Meniere's Disease and Syndrome
Vertigo is Curable
@Mitsuo Shichinohe, M.D., Ph.D
@Sapporo Towa Hospital
@30-18-8-1, Kita, Higashiku, Sapporo, Hokkaido,
@E-mail : firstname.lastname@example.org
@A mail from U.S.A.
@Date : 5 Nov. 2003
@Sex : Male
@Age : ?
@Address : WA. U.S.A.
@The name of disease : Meniere's disease
@Effect : !!!!!!
@Dr. Mitsuo Shichinohe
@I have had Meniere's for 3 years and I just found out about your research two weeks ago. My doctor agreed it let me try it out so I took Famvir(500mg three times a day) last week and I have been symptom free for 6 days now !!!!!!
@So I may be premature in thanking you, but I want to say THANK YOU! THANK YOU! THANK YOU! THANK YOU! for your research. I feel like it has saved my life.
@Forever indebted to you.
ml @q @@Chinese Medical Association-Taipein
@2005 Annual Meeting of Chinese Medical Association
Experience of Antiviral Drug Treatment for Menierefs Syndromes
Mitsuo Shichinohe,M.D.,Ph.D. Director, Shichinohe Clinic, Sapporo, Japan
Despite a variety of proposed causes of Menierefs syndromes ( MS ), such as allergy, autonomous nerve disorders, stresses, etc., the real etiology is still indefinite. Viral etiology has also been suggested, however, no trial of anti-viral treatments has been reported except my previous papers. The resemblance of the process and symptoms of MS to those of Bellfs palsy and Ramsay- Hunt syndromes which proved to be caused by Herpes virus infection, led me to the idea that the majority of MS is caused by viral infection, probably Herpes virus infection in vestibulocochlear nerve.
I attempted to administer Acyclovir (ACV) to treat patients with MS and could obtain a dramatic therapeutic effect. In the first clinical series (1990~1997), 301 patients were administered ACV with the dose of 2,000mg/day for 2 weeks. The effectiveness was evaluated mainly by symptoms of patients with a definite criterion. More than 80% of MS patients treated with ACV were evaluated as gmarked effecth or geffectiveh. It was quite impressive that ACV was very effective to vertigo, especially for fresh cases. Most of the patients treated, revealed improvement of clinical symptoms 3-7 days after the administration of ACV. After 10 to 14 days, the patients recovered rapidly and their clinical symptoms disappeared. Side effects of ACV were extremely rare in this series. Follow-up studies of a long period could be performed in many patients. Recurrences were often observed. These cases were re-treat with ACV and could be cured with lowered doses of ACV usually making interval of recurrence longer.
In the second series (2003-2004), several hundred patients with MS were treated with ACV or Valacyclovir. The effectiveness was evaluated by the same criteria as the first series referring AAO-HNS. The results were essentially the same as in the first series. Since 1991, about 3,000 patients with MS have been treated with ACV or Valacyclovir in my clinic, showing the same effectiveness.
Serum antibody to HSV-1 and VZV were determined in patients with MS, however, so far, no significant difference among patients with various symptoms. In randomly selected 70 MS cases, HSV-1 and VZV-DNA were investigated with PCR. Frequency of viral DNA detection in MS cases was not high, while no viral DNA was found in control cases. No significant correlation was found among symptoms of virus-detected and ?non-detected cases.
mAntiviral Drug Treatment for Menierefs Diseasen
Mitsuo Shichinohe, M.D.,Ph.D Director, Shichinohe Clinic, Sapporo, Japan
PD Definition of Menierefs Disease
Menierefs disease (MD) is defined as the idiopathic syndrome of endolymphatic hydrops. Itfs symptom is characterized by spells of vertigo, tinnitus, hearing loss, and a sensation of aural fullness. Detailed definition is described by the American Academy of Otolaryngology- Head and Neck Surgery (AAO-HNS) guidelines (1). In this article, the author defines MD as the disease with symptoms of vertigo, ear tingling (tinnitus aurium), and impaired hearing. Most of the patients listed in this study was diagnosed by the specialists of otolaryngology and the author accepted the diagnosis. It includes Menierefs syndrome (MS), which may be MD but cannot completely exclude other basic diseases, according to the specialists of otolaryngology. Neither MD nor MS has been the target of the treatment by antiviral drugs.
2. Viral Theory of Menierefs Disease
The pathogenesis of Menierefs disease (MD) has remained controversial since 1900s. Many investigators have recognized hydrops or fibrosis of endolymphatic sac of the inner ear as a pathologic feature associated with MD (2,3). Vestibular ganglia have also been postulated as the target tissue of MD (4,5). A number of theories for development of MD have been presented such as allergy, disorder of the autonomic nervous system, autoimmunity, stress, etc.
Viral infection has also been suggested. By immunological techniques, Williams, et al (6) found significant elevations of both humoral and cellular immune responses to viral antigens of herpes simplex (HSV-1), varicella-zoster (VZV), etc. Bance and Rutka (7) reported a case history of a patient who initially had an idiopathic facial palsy that years later developed into a spectrum of vestibular dysfunction associated with the clinical stigmata of herpes zoster. Based on this case and reviewing previous reports, they postulated that Bellfs palsy and other inner ear disorder might have a common underlying viral etiology involving multiple cranial nerves. Serum antibodies in patients with MD were reported using various immunologic techniques such as enzyme-linked immunosorbent assay (8), radioallergosorbent test (9). However, it might be rather difficult to detect immune reactions to viral infection in the serum of patents with MD, which may affect a local lesion in the inner ear. Arnold and Niedermeyer (10) detected IgG antibodies to HSV in the serum and perilymph of patients with MD collected during therapeutic vestibulotomy.. Compared with the corresponding serum sample, the perilymph from the patients with MD showed a higher level of specific anti-HSV IgG. The results supported the hypothesis that HSV might play an important role in the pathogenesis of MD.
Takahashi, et al (11), examined the existence of HSV-1 or VZV DNA by nested polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC) of patients with MD. They detected HSV-1 or VZV DNA in PBMC of three of 28 patients, but detected in none of the control group. Vrabec (5) investigated vestibular ganglia obtained from archival surgical pathology specimen from patients with Menierefs disease undergoing vestibular neurectomy. Using nested PCR HSV DNA was more commonly detected in vestibular ganglia of patients with MD than the general population.
These studies of immunology and molecular biology may provide supportive evidence for a viral etiology of MD.
3. Experience of Antiviral Drug Treatment for Menierefs Disease.
Treatment for MD have generally centered to improve symptoms, for example, diuretics, vasodilatators, steroids, other chemicals, surgical labyrinthectomy, endolymphatic shunt, intratympanic gentamycin treatment, etc. However, none of these treatments have been decisively effective.
@@@As described above, virus etiology, especially HSV-infection, of MD (including MS) have been postulated by a considerable number of investigators, however, no trial of antiviral treatments have been reported except the authorfs previous papers (12-14) and one paper (15) recently published. Therefore, the author will describe his own experience of antiviral treatments for MD.
More than fifteen years, the author has independently had the idea that MD is
developed by HSV infection in the inner ear. The process of MD resembles that of a latent infection and recurrence in herpes labialis and herpetic gingivostomatitis and time-course of the symptoms of MD is similar to latent virus that reactivates, causes inflammation and then returns to latent status. Bellfs palsy and Ramsay-Hunt syndrome are now considered to be involved by HSV infection in the facial nerve and VZV infection in the trigeminal nerve, respectively. For these diseases, Acyclovir (ACV) is commonly used. HSV and VZV may invade other cranial nerves, such as vestibulocochlear nerve. As Bance and Rutka (7) postulated, a number of inner ear disorders might have a common underlying viral etiology with facial palsy showing a spectrum of vestibular dysfunction. The use of antiviral agents has the potential to treat one possible agent inducing MD and provide more than symptomatic relief. Based on this idea, the author has administered ACV to patients with MD. Since 1991, about 3000 patients with MD have been treated with ACV or Valaciclovir in the authorfs clinic, showing almost the same effectiveness. In this article, experience in the first series of 301 cases will be mainly described, second series of 574 cases will be also reported and both series will be compared.
@@@@2) Observations of the First Series
@@@@ Three hundred and one patients who visited Shichinohe Clinic, between 1990-1997, with symptoms of vertigo, ear tingling and impaired hearing were studied. In this study, the author accepted the test results and diagnoses of specialists of otolaryngology, neurology and neurosurgery, where the patients experienced such test as CT, MRI, intelligence tests, psychoanalyses, etc, except 10 cases which the author diagnosed according to the typical clinical symptoms of the patients. Out of 301 cases, 135 were diagnosed as MD, 99 as Menierefs syndrome (MS), 52 as vestibular dysfunction and 15 as others. These diagnoses were made mainly by the otolaryngologists, however, it may be possible that the patients diagnosed as MD, MS and vestibular dysfunction were affected by the same pathologic agents. Ninety-six were male ranging from 13 to 81 years of age and 205 were female ranging from 19 to 84 years of age. Duration of the disease (the period between the first attack and the administration of ACV) varied from 1-20 days for the patients with first attack to 1-30 years for the chronic patients who had repeated attacks, exacerbation, recurrences and partial remissions.
b) Treatment with ACV
The dosage and the duration of administration of ACV were determined in accordance with the treatment of herpes simplex, genital herpes or herpes zoster. Patients diagnosed as MD, MS or vestibular dysfunction were usually administered ACV with the dose of 2,000mg/day for 2 weeks. Patients whose body weight was less than 50kg were given less dose of ACV. This dose seems appropriate considering the clinical results and in the 15 years experience of the author. No serious adverse events were observed.
c) Evaluation of effectiveness of the treatment
The randomized well-controlled study should be required to determine the effectiveness of the new trial of treatment for a disease. However, the author could not carry out a double-blinded controlled study in his private clinic. A guideline for evaluating improvement of dizziness, hearing and equilibrium in MD (AAO-HNS criteria) has been reported(1), however, assessment of hearing loss could not always be made for all of the patients, In this study, the author used his own criteria. The process of the disease was recorded in detail in the records of the patients. The subjective symptoms were told and described by the patients themselves and objective findings by the family members and recorded by the author. Special attention was paid to frequency and severity of spells of vertigo, intensity of tinnitus, which were described by the patients, referring to AAO-HNS criteria. Many patients were sent to otolaryngologists and examined with audiogram tests.
Effectiveness of the treatment was evaluated by the improvement of symptoms (frequency and severity of spells of vertigo, intensity of tinnitus and hearing disorder) by the ACV treatment. The results were described as follows; Marked effect; vertigo and tinnitus completely disappeared, effective: vertigo disappeared, tinnitus and hearing improved, Unclear effect: vertigo and tinnitus improved, hearing not improved, No effect: vertigo, tinnitus and hearing not improved. Not evaluatable: no follow-up information was obtained. These criteria are clear to judge and seem to work well.
d) Results of ACV treatment. (Table)
Out of 301 cases treated with ACV, 250 cases were evaluatable. Fifty one patients did not contact with doctors after the treatment and were non-evaluatable. Eight nine cases showed g marked effecth and 116 cases were g effectiveh, indicating total 205 effective cases out of 250 evaluatable cases (205/250, 82.0%). Twenty-four cases were g unclear effect g (24/250, 9.6%). Only 21 cases (21/250, 8.4%) were g no effecth. (Table)
About the same frequencies of g marked effect g plus geffectiveh were obtained in patients diagnosed as MD (94/114, 82.5%), MS ( 69/80, 85.0% ) and vestibular dysfunction ( 41/46, 89.1% ), indicating the existence of similar causes among cases diagnosed differently.
It was quite impressive that ACV was extremely effective to vertigo. Relatively smaller effects were observed for hearing. Most of the patients treated revealed improvement of clinical symptoms 3-7 days after the administration of ACV. After 10 to 14 days, many patient rapidly recovered and clinical symptoms disappeared.
There was a significant relationship between effectiveness of ACV therapy for MD and duration of the disease. The ACV treatment was more effective for patients with shorter duration of the disease from onset than for patients with longer duration. In other words, the longer duration the cases had, the more number of ineffective cases increased. Cases with duration of less than 6 months included 43 cases (95.6%) out of 45 cases of gmarked effect g plus geffectiveh, whereas cases with duration of more than 10 years revealed the increase of ineffective cases showing 19 cases (28.3%) out of 67 cases of gunclear effecth plus gno effecth.
Recurrences were often observed. Out of 250 effective cases, 39 cases (19.0%) re-visited the authorfs clinic having recurrences in the period of 4-24 months after the ACV treatment but they usually cured by ACV treatment with lower doses (less than half of the first administration of ACV) within shorter period (less than half period of the first ACV treatment). The second recurrence, if it occurs, is usually delayed about twice longer period compared to the first recurrence. If MD would be caused by HSV, it should be natural to presume recurrences occur. In the case of HSV infection, it is known that re-treatment with ACV make the interval of recurrences longer or prevent recurrences for several years. It is confirmed that the same is true in ACV-therapy of MD.
@@@3) Observation of the second series
In the second series (2003-2004), 574 patients with MD were treated with ACV or Valaciclovir. Four hundred seventy-six patients were entered for evaluation (Table). The effectiveness was evaluated by the same criteria as the first series referring AAO-HNS Guideline. The results were essentially the same as in the first series as shown in the Table. The percentage of g marked effect g plus geffectiveh was 81.1% and g no effect g was 8.0%, which was confirmed almost the same as in the first series. Percentage of effective cases of patients diagnosed as MD, MS or vestibular dysfunction was 85% (84/99), 81% (76/93) or 88% (56/64), respectively, suggesting these categories of disease might be induced by a common causative factor (patients in 2003). Recurrences were 180 cases (47%) out of 386 effective cases within 16 months after the treatment. The higher frequency of recurrences might be ascribed to that the patients realized the ACV effect and visited the authorfs clinic, wishing to be re-treated with ACV. Generally speaking, recurrence of the disease of the patients treated with ACV or Valaciclovir could be cured by about half doses making the intervals of the spell twice longer.
@@@ Since 1991, almost 3000 patients with MD have been treated with ACV or Valaciclovir in the authorfs clinic showing about the same effectiveness as described in the first series as shown in the Table.
4) Immunological and Molecular Biological investigation of the Present Cases
The dramatic effects of the treatment with ACV for MD strongly suggested that MD is caused by the viral infection. Judging from the pharmacological effect of ACV, HSV and VZV are suggested to be causative agents. Serum antibody to HSV and VZV were determined in patients with MD, however, so far no significant difference among patients with various symptoms. As described above, Takahashi, et al (10) examined the patients with MD in the authorfs clinic, and detected HSV or VZV DNA in PBMC using nested PCR. Though the frequency of HSV or VZV detection was low in the patients with MD, these findings may imply that reactivation of HSV-1 or VZV may be associated with the development of some cases of Menierefs disease. In randomly selected 70 MD cases in the authorfs clinic, HSV-1 and VZV DNA in PBMC were investigated with PCR by Light Cycler.. Frequency of viral DNA detection in MD cases was not high, while no viral DNA was found in control 100 cases. No significant correlation was found among symptoms of virus-detected and non-detected cases. Difficulties to detect the involvement of HSV might be attributed to that the lesion of MD is restricted locally in inner ear.
5) Hope to Antiviral Treatment for Menierefs Disease
In spite of a considerable amount of suggestions of the viral etiology of MD, there have been no reports of antiviral drug treatment for MD except the authorfs previous papers (11-14) and one paper (15) recently published. Derebery, et al (15) conducted a randomized, double-blinded placebo-controlled trial of Famciclovir (anti-herpetic drug) for symptoms MD diagnosed according to AAO-HNS guidelines. Twelve subjects in the treatment and 11 in the placebo arm were examined. Effectiveness was assessed by AAO-HNS guidelines. Twenty-five percent of the treatment (250 mg, 3 times a day for 10 days, followed by 250mg twice a daily for 80 days) group and 18% of the placebo group showed a reduction in number of spells. This difference was not statistically significant and no dramatic effects of Famciclovir were found on vertigo or dizziness. They concluded that Famciclovir might suppress the fluctuation of hearing in MD but had minimal effects on vertigo or dizziness symptoms in this study, and further studies required to be conducted to determine the effects of antiviral medications. This study was conducted by well-controlled design and should be evaluated highly, since this was the first paper dealing with antiviral drug therapy for MD except the authorfs previous papers. The results were rather disappointing, however, these did not mean to deny the effectiveness of antiviral drug on MD. There are many points, which should be considered to reach the right and reasonable evaluation of antiviral treatment of MD. The author believes that evaluation of effectiveness of anti-MD drug should be the same as that of acute or chronic infectious diseases, just like judgment of effects of antibiotics on pneumonia. From this viewpoint, AAO-HNS guideline seems inappropriate as far as evaluation of effectiveness of treatment for MD concerned. Therefore, selection of cases entered in evaluation and criteria of improvement of symptoms should be changed. The author sincerely hope that many investigators will try to prove the viral theory of MD and many clinicians will conduct antiviral treatment of MD and evaluate the real effectiveness of the antiviral drug therapy.
Lastly, let the author transcribe here a e-mail from a patient (female, age not known) who was treated with Famciclovir in US.
g----- I have had Menierefs for 3 years and I just found out about your research two weeks ago. My doctor agreed to let me try it out so I took Famvir (500mg three times a day) last week and I have been symptom free for 6 days now !!!!!
So I may be premature in thanking you, but so happy to be not dizzy or nauseous that I want to say THANK YOU ! THANK YOU! THANK YOU! THANK YOU! for your research. I feel like it has saved my life.
Forever indebted to you,
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2 Wackym,P.A.@Histopathologic finding in Menierefs disease. Otolaryngol Head Neck Surg. 1995; 112: 90-100
3 Paparella MM, Djalilian HR. Etiology, pathophysiology of symptoms, and pathogenesis of Menierefs disease. Otolaryngol Clin North Am. 2002; 35: 529-45
4 Furuta Y, Takasu T, Fukuda S, Inuyama Y, Sato KC, Nagashima K. Latent herpes simplex rirus type 1 in vestibular ganglia. Acta Otolaryngol Suppl. 1993; 503; 85-9
5 Vrabec JT. Herpes simplex virus and Menierefs disease. Laryngoscope. 2003; 113; 1431-8
6 Williams LL, Lowery HW, Shannon BT. Evidence of persistent viral infection in Menierefs disease. Arch Otolaryngol Head Neck Surg. 1987; 113: 397-400
7 Bance M, Rutka J. Speculation into the etiologic role of viruses in the development of Bell palsy and disoders of inner ear dysfunction a case history and review of the literature. J Otolaryngol. 1990; 19: 46-9
8 Bergstrom T, Edstrom S, Tjellstrom A Vahlne A. Menierefs disease and antibody reactivity to herpes simplex virus type 1 polypeptide. Am J Otolaryngol. 1992; 13: 295-300
9 Calenoff E, Zhao JC, Derlackki EL, Harrison WH, Selmeczi K, Dutra JC, Olson IR, Hanson DG. Patients with Menierefs disease possess IgE reacting with herpes family viruses. Arch Otolaryngol Head Neck Syrg 1995; 121: 861-4
10 Anold W, Niedermeyer HP. Herpes simplex virus antibodies in the perilymph of patients with Menierefs disease. Arch Otolaryngol Head Neck Surg 1997; 123: 53-6
11 Takahashi K, Aono T, Shichinohe M, Tamura M, Iwata Y, Yamanishi K, Shigeta S, Herpes virus DNA in peripheral blood mononuclear cells of some patients with Menierefs disease. Microbiol Immunol. 2001; 45: 635-8
12 Shichinohe M. Effectiveness of ACVG for Menierefs disease. Igaku no Ayumi (J Clin Exp Med ) 1994; 169: 796-7
13 Shichinohe M. Effectiveness of ACV for Menierefs diseaseU. Report of 10 cases. Shindan to Chiryo (Diagnosis and Treatment) 1994; 82: 1860-4
14 Shichinohe M Effectiveness of acyclovir on Menierefs syndromeV Observation of clinical symptoms in 301 cases. Sapporo Med J. 1999; 6871-7
15 Derebery MJ, Fisher LM, Iqbal Z. Randomized double-blinded, Placebo-controlled clinical trial of famciclovir for reduction of Menierefs disease symptoms. Otolaryngol Head Neck surg. 2004; 131: 877-84
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Mitsuo Shichinohe, M.D.,Ph.D., Curriculum Vitae
Present Position and Institution
Director, Shichinohe clinic
Date and place of Birth; February 26, 1931. Esutoru mati, Karafuto,Japan
Marital Status; Married, two sons
1958 M.D Sapporo Medical University, Sapporo
1958-1963 Graduate,School, Department of Physiology(pharmacology),Sapporo Medical@University, Sapporo
1973-2005 Opened Shichinohe Clinic in Sapporo,Japan
1900 The first administration of Acyclovir ( anti-viral drug ) to a patient with Menierefs disease.
1994 Publication in theh Journal of Clinical and Experimental Medicine
( Igaku no ayumi)
1996 Presentation at theh 9th International Conference on Antiviral Research (ICAR) on 179 cases. Fukushima Japan
@1998 Presentation at the g 11th ICAR on 301 cases. San-Diego USA
1999 Effectiveness of Acyclovir on Menierefs Syndrome 111 Observation of Clinical Symptoms in 301 Cases.
( The Sapporo Medical Journal Vol. 68, No. 4-6, December, 1999
2004 Vertigo is Curable Apublished from the BUNGEISHUNJU Co.Ltd.
During the above period, the treatment was widely introduced in a number of health magazines. My home-page is visited by about 100,000 patients now. My clinic received anxious patients from all over Japan. I have received and replied to e-mail inquiries from patients in Japan, USA, Canada, Australia, Italy, ext.