Description of the condition
Tinnitus can be described as the perception of sound in the absence of external acoustic stimulation. For the patient it may be trivial or it may be a debilitating condition (Luxon 1993). The quality of the perceived sound can vary enormously from simple sounds such as whistling or humming to complex sounds such as music. The patient may hear a single sound or multiple sounds. Tinnitus may be perceived in one or both ears, within the head or outside the body. The symptom may be continuous or intermittent. Tinnitus is described in most cases as subjective - meaning that it cannot be heard by anyone other than the patient. While, for the patient, this perception of noise is very real, because there is no corresponding external sound it can be considered a phantom, or false, perception. Objective tinnitus is a form of tinnitus which can be detected by an examiner, either unaided or using a listening aid such as a stethoscope or microphone in the ear canal. This is much less common and usually has a definable cause such as sound generated by blood flow in or around the ear or unusual activity of the tiny muscles within the middle ear. Tinnitus may be associated with normal hearing or any degree of hearing loss and can occur at any age.
It is important to distinguish between clinically significant and non-significant tinnitus (Davis 2000) and several different classifications have been proposed (Dauman 1992; McCombe 2001; Stephens 1991). Dauman, for example, makes a distinction between 'normal' (lasting less than five minutes, occurring less than once a week and experienced by most people) and 'pathological' tinnitus (lasting more than five minutes, occurring more than once a week and usually experienced by people with hearing loss).
Almost any form of disorder involving the outer, middle or inner ear or the auditory nerve may be associated with tinnitus (Brummett 1980; Shea 1981). However, it is possible to have severe tinnitus with no evidence of any aural pathology. Conversely, tinnitus can even exist without a peripheral auditory system: unilateral tinnitus is a common presenting symptom of vestibular schwannomas (acoustic neuromas), which are rare benign tumours of the vestibulo-cochlear nerve. When these neuromas are removed by a translabyrinthine route, the cochlear nerve can be severed. Despite the effective removal of their peripheral auditory mechanisms, 60% of these patients retain their tinnitus postoperatively (Baguley 1992). This suggests the fundamental importance of the central auditory pathways in the maintenance of the symptom, irrespective of trigger.
Many environmental factors can also cause tinnitus. The most relevant and frequently reported are:
Over 50 years ago, Heller and Bergman demonstrated that if 'normal' people (with no known cochlear disease) were placed in a quiet enough environment, the vast majority of them would experience sounds inside their head. They concluded that tinnitus-like activity is a natural phenomenon perceived by many in a quiet enough environment (Heller 1953).
Mazurek has shown that pathologic changes in the cochlear neurotransmission, e.g. as a result of intensive noise exposure or ototoxic drugs, can be a factor in the development of tinnitus (Mazurek 2007).
In the 'neurophysiological model' of tinnitus (Jastreboff 1990; Jastreboff 2004) it is proposed that tinnitus results from the abnormal processing of a signal generated in the auditory system. This abnormal processing occurs before the signal is perceived centrally. This may result in 'feedback', whereby the annoyance created by the tinnitus causes the individual to focus increasingly on the noise, which in turn exacerbates the annoyance and so a 'vicious cycle' develops. In this model tinnitus could therefore result from continuous firing of cochlear fibres to the brain, from hyperactivity of cochlear hair cells or from permanent damage to these cells being translated neuronally into a 'phantom' sound-like signal that the brain 'believes' it is hearing. For this reason tinnitus may be compared to chronic pain of central origin - a sort of 'auditory pain' (Briner 1995; Sullivan 1994).
The relationship between the symptom of tinnitus and the activity of the prefrontal cortex and limbic system has been emphasised. The limbic system mediates emotions. It can be of great importance in understanding why the sensation of tinnitus is in many cases so distressing for the patient. It also suggests why, when symptoms are severe, tinnitus can be associated with major depression, anxiety and other psychosomatic and/or psychological disturbances, leading to a progressive deterioration of quality of life (Lockwood 1999; Sullivan 1989; Sullivan 1992; Sullivan 1993).
Epidemiological data reports are few. The largest single study was undertaken in the UK by the Medical Research Council Institute of Hearing Research and was published in 2000 (Davis 2000). This longitudinal study of hearing questioned 48,313 people; 10.1% described tinnitus arising spontaneously and lasting for five or more minutes at a time and 5% described it as moderately or severely annoying. However, only 0.5% reported tinnitus having a severe effect on their life. This is another of the paradoxes of tinnitus: the symptom is very common but the majority of people who experience it are not particularly concerned by it. These figures from the UK are broadly consistent with data collected by the American Tinnitus Association (ATA) which suggest that tinnitus may be experienced by around 50 million Americans, or 17% of the US population (ATA 2004). Data also exist for Japan, Europe and Australia (Sindhusake 2003), and estimates suggest that tinnitus affects a similar percentage of these populations, with 1% to 2% experiencing debilitating tinnitus (Seidman 1998). The Oregon Tinnitus Data Archive (Oregon 1995) contains data on the characteristics of tinnitus drawn from a sample of 1630 tinnitus patients. The age groups with the greater prevalence are those between 40 and 49 years (23.9%) and between 50 and 59 years (25.6%).
Olszewski showed in his study that the risk of tinnitus increases in patients over 55 years old who suffer from metabolic conditions and cervical spondylosis (Olszewski 2008).
Firstly a patient with tinnitus may undergo a basic clinical assessment. This will include the relevant otological, general and family history, and an examination focusing on the ears, teeth and neck and scalp musculature. Referral to a specialist is likely to involve a variety of other investigations including audiological tests and radiology. Persistent, unilateral tinnitus may be due to a specific disorder of the auditory pathway and imaging of the cerebellopontine angle is important to exclude, for example, a vestibular schwannoma (acoustic neuroma) - a rare benign tumour of the cochleo-vestibular nerve. Other lesions, such as glomus tumours, meningiomas, adenomas, vascular lesions or neuro-vascular conflicts, may also be detected by imaging (Marx 1999; Weissman 2000).
At present no specific therapy for tinnitus is acknowledged to be satisfactory in all patients. Many patients who complain of tinnitus, and also have a significant hearing impairment, will benefit from a hearing aid. Not only will this help their hearing disability but the severity of their tinnitus may be reduced.
A wide range of therapies have been proposed for the treatment of tinnitus symptoms. Pharmacological interventions used include cortisone (Koester 2004), vasodilators, benzodiazepines, lidocaine and spasmolytic drugs. The use of anticonvulsants in treating tinnitus was found to be ineffective in a Cochrane review, and 18% of patients experienced side effects (Hoekstra 2011). Antidepressants are commonly prescribed for tinnitus. However, two reviews (Baldo 2012; Robinson 2007) showed that there is no indication that tricyclic antidepressants have a beneficial effect.
Hyperbaric oxygen therapy (HBOT) can improve oxygen supply to the inner ear which, it is suggested, may result in an improvement in tinnitus, however a Cochrane review found insufficient evidence to support this (Bennett 2012).
Studies have been carried out into the effect of cognitive behavioural therapy (CBT) on tinnitus (Andersson 1999). Another Cochrane review has shown that CBT can have an effect on the qualitative aspects of tinnitus and can improve patients' ability to manage the condition (Martinez-Devesa 2010).
Other options for the management of patients with tinnitus include transcranial magnetic stimulation (Meng 2011), tinnitus masking (use of 'white noise' generators) (Hobson 2012), music therapy (Argstatter 2008), reflexology, hypnotherapy and traditional Chinese medicine (TCM), including acupuncture (Li 2009).
Description of the intervention
Extracts of Ginkgo biloba leaves have been used for medicinal purposes for at least 5000 years in China, where they form an important component of the traditional Chinese pharmacopoeia (a book which lists drugs and instructions for their use). More recently the extracts have been used in Western countries. In several countries, including the USA, Canada and the UK the extracts are widely available in the form of non-prescription food supplements. In parts of Europe, particularly France and Germany, the extract is registered as a drug and is consistently one of the most commonly prescribed medications.
There are several components in the available preparations. A purified and enriched liquid extract is prepared from dried leaves of the maidenhair plant. The liquid extract is dried to give one part extract from 50 raw leaves. The most important active chemical compounds fall into two categories: flavonoids (ginkgo-flavone glycosides) and terpenoids (ginkgolides A, B, C, J and bilobalide). Ginkgolides appear to be unique to Ginkgo biloba and have not been isolated from any other plant species. There are several commercially available preparations but the four that have been used in most trials of Ginkgo biloba contain standardised amounts of these substances. EGb761 (Tebonin®, Tanakan®, Rökan®) contains 24% ginkgo-flavone glycosides and 6% terpenoids. LI 1370 (Kaveri®) contains 25% ginkgo-flavone glycosides and 6% terpenoids (Blumenthal 1998). Although the quantities are standardised the manufacturing process is different and the ratio of active ingredients within each sub-class may be different. There is no standardisation for food supplement preparations.
Several mechanisms of action of Ginkgo have been proposed in the light of the many active ingredients. Human, animal and in vitro studies (Kleijnen 1992) have suggested the following effects:
A vasoregulatory effect (altering the tone of blood vessels) promoting increased blood flow. A double-blind randomised trial (Koltringer 1989) in 30 patients of 200 mg EGb 761 daily for four days showed increased skin perfusion (greater blood flow) with reduced blood viscosity and elasticity compared to control. Another small randomised trial demonstrated increased nail-fold capillary blood flow and decreased erythrocyte (red blood cell) aggregation (Jung 1990).
Antagonism of platelet activating factor (PAF). This effect is specific to the ginkgolides (predominantly B). PAF causes platelet (a blood constituent involved in blood clot formation) aggregation, neutrophil degranulation (activation of immune cells within the blood stream) and oxygen radical production. Ginkgolides appear to protect against the effects of hypoxic brain injury from cerebral ischaemia (permanent brain damage caused by insufficient blood and oxygen supply) in laboratory animals (Braquet 1991; DeFeudis 1991a).
Changes in neuron (nerve cell) metabolism in animal studies (DeFeudis 1991b). In elderly patients with cerebral insufficiency (see definition below) beneficial EEG (an electroencephalogram which measures patterns of the brain's electrical activity) changes have been reported (Hofferberth 1989; Hofferberth 1991).
Prevention of cell membrane damage by free radicals. Ginkgo extracts have free radical scavenging properties as demonstrated by in vitro studies (Pincemail 1989).
Ginkgo has been most widely prescribed as a treatment for peripheral vascular disease (insufficient blood flow to the limbs because of damage to blood vessels) and cerebral insufficiency. Cerebral insufficiency is difficult to define precisely but conventionally refers to a syndrome including one or more of: concentration difficulties; loss of memory; confusion; lack of energy; tiredness; reduced physical performance; depressive mood; anxiety; dizziness; headache; tinnitus and absent mindedness. Experimental evidence for its effects on cognitive functions in various forms of dementia are presented by several authors (Hopfenmuller 1994; Kleijnen 1992; Knipschild 1994; Oken 1998; Soholm 1998).
The most commonly reported side effect of Ginkgo biloba is mild gastrointestinal disturbance (e.g. stomach pains, change in bowel habit). Serious side effects are rare, but include bleeding problems, interaction with anticoagulant medication and seizures (Ernst 2002).
There are a number of reports in the literature suggesting that Ginkgo biloba may be effective in the management of tinnitus (Artieres 1978; Coles 1988; Gananca 1986; Sprenger 1986; Ziegler 1969). A previous systematic review identified only a small number of randomised controlled trials, most of which were of low methodological quality. Only one trial appeared methodologically sound, and reported a small effect of Ginkgo biloba in reducing the perceived loudness of tinnitus (Ernst 1999). However, there also appears to be a strong placebo effect in tinnitus management. Duckert et al (Duckert 1984) demonstrated the importance of this. They performed an initial double-blind randomised trial of the effects of lignocaine (a local anaesthetic) on tinnitus sufferers; 25% of patients in the control group reported a significant change in their tinnitus. However, following completion of the trial the 25 patients who had received the 'placebo' injection of saline (salty water) were contacted and offered the 'real' treatment, although once again received only a saline injection. Of the 20 patients who received this second injection eight (40%) reported a change of greater than 25% in their tinnitus severity (six patients improved, two deteriorated).