Flammer syndrome and TSS, a Kampo medicine
Flammer syndrome is a primary vascular dysregulation that is associated with characteristic
clinical symptoms and examination findings [1, 2]. Although most patients with Flammer
syndrome do not develop unrelated or distinct disease states, normal-tension glaucoma
(NTG) has been reported as an associated condition [1, 2]. Konieczka et al. hypothesized
that Flammer syndrome is associated with multiple sclerosis and other diseases [1–3]
and suggested that treatment for Flammer syndrome may be prophylactic against related
diseases that result from vascular dysregulation [3]. Currently, standardized diagnostic
criteria or treatment protocols for Flammer syndrome have not been established [1].
However, based on traditional Japanese (Kampo) medicine, the formula tokishakuyakusan
(TSS) could potentially affect Flammer syndrome.
Kampo medicine was introduced to Japan about 1500 years ago and was derived from traditional
Chinese medicine. Since then, Kampo medicine has been evolving according to Japanese
character, physical constitution, environment, and circumstances. In Japan, TSS (Danggui
Shaoyao San in Chinese) is primarily administered to women with gynecological disorders
who experience a cold sensation in their extremities [4, 5]. According to the theory
of Kampo medicine, TSS remedies blood deficiencies and improves blood circulation,
as well as alleviates abnormal fluid retention in the body. Previous studies have
indicated that TSS improves iron deficiency anemia [6–8] and leukorrhagia [9]. Moreover,
it had been reported that TSS may increase cerebral blood flow [10, 11], reduce oxidative
stress in the central nervous system [12], inhibit platelet aggregation [13], regulate
thrombosis in endothelial cells [14], and relax vascular smooth muscle [15].
Table 1 shows the comparative clinical symptoms and signs between Flammer syndrome
and the indications for use of TSS. The major characteristics of Flammer syndrome,
which are more common in women, including low body mass index, cold extremities, and
low blood pressure, are similar to the indications for use of TSS. In addition, other
features that are not identified are described in Table 1.
Table 1
Comparative characteristics of clinical symptoms and signs in patients with Flammer
syndrome and indications for the use of tokishakuyakusan
Flammer syndrome
Indications for TSS use
Common features
Common in women
Common in women
Low body mass index
Low body mass index
Cold extremities
Cold extremities
Low blood pressure
Low blood pressure
Dizziness
Dizziness
Reduced feeling of thirst
With or without thirst
Feeling cold
Feeling cold
Headaches
Headaches
Tinnitus
Tinnitus
Other features
Migraines
Anemia
Long sleep onset time
General fatigue
Increased pain sensitivity
Edema
Increased drug sensitivity
Numbness of extremities
Good smell perception
Soft stool
Reversible skin blotches
Menstrual irregularity
Perfectionism
Dysmenorrhea
Vaginal discharge
Flammer syndrome and NTG
NTG is a major comorbid disease of Flammer syndrome [1, 2]. In patients with Flammer
syndrome, there is an increased rigidity of retinal vessels and impaired autoregulation
of the ocular blood flow. In patients with comorbid glaucoma and Flammer syndrome,
additional signs are observed including disc hemorrhages, increased retinal venous
pressure, and activation of retinal astrocytes [1, 2]. Although glaucoma is one of
the leading causes of vision loss, reduction of intraocular pressure is the only proven
approach to treatment. However, reducing the intraocular pressure alone does not prevent
the progression of visual field loss in all patients, since impaired ocular circulation
can also contribute to the progression of glaucoma [16, 17].
Potential of TSS for treatment of NTG and Flammer syndrome
Recently, we reported that TSS increases ocular blood flow in healthy participants
without decreasing blood pressure [18]. We are currently investigating whether TSS
improves ocular blood flow in patients with NTG. Herein, we describe a representative
case of a 42-year-old man with migraine and cold sensitivity who was diagnosed as
having NTG in October 2013. His intraocular pressure was 16/16 mmHg without treatment.
Figure 1 shows a photograph of the fundus at the patient’s first visit to our hospital,
which indicates enlarged optic nerve cupping and retinal nerve fiber layer defects.
Visual field defects were also detected in this patient (Fig. 2). We administered
TSS extract granules (Tsumura and Co., Tokyo, Japan), at 7.5 g/d for 33 weeks, from
February to September 2014. Following TSS treatment, the major symptoms of Flammer
syndrome in the patient including sensitivity to cold and migraine frequency clearly
improved. Figure 3 shows the changes in ocular blood flow measured using laser speckle
flowgraphy of the optic nerve head. The mean blur rate, which is the relative ocular
blood flow in arbitrary units, improved after 9 and 33 weeks, as compared to the pre-treatment
measurement. The mean changes in visual field during treatment for TSS were +0.07 db/year
in the right eye and −0.25 db/year in the left eye. The ocular pressure of the patient
before TSS treatment, after 9 weeks, and after 33 weeks were 16, 14, and 14 mmHg in
the right eye and 17, 14, and 14 mmHg in the left eye, respectively. Blood pressure
and pulse rate at the same time intervals were 108/75/89, 103/69/81, and 106/72/80,
respectively.
Fig. 1
Fundus photograph of a representative case (right/left). Retinal layer defects were
observed (yellow arrows)
Fig. 2
Visual field examination (right/left). A Humphrey 24-2 visual field test of the patient’s
right eye shows an inferior-nasal defect. In addition, the visual field of the left
eye shows inferior and upper-nasal defects associated with NTG
Fig. 3
a Laser speckle flowgraphy images of the patients’ ocular circulation. The mean blur
rate (MBR) images of the entire optic nerve head (ONH) before administration and at
9 and 33 weeks of TSS treatment (both eyes) (i): Composite blood flow map of the ONH
before the administration of TSS. The MBR values are 12.5 (right eye) and 14.3 (left
eye) (ii): Composite blood flow map of the ONH at 9 weeks of TSS treatment. The MBR
values are 14.0 (right eye) and 16.8 (left eye) (iii): Composite blood flow map of
the ONH at 33 weeks of TSS treatment. The MBR values are 14.5 (right eye) and 17.1
(left eye). b Dynamic changes in ocular blood flow (OBF) in response to TSS treatment.
The rates of changes in ocular blood flow improved after 9 and 33 weeks, as compared
to the pre-treatment measurements in both eyes
Discussion
This case highlights that TSS can improve both the clinical symptoms of Flammer syndrome,
as well as ocular blood flow, and prevent the progression of NTG. Visual field defects
were not progressive during the entire TSS treatment duration. No change in the hemodynamics
of the case due to the TSS treatment was found and was consistent with the result
of our previous study [18]. We are currently conducting a study on a larger population
to confirm these findings.
Impaired regulation of ocular blood flow is considered to be one of the causes of
NTG. It has been reported that plasma endothelin-1 (ET-1) levels of NTG patients are
significantly higher than those of healthy participants [19]. TSS extract granules
weighing 7.5 g produced by Tsumura and Co. (Tokyo, Japan) contained 4.0 g Paeoniae
Radix, 4.0 g Atractylodis Lanceae Rhizoma, 4.0 g Alismatis Rhizoma, 4.0 g Poria Sclerotium,
3.0 g Cnidii Rhizome, and 3.0 g Angelicae Radix. A previous study has reported that
Alismatis Rhizoma and Poria Sclerotium inhibit the synthesis and expression of ET-1
in the glomeruli of nephritic rats [20]. Moreover, some studies have shown that TSS
decreases ET levels in the ovary of rats but do not affect plasma ET levels [21, 22].
These studies suggest that TSS may inhibit the production of ET-1 at peripheral tissues
without affecting ET-1 levels in plasma. However, no studies have evaluated the effects
of TSS on ET-1 levels of retinal tissue and optic nerve head. Further study is needed
to investigate the mechanism of the effect of TSS on ocular blood flow.
Recently, the concept of suboptimal health status (SHS) was advocated from the perspective
of predictive, preventive, and personalized medicine [23, 24]. SHS is characterized
by ambiguous health complaints and recognized as a subclinical, reversible stage of
chronic disease. This perspective is highly associated with Flammer syndrome, which
may contribute to the progression or development of chronic diseases.
Limitation
The findings described herein are based on a single case; additional data from a case
series are required to validate the efficacy of TSS. We have not yet investigated
whether TSS statistically improves the clinical symptoms and signs of Flammer syndrome.
Other common features may exist between Flammer syndrome and patients for whom TSS
is indicated. Moreover, there are no reports on the frequency of Flammer syndrome
in Japanese NTG patients. Further research is needed to determine the relationship
between Flammer syndrome and TSS.
Conclusion
Several common clinical features exist between subjects with Flammer syndrome and
those for whom TSS is indicated. If TSS significantly increases the ocular blood flow
in patients with NTG, TSS would be a potential treatment for patients with comorbid
normal tension glaucoma and Flammer syndrome. Kampo medicine has been used for disease
treatment, as well as for minor physical and mental health conditions. TSS may have
a prophylactic effect in patients with Flammer syndrome who are at risk of developing
related diseases.