Expert: Ivan Goldberg, M.D. - 2/27/2010

Question
Dr Goldberg,

I just read the question about Borna Virus dated 1/28/09 and found very striking similarities between M's symptoms and mine.  So far this is the closest match I've found in my searches on the Internet so I want to follow on from M's question in the hope that there is more information available now, or at least I can be pointed in some helpful directions for more investigation.

The symptoms of the deterioration of my brain function arose during an illness that had much of the symptoms of mononucleosis (that's the what the doctor at the time diagnosed).  While I was sick, I had ongoing severe anxiety, my moods would plummet into profound sadness where I would sob uncontrollably, I could barely sleep because of vivid, disturbing dreams.  During this illness and for several months later I was very weak (it was several months before I had the strength to work a full day).   Also, this is kind of odd I think, but before the illness I'd had ongoing problems with constipation.  Since the illness, I've had the opposite problem.  Also, I seem to have retained much of the knowledge I'd acquired before the illness (eg. I still have a fairly good vocabulary, but it is difficult to form thoughts clearly).

After I recovered from the most debilitating part of this illness, which lasted about 3 weeks, I've had almost exactly the same symptoms described by M.  Additionally, my spatial abilities suddenly diminished (I get lost very easily now).  I struggle with basic arithmetic.  And I find that I am always pushing through a feeling of fatigue, and often feel a kind of drowsy separation from the world around me as if perceiving it through a kind of haze.  I experience anxiety attacks (a low tolerance for stress), sudden mood swings and severe depressive episodes.  I've had a few relapses of this illness over the years, although not as severe as the first time.  These symptoms have persisted and gradually gotten worse over the years.

I've read about the apparent psychological effects of Borna Virus.  I've also read about human endogenous retrovirus (HERV), but I don't understand much of what I've read, but it seems to be related.  I read the followup comment and checked out COMT gene but I didn't really understand much of what I read.

So, please, any insight or advice you can offer would be greatly appreciated.  As the symptoms gradually worsen it's becoming increasingly difficult to function from day to day.

Thank you.

Dave

Answer
Hi Dave . . .

The major problem regarding the possibility of human infection with Borna virus is that as far as I can determine the test for Borna infection is not available in North America.

You can read more about human Borna infection at:
http://www.psycom.net/depression.central.borna.html

The treatment for Borna infection is the relatively benign drug amantadine. Here are some  abstracts regarding the use of this medication:

1.APMIS Suppl. 2008;(124):66-9.

The history and treatment of a bipolar patient diagnosed with Borna disease virus infection. Case report.
[No authors listed]

A description of Bipolar Disorder and its treatment costs. The prevalence of various psychiatric disorders in the United States in which Borna Disease Virus (BDV) may play a role. My personal history of Bipolar Disorder including: diagnoses and treatment of Borna Disease Virus infection.

PMID: 18771102 [PubMed - indexed for MEDLINE]

2.APMIS Suppl. 2008;(124):61-5.

Human Borna disease virus-infection and its therapy in affective disorders.
Dietrich DE, Bode L.

Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Germany. dietrich.detlef@mh-hannover.de

Patients with affective disorders show an enhanced prevalence of Borna disease virus (BDV)-infection. Furthermore, BDV causes latent infection preferably in limbic central nervous structures and is suggested to be causally related to subtypes of affective disorders, especially with melancholic clinical features or bipolarity. Such a possible link was highlighted by the first report of amantadine showing an antidepressive and an antiviral efficacy against BDV in a patient with a bipolar disorder. This article summarizes clinical studies which followed this first report on the use of amantadine in BDV-infected patients with an affective disorder. A special focus is given on an open clinical study in patients with depression (n = 25), a study in remitted patients with affective disorders (n = 16), and the effect of amantadine on severe hypomanic or moderately manic patients with a bipolar disorder in an on-off-on study. In these studies amantadine reduced clinical symptoms paralleled by a reduction of BDV-infection in depressive patients, it also reduced all three BDV-parameters (BDV-Ab, -AG, and -CICs) in remitted patients, and it even reduced severe hypomania and moderate mania in bipolar patients. These data suggest the existence of an etiopathogenetic link between BDV and subtypes of affective disorders.

PMID: 18771101 [PubMed - indexed for MEDLINE]

3.Pharmacopsychiatry. 2008 Sep;41(5):202-3. Epub 2008 Sep 1.

Amantadine reduces mania in borna disease virus-infected non-psychotic bipolar patients.
Ohlmeier MD, Zhang Y, Bode L, Sieg S, Feutl S, Ludwig H, Emrich HM, Dietrich DE.

PMID: 18763224 [PubMed - indexed for MEDLINE]

4.Clin Microbiol Rev. 2003 Jul;16(3):534-45.

Borna disease virus infection, a human mental-health risk.
Bode L, Ludwig H.

Project Bornavirus Infections, Robert Koch Institute, 13353 Berlin, Germany.

This article focuses on human Borna disease virus (BDV) infections, most notably on the development of valid diagnostic systems, which have arisen as a major research issue in the past decade. The significance of a novel modular triple enzyme-linked immunosorbent assay that is capable of specifically measuring anti-BDV antibodies as well as major structural proteins N (p40) and P (p24) in the blood, either as free antigens in the plasma or as antibody-bound circulating immune complexes (CICs), is explained. The impact of CICs and plasma antigen, which indicate periods of antigenemia in the course of BDV infection, along with other infection markers that are still in use is discussed. The review further provides new insight into possible links of BDV to human diseases, summarizing cross-sectional and longitudinal data which correlate acute depression with the presence and amount of antigen and CICs. Moreover, BDV prevalence in healthy people is reevaluated, suggesting that this was previously underestimated. Antiviral efficacy of amantadine, in vivo and in vitro, is outlined as well, with emphasis on wild-type (human and equine) versus laboratory strains. Finally, the pros and cons of the association of BDV with human disease, as detailed in the literature, are critically discussed and related to our data and concepts. This article supports existing correlative evidence for a pathogenic role of BDV infection in particular human mental disorders, in analogy to what has been proven for a variety of animal species.

PMID: 12857781 [PubMed - indexed for MEDLINE]

5.Bipolar Disord. 2000 Mar;2(1):65-70.

Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial.
Dietrich DE, Bode L, Spannhuth CW, Lau T, Huber TJ, Brodhun B, Ludwig H, Emrich HM.

Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, Germany. dietrich.detlef@mh-hannover.de

OBJECTIVE: Originally introduced into pharmacotherapy as an antiviral compound, amantadine was shown to also have multiple pharmacological eftfects on the central nervous system. In addition. only a few studies reported on certain antidepressive properties of amantadine. This effect was highlighted by the discovery of its antiviral effect on Borna disease virus (BDV), which is hypothesized to be an etiopathogenetic factor to subtypes of affective disorders. Therefore, the therapeutical use of amantadine in BDV-infected depressive patients was investigated. METHODS: In this open trial, amantadine was added to antidepressive and or mood-stabilizing compounds treating BDV-infected depressed patients (n = 25) with bipolar or major depressive disorders. Amantadine was given twice a day (100-300 mg/day) for a mean of 11 weeks. Antidepressive treatment response was measured on the Hamilton rating scale for depression (HAM-D) and/or with an operationalized diagnostic criteria system (OPCRIT: version 3.31). Virological response was measured by expression of BDV infection parameters in blood samples. RESULTS: The overall response rate of the amantadine augmentation in the BDV-infected patients with regard to depressive symptoms was 68% after a mean of 2.9 weeks of treatment. Bipolar I patients improved faster and did not show any following hypomania. In addition, the decrease of depression tended to correspond with the decrease in viral activity. CONCLUSION: Amantadine appears to show a remarkable antidepressive efficacy in BDV-infected depressive patients. The antidepressive effect in this open trial appeared to be comparable to standard antidepressives, possibly being a result of its antiviral effect against BDV as a potentially relevant etiopathogenetic factor in these disorders.

PMID: 11254023 [PubMed - indexed for MEDLINE]

6.Rev Sci Tech. 2000 Apr;19(1):259-88.

Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology.
Ludwig H, Bode L.

Institute of Virology, Free University Berlin, Königin-Luise-Strasse 49, 14195 Berlin, Germany.

A 'disease of the head' affecting horses, as described in the 17th Century is now known as Borna disease. Research over the past 100 years has established that the aetiological agent, Borna disease virus (BDV), is an unsegmented, single- and negative-stranded, enveloped ribonucleic acid (RNA) virus which represents the family Bornaviridae in the order Mononegavirales. The virus exists world-wide in horses, sheep, cattle, cats, dogs and ostriches. The infection can be fatal, but the majority of carriers are persistently infected without showing symptoms. The association with psychiatric diseases in humans led to an international explosion of research on BDV, with centres established in Germany, the United States of America and Japan. Experimental infections of tree shrews and rats served to examine the effects of persistent and overt disease, most excitingly, virus-induced behavioural changes, and emotional and learning deficits. This 'emerging' virus infection shows complex pathogenetic mechanisms in the nervous system, but also spreads through myelo-monocytic cells. Diagnosis can be made serologically, but detection of antigen markers in peripheral white blood cells, combined with nucleic acid amplification is more profitable. Comparative RNA studies reveal an unusually high genetic homology of viruses. Isolates recovered from humans and equines suggest species-specificity. Vaccination is not an advisable strategy, but antiviral therapy, especially with amantadine sulphate, promises efficacy in human mood disorders, and is effective in vitro. Infections with BDV follow a vulnerability principle to cause disease. Although cross-species transmission of this commensal virus has not been proven, zoonotic aspects of BDV should be carefully considered.

PMID: 11189720 [PubMed - indexed for MEDLINE]

7.Pharmacopsychiatry. 2000 Nov;33(6):221-8.

Word recognition memory before and after successful treatment of depression.
Dietrich DE, Kleinschmidt A, Hauser U, Schneider U, Spannhuth CW, Kipp K, Huber TJ, Wieringa BM, Emrich HM, Johannes S.

Department of Clinical Psychiatry and Psychotherapy, Medizinische Hochschule Hannover, Germany.

One of the most frequent and neuropsychologically well investigated symptoms in depression is reduced memory capacity. In this study, we investigated the course of disease in 16 patients with moderate depression and Borna disease virus (BDV) infection. Recently, it could be shown that BDV infection might play an important role in the etiology of subtypes of depression. Amantadine treatment was used as an antidepressant and antiviral compound. In order to assess memory capacity, event-related potentials (ERPs) were evaluated in ten of sixteen patients in a continuous word recognition experiment using a series of emotionally neutral, positive or negative words. During the treatment period the patients' clinical condition improved significantly. ERPs showed a reduced old/new effect before and after treatment independent of the words' emotional content. These findings suggest a reduced memory capacity being relatively independent of clinical outcome and ability to use emotional connotations for memory mechanisms. However, a significant positive shift over frontal electrodes did occur, which was concomitant with the improvement of depression, suggesting evidence for changed frontal cortical activity.

PMID: 11147930 [PubMed - indexed for MEDLINE]

8.Pharmacopsychiatry. 1999 Jul;32(4):142-7.

Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection.
Ferszt R, Kühl KP, Bode L, Severus EW, Winzer B, Berghöfer A, Beelitz G, Brodhun B, Müller-Oerlinghausen B, Ludwig H.

Department of Gerontopsychiatry, Freie Universität Berlin, Germany. ferszt@zedat.fu-berlin.de

Amantadinesulfate is a well known substance which has proven useful in the treatment and prophylaxis of viral infections, in treating symptoms of Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It has also been reported as having mild antidepressive effects not sufficient to warrant its use as an antidepressant. Striking antidepressive effects in some patients have been attributed to its antiviral activity against human Borna disease virus (BDV) infection which is frequently seen in patients with depressive episodes. In this 8 to 12 week open study of oral amantadine in 30 depressed patients with various states of BDV infection we found a significant antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute infection was cleared in both responders and non-responders, but only in responders peripheral infection was significantly reduced.

PMID: 10505484 [PubMed - indexed for MEDLINE]

9.Pharmacopsychiatry. 1999 Mar;32(2):47-55.

Possible use of amantadine in depression.
Huber TJ, Dietrich DE, Emrich HM.

Department of Clinical Psychiatry, Medical School of Hanover, Germany.

Amantadine, originally used in the treatment and prophylaxis of influenza infection, has also proved beneficial in drug-induced Parkinsonism, Parkinson's disease, traumatic head injury, dementia, multiple sclerosis and cocaine withdrawal. Amantadine appears to act through several pharmacological mechanisms, none of which has been identified as the one chief mode of action. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels. However, it is still uncertain which of these actions are relevant in therapeutic doses. One new aspect is the antiviral effect of amantadine on Borna disease virus, which it is suspected may possibly play a role in affective disorders. All of these actions could constitute an antidepressant property, and it is suggested that amantadine might work as an antidepressant not through one, but through several mechanisms thought to be related to antidepressant activity. Effects of amantadine on symptoms of affective disorders have been demonstrated in several trials administering it for varying purposes. Additionally, animal studies as well as clinical trials in humans have hinted at an antidepressant activity of amantadine. We present here an overview of the current data. However, only a limited body of evidence is available, and further studies are needed to investigate the efficacy of amantadine as well as its modes of action in depression.

PMID: 10333162 [PubMed - indexed for MEDLINE]

10.Med Microbiol Immunol. 1998 Mar;186(4):195-200.

Lack of antiviral effect of amantadine in Borna disease virus infection.
Stitz L, Planz O, Bilzer T.

Institut für Impfstoffe, Bundesforschungsanstalt für Viruskrankheiten der Tiere, Tübingen, Germany. lothar.stitz@tue.bfav.de

The antiviral effect of amantadine (1-aminoadamantane) was tested in vitro as well as in vivo. Treatment of persistently Borna disease virus (BDV)-infected cell lines of different origin and for various length of time did not result in a general reduction of virus titer or clearance of virus from infected cells. In vivo, rats were treated with amantadine by daily oral application or by use of osmotic pumps, and in both cases treatment was started before infection. Neither route of application of the drug had any influence on the time of onset of disease, on antiviral antibody titers, on virus titer in the brain, on the severity of the inflammatory reaction in the brain, or on the severity of neurological symptoms. These experiments, although revealing negative results and obtained using a virus from a natural case of Borna disease grown after isolation in vitro for a long period of time, should caution from the general use of amantadine as a curative agent against BDV infection as has been implicated recently [Bode et al. (1997) Lancet 349:178-179].

PMID: 9574902 [PubMed - indexed for MEDLINE]

11.J Virol. 1998 Jan;72(1):783-8.

Mechanism of Borna disease virus entry into cells.
Gonzalez-Dunia D, Cubitt B, de la Torre JC.

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.

We have investigated the entry pathway of Borna disease virus (BDV). Virus entry was assessed by detecting early viral replication and transcription. Lysosomotropic agents (ammonium chloride, chloroquine, and amantadine), as well as energy depletion, prevented BDV infection, indicating that BDV enters host cells by endocytosis and requires an acidic intracellular compartment to allow membrane fusion and initiate infection. Consistent with this hypothesis, we observed that BDV-infected cells form extensive syncytia upon low-pH treatment. Entry of enveloped viruses into animal cells usually requires the membrane-fusing activity of viral surface glycoproteins (GPs). BDV GP is expressed as two products of 84 and 43 kDa (GP-84 and GP-43, respectively). We show here that only GP-43 is present at the surface of BDV-infected cells and therefore is likely the viral polypeptide responsible for triggering fusion events. We also present evidence that GP-43, which corresponds to the C terminus of GP-84, is generated by cleavage of GP-84 by the cellular protease furin. Hence, we propose that BDV GP-84 is involved in attachment to the cell surface receptor whereas its furin-cleaved product, GP-43, is involved in pH-dependent fusion after internalization of the virion by endocytosis.

PMID: 9420287 [PubMed - indexed for MEDLINE]

12.Arch Virol. 1997;142(10):2043-8.

Borna disease virus is not sensitive to amantadine.
Hallensleben W, Zocher M, Staeheli P.

Abteilung Virologie, Universität Freiburg, Federal Republic of Germany.

Successful inhibition of Borna disease virus (BDV) by amantadine in cultured cells and in an infected human individual has been reported [Bode et al. (1997) Lancet 349: 178-179]. We now found that infection of monkey Vero cells by laboratory strains of BDV was not influenced by amantadine under conditions that reduced the yields of influenza A virus by about 400 fold. Amantadine treatment of Vero cells persistently infected with BDV did not result in reduced viral RNA levels, and application of the drug to persistently infected BALB/c mice had no effect on the concentration of BDV in their brains. Thus, susceptibility to amantadine is not a characteristic of BDV, although it may be observed with certain primary virus isolates.

PMID: 9413512 [PubMed - indexed for MEDLINE]

13.Arch Virol. 1997;142(10):2035-42.

Amantadine does not have antiviral activity against Borna disease virus.
Cubitt B, de la Torre JC.

Department of Neuropharmacology, Scripps Research Institute, La Jolla, California, USA.

We have investigated the antiviral activity of amantadine (AD) against Borna disease virus (BDV) in several culture cell systems. We present evidence that AD, in the range 5 to 10 microM, does not have antiviral activity against BDV. Treatment of BDV infected cells with AD for six days caused neither a reduction in the number of infected cells, nor a decrease in steady state levels of BDV RNA or proteins. Moreover, treatment of cells with AD prior infection did not affect BDV multiplication, whereas influenza A virus yield was less than 1% with respect to that obtained in untreated control cells.

PMID: 9413511 [PubMed - indexed for MEDLINE]

It might be possible that you can find a physician who will be willing to treat you with amantadine.

Best regards . . .

Ivan
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