

High-dose thiamine as initial treatment for Parkinson's disease.
            (Costantini et al., 2013a) Download
Parkinson's disease (PD) is a systemic disease with motor and non-motor deficits. We recruited three patients with newly diagnosed PD. They were not under anti-Parkinson's therapy. Plasmatic thiamine was within healthy reference range. We performed the Unified Parkinson's Disease Rating Scale (UPDRS) and started a parenteral therapy with high doses of thiamine. The therapy led to a considerable improvement in the motor part of the UPDRS ranging from 31.3% to 77.3%. From this clinical observation, it is reasonable to infer that a focal, severe thiamine deficiency due to a dysfunction of thiamine metabolism could cause a selective neuronal damage in the centres that are typically hit in this disease. Injection of high doses of thiamine was effective in reversing the symptoms, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.


 

High-dose thiamine improves the symptoms of fibromyalgia.
            (Costantini et al., 2013d) Download
Living with fibromyalgia means living with chronic pain, fatigue, sleep disorders and other associated key symptoms. To date, pharmacotherapy generally produces modest benefits. Some observations indicate that the large majority of symptoms of fibromyalgia could be the clinical manifestation of a mild thiamine deficiency due to a dysfunction of the active transport of thiamine from the blood to the mitochondria or to enzymatic abnormalities. Between June and July 2011, we recruited three female patients affected by fibromyalgia. We proceeded with the study of the patients' history, a physical examination, an evaluation of chronic widespread pain using the Visual Numeric Scale and an evaluation of the fatigue using the Fatigue Severity Scale were also performed. The levels of thiamine and thiamine pyrophosphate in the blood were determined. After the therapy with high doses of thiamine, in the patients, there was an appreciable improvement of the symptoms.

High-dose thiamine improves the symptoms of Friedreich's ataxia.
            (Costantini et al., 2013d) Download
Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterised by progressive gait and limb ataxia, dysarthria, areflexia, loss of position sense and a progressive motor weakness of central origin. Some observations indicate that all symptoms of FRDA ataxia could be the manifestation of a thiamine deficiency because of enzymatic abnormalities. Two patients with FRDA were under rehabilitative treatment from February 2012 to February 2013. The scale for assessment and rating of ataxia was performed. The patient began an intramuscular therapy with 100 mg of thiamine every 3-5 days. Injection of high-dose thiamine was effective in reversing the motor failure. From this clinical observation, it is reasonable to infer that a thiamine deficiency due to enzymatic abnormalities could cause a selective neuronal damage in the centres that are typically affected by this disease.

Thiamine and fatigue in inflammatory bowel diseases: an open-label pilot study.
            (Costantini and Pala, 2013) Download
OBJECTIVES:  To demonstrate that fatigue and other disorders related to ulcerative colitis and Crohn's disease are the manifestation of an intracellular mild thiamine deficiency and not due to malabsorbtion, augmented requirements, or nutritional factors, and that this dysfunction is curable with high doses of thiamine administered orally or parenterally. DESIGN:  In this pilot study, we treated fatigue in eight patients with ulcerative colitis and four patients affected by Crohn's disease from January to April 2011. The patients were recruited through general practitioners' surveys and among personnel and affiliated personnel of the clinic Villa Immacolata. Fatigue was measured using the chronic fatigue syndrome scale, and the determination of thiamine and thiamine pyrophosphate levels in the blood was carried out through blood tests. The levels of thiamine and thiamine pyrophosphate in the blood were normal. All patients were assigned to receive high doses of thiamine orally. Depending upon the body weight of each patient, dosage ranged from 600 mg/day (60 kg) to 1,500 mg/day (90 kg). The chronic fatigue syndrome scale as well as thiamine and thiamine pyrophosphate levels in the blood were measured 20 days after the beginning of the therapy. RESULTS:  Ten patients out of twelve showed complete regression of fatigue, while the remaining two patients showed nearly complete regression of fatigue compared to the chronic fatigue syndrome scale scores before therapy. CONCLUSIONS:  The absence of blood thiamine deficiency and the efficacy of high-dose thiamine in our patients suggest that fatigue is the manifestation of a thiamine deficiency, likely due to a dysfunction of the active transport of thiamine inside the cells, or due to structural enzymatic abnormalities. The administration of large quantities of thiamine increases the concentration in the blood to levels in which the passive transport restores the normal glucose metabolism in all cells and leads to a complete regression of fatigue.

Thiamine and spinocerebellar ataxia type 2.
            (Costantini et al., 2013b) Download
Spinocerebellar ataxia type 2 is a genetic disorder characterised by the degeneration of the cerebellum, its connections and degeneration in brainstem areas. Some observations indicate that high doses of thiamine may lead to the partial regression of the symptoms. One patient was under rehabilitative treatment from June 2011 to July 2012. We assessed the level of fatigue using the Fatigue Severity Scale. We performed the Scale for Assessment and Rating of Ataxia and Robertson Profile for Dysarthria (Italian version). Thiamine and thiamine pyrophosphate levels in the blood were within the healthy reference range. We started a parenteral therapy with 100 mg intramuscular every 7 days. The therapy led to a partial regression of fatigue within a few days. After about 3 months, a discreet improvement of motor symptoms especially in speech was observed. The symptoms could derive from a focal thiamine deficiency that could determine a selective neuronal loss.


 

High-dose thiamine improves fatigue after stroke: a report of three cases.
            (Costantini et al., 2014) Download
BACKGROUND AND OBJECTIVES:  A previous study on fatigue and related disorders in inflammatory bowel disease, patients improved after therapy with high-dose thiamine. Chronic fatigue that accompanies inflammatory and autoimmune diseases could be the clinical manifestation of a mild thiamine deficiency, probably due to a dysfunction of intracellular transport or enzymatic abnormalities. Fatigue is a common symptom after stroke. Some studies show a severe functional effect of this symptom, as well as a high mortality rate. Necrotic cell death after cerebral ischemia triggers the activation of the immune system, followed by an inflammatory response. It is likely that fatigue related to stroke could benefit from high-dose thiamine. Consequently, the authors began treating poststroke patients with oral or parenteral high-dose thiamine. DESIGN:  Case study. MATERIALS AND METHODS:  Three patients with stroke who also experienced fatigue were recruited. Severity of the fatigue was assessed by using the Fatigue Severity Scale. Blood free thiamine and thiamine pyrophosphate levels were within the healthy reference range in all the patients. Oral or parenteral therapy with high-dose thiamine was started. RESULTS:  The therapy led to an appreciable improvement of fatigue. CONCLUSION:  This observation suggests that poststroke fatigue and related disorders could be the manifestation of mild thiamine deficiency due to a dysfunction of intracellular transport of thiamine or to structural enzymatic abnormalities.

Thiamine and Hashimoto's thyroiditis: a report of three cases.
            (Costantini and Pala, 2014) Download
OBJECTIVES:  In a previous study on fatigue and related disorders in inflammatory bowel disease (IBD), we observed that IBD patients improved after treatment with high-dose thiamine. We hypothesized that the chronic fatigue accompanying inflammatory and autoimmune diseases is the clinical manifestation of a mild thiamine deficiency that is probably due to a dysfunction of the intracellular transport or to enzymatic abnormalities. Hashimoto's thyroiditis is both a common automimmune disease and cause of hypothyroidism. Although levothyroxine, a thyroid hormone, is the treatment of choice for hypothyroidism, a significant number of patients on thyroid hormone replacement therapy report not feeling well despite having thyroid function tests within the healthy range. Based on our hypothesis, we started treating the fatigue in patients affected by Hashimoto's thyroiditis and taking a thyroid hormone with thiamine. This is a report of the outcomes of three cases in which the fatigue component reported by patients with Hashimoto's thyroiditis was treated with thiamine. DESIGN:  Three patients on thyroid hormone replacement because of Hashimoto's thyroiditis were treated for the fatigue component of the disease from May to July 2011. Fatigue was measured using the Fatigue Severity Scale. Free thiamine in the serum and thiamine pyrophosphate in red cells were tested before and after the therapy. All three patients received oral (600 mg/day) or parenteral (100 mg/ml every four days) doses of thiamine. RESULTS:  Treatment with thiamine led to partial or complete regression of the fatigue within a few hours or days. CONCLUSION:  As the administration of thiamine led to a partial or complete regression of the fatigue and related disorders, it is reasonable to infer that the administration of large quantities of thiamine restores thiamine-dependent processes. The mild thiamine deficiency suggested by fatigue and related disorders may be due a dysfunction of the intracellular transport of thiamine or to enzymatic abnormalities most likely related to the autoimmune process of the disease.

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.
            (Costantini et al., 2015) Download
OBJECTIVES:  To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). DESIGN:  Observational open-label pilot study. SETTING:  Outpatient neurologic rehabilitation clinic. PATIENTS AND METHODS:  Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age, 70.4 ± 12.9 years; mean disease duration, 7.3 ± 6.7 years). All the patients were assessed at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. RESULTS:  Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean UPDRS scores (parts I-IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10(-14), t test for paired data) within 3 months and remained stable over time; motor UPDRS part III score improved from 22.01 ± 8.57 to 9.92 ± 8.66 (p = 3.1 × 10(-22)). Some patients with a milder phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved from 53.00 ± 8.17 to 23.60 ± 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged from 95 to 831 days (mean, 291.6 ± 207.2 days). CONCLUSIONS:  Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. Thiamine could have both restorative and neuroprotective action in PD.


 

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study
            (Fancellu et al., 2015) Download
Abstract Objectives: To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). Design: Observational open-label pilot study. Setting: Outpatient neurologic rehabilitation clinic.  ...

High-Dose Thiamine as possible medical treatment for Spinocerebellar Ataxias
            (Fancellu et al., 2014) Download
From July 2012 we recruited 23 FRDA patients, 2 SCA2 patients, and 2 patients with sporadic idiopathic ataxia. All patients were treated with 100 mg thiamin i.m. twice a week. In all patients, basal levels of plasma thiamine were normal. In FRDA group, total SARA scores improved frm 26.7 to 23.5. Moreover, 13 of 17 patients, with absnce of deep tendon reflexes at baseline showed normal reflexes at one month of treatment, and swallowing improved in more than 50% of patients.

 


 

References

Costantini, A, et al. (2013a), ‘High-dose thiamine as initial treatment for Parkinson’s disease.’, BMJ Case Rep, Aug 28 PubMed: 23986125
Costantini, A and MI Pala (2013), ‘Thiamine and fatigue in inflammatory bowel diseases: an open-label pilot study.’, J Altern Complement Med, 19 (8), 704-8. PubMed: 23379830
——— (2014), ‘Thiamine and Hashimoto’s thyroiditis: a report of three cases.’, J Altern Complement Med, 20 (3), 208-11. PubMed: 24351023
Costantini, A, et al. (2014), ‘High-dose thiamine improves fatigue after stroke: a report of three cases.’, J Altern Complement Med, 20 (9), 683-85. PubMed: 25192035
Costantini, A, et al. (2015), ‘Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.’, J Altern Complement Med, 21 (12), 740-47. PubMed: 26505466
Costantini, A, et al. (2013b), ‘Thiamine and spinocerebellar ataxia type 2.’, BMJ Case Rep, Jan 10 PubMed: 23314445
Costantini, A, et al. (2013c), ‘High dose thiamine improves fatigue in multiple sclerosis.’, BMJ Case Rep, Jul 16 PubMed: 23861280
Costantini, A, et al. (2013d), ‘High-dose thiamine improves the symptoms of fibromyalgia.’, BMJ Case Rep, May 20 PubMed: 23696141
Fancellu, R, S Proietti, and M Colangeli (2014), ‘High-Dose Thiamine as possible medical treatment for Spinocerebellar Ataxias’, J Alt Comp Med, 35 S42. PubMed:
——— (2015), ‘Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study’, J Alt Comp Med, 21 (12), S81. PubMed: