Lähettäjä: Soijuv Lähetetty: 30.1.2006 17:51
Borrelioosin, MS-taudin ja skitsofrenian välillä yhtäläisyyksiä. Taudit esiintyvät ajallisesti ja maantieteellisesti samoilla alueilla.Tauteja esiintyy erityisen runsaasti alueilla joilla on paljon borreliabakteereita (spirokeettoja) kantavia punkkeja:
International Journal of Health Geographics Volume 1 Issue 1 ? Full text ? PDF (654KB)
Research
http://bmc.ub.uni-potsdam.de/1476-072X-1-5/
Geographical and seasonal correlation of multiple sclerosis to sporadic schizophrenia
Markus Fritzsche
Clinic for Internal Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland
International Journal of Health Geographics 2002 1:5
The electronic version of this article is the complete one and can also be found online at: http://www.ij-healthgeographics.com/content/1/1/5
Received 28 November 2002
Accepted 20 December 2002
Published 20 December 2002
© 2002 Fritzsche; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract
Background
Clusters by season and locality reveal a striking epidemiological overlap between sporadic schizophrenia and multiple sclerosis (MS). As the birth excesses of those individuals who later in life develop schizophrenia mirror the seasonal distribution of Ixodid ticks, a meta analysis has been performed between all neuropsychiatric birth excesses including MS and the epidemiology of spirochaetal infectious diseases.
Results
The prevalence of MS and schizophrenic birth excesses entirely spares the tropical belt where human treponematoses are endemic, whereas in more temperate climates infection rates of Borrelia garinii in ticks collected from seabirds match the global geographic distribution of MS. If the seasonal fluctuations of Lyme borreliosis in Europe are taken into account, the birth excesses of MS and those of schizophrenia are nine months apart, reflecting the activity of Ixodes ricinus at the time of embryonic implantation and birth. In America, this nine months' shift between MS and schizophrenic births is also reflected by the periodicity of Borrelia burgdorferi transmitting Ixodes pacificus ticks along the West Coast and the periodicity of Ixodes scapularis along the East Coast. With respect to Ixodid tick activity, amongst the neuropsychiatric birth excesses only amyotrophic lateral sclerosis (ALS) shows a similar seasonal trend.
Conclusion
It cannot be excluded at present that maternal infection by Borrelia burgdorferi poses a risk to the unborn. The seasonal and geographical overlap between schizophrenia, MS and neuroborreliosis rather emphasises a causal relation that derives from exposure to a flagellar virulence factor at conception and delivery. It is hoped that the pathogenic correlation of spirochaetal virulence to temperature and heat shock proteins (HSP) might encourage a new direction of research in molecular epidemiology.
BORRELIOOSI/MS/SKITSOFRENIA
Valvojat: Jatta1001, Borrelioosiyhdistys, Bb
BORRELIOOSI/MS/SKITSOFRENIA
Viimeksi muokannut Bb, La Maalis 07, 2009 00:29. Yhteensä muokattu 1 kertaa.
Lähettäjä: Soijuv Lähetetty: 27.3.2006 8:32
Tsekkiläisessä tutkimuksessa selvitettiin mm. borrelioosin ja MS-taudin eroja. Borreliavasta-aineita tavataan n. 5 - 10 %:lla ihmisistä mutta noin 1 - 4 sadasta henkilöstä saa oireita.
MS-potilaillla (88 %) esiintyi tyypillisesti korkeita vasta-ainepitoisuuksia tuhkarokkoa, vihurirokkoa ja vesirokkoa (MRZ) vastaan. Suurimmalla osalla neuroborrelioosia sairastavista selkäydinnesteen/seerumin albumiini oli koholla. MS-tautia sairastavista se oli koholla noin kolmasosalla.
Kummassakin sairaudessa on myös yhteisiä piirteitä kuten fatiikki, tominnallisia häiriöitä, selkäydinnesteessä samantyyppisiä muutoksia jne.
Relevance of immunological variables in neuroborreliosis and multiple sclerosis
Bednarova´ J, Stourac P, Adam P.
Acta Neurol Scand 2005: 112: 97?102.
Blackwell Munksgaard 2005.
P. tourac?, Department of Neurology, Faculty Hospital,
Jihlavsk 20, 625 00 Brno, Czech Republic
Tel.: +420-5-3223 3396
Fax: +420-5-3223 2249
e-mail: pstourac@fnbrno.cz
Objectives ? The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities.
Methods ? Three cohorts of patients were investigated: MS (n ¼ 42), NB (n ¼ 27) and other neurological diseases (OND) (n ¼ 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Qalb (CSF/ serum albumin ratio) as a marker of blood?CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining.
Results ? Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually antimeasles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Qalb in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Qalb in 81.5% and normal cell count in 7.4%.
Conclusion ? MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.
Borreliosis is caused by the tick-borne spirochete Borrelia burgdorferi. The spirochetes may invade different organs including the nervous system,
heart, joints and skin. Involvement of the nervous system called neuroborreliosis (NB) is an inflammatory disease manifesting with meningitis, cranial neuritis, radiculoneuritis and other symptoms often reported as Bannwarth syndrome (1). Various encephalomyelitic forms of the disease can also occur posing the tendency to chronicity (2?4). The Czech Republic is an area of borreliosis endemicity with an estimated incidence of 61 cases per 100,000 inhabitants (5). According to different sources at least 20% of cases of borreliosis develop neurologic complications (6).
The high prevalence of borrelia antibodies in the population (5?10%) indicates that the risk of getting an infection is quite high (7). However, only in one to four out of 100 tick bites, symptoms consistent with the disease occur (8 ). The diagnosis of the acute stage of NB seems to be relatively easier when compared with the potential chronic course of NB and other chronic autoimmune diseases of the nervous system.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease with polysymptomatic clinical pattern and the most common cause of
neurologic disability in young adults. The prevalence of MS is about 60 per 100,000 in the Czech Republic. In spite of fast evolution of paraclinical
methods like magnetic resonance and electrophysiology, MS diagnosis is still based on clinical pattern and course, supported by cerebrospinal
fluid (CSF) analysis confirming inflammatory origin of the disease.
Because of some clinical similarities and differential diagnostical difficulties during the clinical course of MS and NB and considering the theory that chronic form of NB can be of an autoimmune origin, we decided to investigate selected parameters of CSF which are considered as characteristics for nervous diseases of autoimmune origin, i.e. intrathecal synthesis of antiviral antibodies called MRZ reaction (M ? measles, R ? rubella, Z ? varicella zoster) in the context of additional relevant parameters [Qalb as a marker of blood?CSF barrier function, specific B. burgdorferi antibody index (AI), cytology]. As MRZ reaction and oligoclonal bands (OB) are expressed in IgG class only, we focused on IgG antibodies in NB and omitted IgM synthesis in order to keep the consistency among examined parameters. Intrathecal synthesis of both specific and non-specific antibodies is expressed in the form of AI reflecting the status of blood/CSF barrier and determining the portion of antibodies synthetized intrathecally. The AI solely cannot differentiate among acute, chronic or past infection with B. burgdorferi.
There is only an exceptional report that MRZ reaction can be present in a chronic course of NB till now (9).
Both diseases share some common clinical features especially in chronic course as fatigue, transient or residual motor and sensory symptoms. There are some similarities in CSF variables between NB and MS. The main similarities include predominantly slight lymphocytic pleocytosis and presence of oligoclonal IgG bands. Considering different immunological regulations in CSF vs blood (no classical switch from IgM to IgG phase during the course of the disease, long persistence of antibodies of different classes, equivocal interpretation of the presence of specific antibodies in endemic areas), the differential diagnosis between NB and MS especially in subacute and chronic course could be improved by using some additional CSF and blood variables.
In order to further improve the differential diagnosis between MS and NB we asked the following questions:
a) How often is the MRZ reaction positive in NB?
b) What is the typical CSF variables profile in NB?
c) How often is the MRZ reaction positive in MS?
d) What is the typical CSF variables profile in MS?
e) Can we use the MRZ reaction as reliable CSF parameter especially in equivocal cases between MS and NB?
Results:
Intrathecal synthesis
The intrathecal synthesis of specific IgG antibodies against measles (M), rubella (R), varicella zoster (Z) viruses and B. burgdorferi (Bb) was evaluated by calculating the AI for each species. The frequencies of positive intrathecal synthesis in patients with MS are reported in Table 1. Eighty-eight percent of MS patients had a combined intrathecal synthesis against one, two or three of the M, R and Z viruses. The most frequent intrathecal synthesis was observed for measles antibodies in 73.8% MS patients with AI in the range 1.5?20.2 and AI median 2.6. Positive intrathecal synthesis of rubella antibodies was observed in 40.5% MS patients with AI in the range 1.5?51.0 and AI median 2.9. Positive intrathecal synthesis of varicella zoster antibodies was detected in 35.7% MS patients with AI in the range 1.5?10.6 and AI median 2.2. Combination of positive intrathecal synthesis of M + R was observed in 11.9%, M + Z in 14.3%, R + Z in 7.1% and M + R + Z in 14.3% patients with MS. The intrathecal synthesis against B. burgdorferi was observed in 26.2% MS patients with AI in the range 2.1?9.3 with AI median 3.5. The CSF AU of antibodies against B. burgdorferi of these patients were in the range 0.5?65.0 with AU median 1.8 and AU mean 8.5 (Table 2).
Table 1 Frequencies (%) of positive intrathecal synthesis in MS, NB and OND patients
Table 2 Frequencies and intensity of positive anti-borrelia intrathecal synthesis in MS and NB patients
The frequencies of positive intrathecal synthesis in patients with NB are reported in Table 1. Eighty-nine percent of NB patients had positive intrathecal synthesis against B. burgdorferi with AI in the range 1.5?33.0 with AI median 4.1. The CSF AU of antibodies against B. burgdorferi of these patients were in the range 4.0?100.0 with AU median 100.0 and AU mean 78.9. The frequencies, AI and AU of MS and NB patients with positive intrathecal synthesis against B. burgdorferi are summarized in Table 2. One NB patient (3.7%) had positive intrathecal synthesis against measles with AI ¼ 2.5 and one patient (3.7%) had positive intrathecal synthesis against rubella with AI ¼ 3.2. The AI against M, R and Z were negative in all patients with OND. One OND patient (6.7%) had positive intrathecal synthesis against B. burgdorferi with AI ¼ 2.5. The serum IgG and IgM titers for borrelia antibodies were negative in this patient.
Oligoclonal IgG bands
Positive oligoclonal IgG bands were detected in 81% MS patients, 74% NB patients and 6.7% OND patients.
Blood?CSF barrier function
Function of blood?CSF barrier is expressed by albumin CSF/serum concentration quotient, Qalb. Increased values of Qalb indicate dysfunction of blood?CSF barrier, because albumin originates exclusively from blood (12). In MS patients, Qalb was increased by 31% mostly lightly, in NB patients by 81.5% and in OND patients by 66.7%.
Cellular immune response
Values of total cell count are reported in Table 3. In the MS subgroup 66.7% patients had normal cell count (<5/ll), only 4.8% patients had values >40/ll and the highest value was 81/ll. In NB 7.4% patients had normal cell count, 74% patients had values >40/ll and the highest value was 450/ll. In OND 33.3% patients had normal cell count.
Table 3 Total cell count, oligoclonal IgG bands (OB) and Qalb in CSF in MS, NB and OND patients
Figure 1. The profiles of antibody indices against measles, rubella, varicella zoster (MRZ reaction) and Borrelia burgdorferi (anti-borrelia AI) in MS, NB and OND patients. In MRZ positivity statistically significant differences (P < 0.001) are between MS and NB, MS and OND groups. In antiborrelia AI statistically significant differences (P < 0.001) are between MS and NB, NB and OND groups, respectively.
Statistical analysis
Statistical evaluation first using Pearson?s chisquare test was positive and subsequent paired testing by Fisher?s exact test revealed statistically
significant differences (P < 0.001) in MRZ positivity between MS and NB, MS and OND groups, respectively, but non-significant difference between
NB and OND groups. As far as positivity of intrathecal synthesis against B. burgdorferi (AI) was concerned, significant differences on statistical level (P < 0.001) were confirmed between MS and NB, NB and OND groups, respectively, and nonsignificant difference between MS and OND groups. Calculated sensitivity of MRZ reaction was 88% in MS patients and 7.4% in NB patients. Specificity of MRZ reaction was 100% in both groups. Calculated sensitivity of anti-borrelia AI was 26% in MS group and 89% in NB group. Specificity of anti-borrelia AI was 93% in both groups (Fig. 1).
Discussion:
Multiple sclerosis
A high percentage of MS patients (84?94%) were previously reported having intrathecal antibody synthesis against one, two or three of the M, R,
and Z viruses (MRZ antibodies or MRZ reaction) (9). CombinationsM + R,M + Z or R + Z that are rarely seen in other diseases (e.g. acute infections) are clues to the presence of a chronic, autoimmune disease. In OND the frequency of MRZ reaction is below 1% for the single species and far below 0.1% for M + R + Z, except for very rare instances in which the disease follows a chronic course (12).
MRZ reaction in MS reflects a polyclonal activation of plasma cells with low values of antibody titers compared with specific plasma cell activation in infectious diseases including NB which is reflected by high values of antibody titers against causative antigens (13).
Our present data of MRZ reaction is positive in 88% MS patients and the frequencies of AI correspond to these findings. However, the MRZ reaction is not specific for MS alone, it is also detected in other autoimmune diseases with CNS involvement such as lupus erythematosus, Sjogren?s syndrome or Wegener?s granulomatosis (14).
As a part of oligoclonal, polyspecific immune intrathecal reaction in MS, anti-toxoplasma and anti-dsDNA antibodies are also reported. We also
found specific anti-borrelia antibodies intrathecal production in approximately 26% of patients in our MS cohort. According to previous clinical course and data we do not suppose that these patients had clinically active NB nor they were immunized by contact with borrelia antigen in endemic area. The latter is unlikely because in the OND group only one patient had positive intrathecal anti-borrelia-specific antibody synthesis.
False positivity of anti-borrelia antibodies was excluded according to the results in the OND group. Lower anti-borrelia AU (median, mean) in MS patients compared with high anti-borrelia AU in NB patients reflect polyspecific immune response in MS vs immune response against B. burgdorferi, as the causative antigen in NB. These results correspond to similar findings in Fuchs heterochromic cyclitis (13).
Oligoclonal IgG bands are normally present in 95% patients with clinically definite MS. However, the frequency is lower at the time of first clinical
symptoms and increases during the course of the disease. Presence of OB is important in the diagnosis of early MS, particularly in those with normal brain MRI scans (15). The frequency of OB in patients with optic neuritis, one of the earliest manifestations of MS, is between 34 and 72% depending on the detection technique used (16).
Another report also confirms gradually increasing positivity of OB during MS course, e.g. the statement that MS-like lesions or OB of clinically
isolated syndrome (CIS) are positive only in 50?70% of cases (17). We observed positive oligoclonal IgG bands in 81% MS patients. This lower
number is caused by the above discussed fact that our subgroup of MS patients contained five patients (12%) at the time of first clinical symptoms.
Cellular immune response in MS presents normal cell count or slight pleocytosis with the presence of plasma cells or activated lymphocytes and total cell count usually not exceeding 40 cells/ll. Large cell count (>90 ll) rules out the diagnosis of MS. Blood?CSF barrier function is commonly intact or slightly impaired in MS patients. Large values of Qalb (>20 · 10)3) are not consistent with the diagnosis of MS (12).
According to our results the typical CSF variables profile in MS includes normal and slightly elevated cell count, normal blood?CSF barrier, high percentage of IgG OB in CSF (about 90?95%) and highly specific MRZ reaction (84?94%).
Neuroborreliosis
In our NB subgroup 89% had positive intrathecal anti-borrelia IgG synthesis. In parallel one patient with positive anti-borrelia IgG antibodies and corresponding history of illness had positive intrathecal anti-measles IgG antibodies. Clinically he suffered from aseptic meningitis with pleocytosis in CSF. One patient with positive anti-borrelia IgG antibodies had positive intrathecal synthesis of anti-rubella IgG antibodies and suffered from meningoradiculoneuritis (Bannwarth syndrome) with pleocytosis in CSF. In both cases M, R positivity was due to unspecific stimulation without clinical symptoms of measles or rubella.
Oligoclonal IgG bands are reported in 63% NB cases (18 ). In our cohort 74% NB patients had positive oligoclonal IgG bands either in CSF or both in serum and CSF.
Cellular immune response in NB patients consists of elevated cell count with the presence of plasma cells, activated lymphocytes, neutrophils and total cell count usually exceeding 90 elements per 1 ll. Blood?CSF barrier in NB is usually disturbed in almost all cases (10). Our 81.5% positivity of
elevated Qalb is in consent with this observation.
According to our results the typical CSF variables profile in NB includes mixed pleocytosis, disturbed blood?CSF barrier, high percentage of oligoclonal IgG bands and anti-borrelia-specific intrathecal synthesis and negative MRZ reaction. Concerning OND subgroup, one patient with positive AI-Bb was diagnosed as purulent meningitis with prevailing neutrophil pleocytosis of bacterial origin in CSF. NB was excluded in this patient according to diagnostic criteria. Positive intrathecal synthesis of anti-borrelia antibodies was due to polyspecific immune response accompanying an inflammatory process in the brain. .....................................
Conclusions
Based on our data we confirmed that the MRZ reaction is statistically highly significant (P < 0.001) between MS and NB, respectively, in wider sense among autoimmune and infectious diseases of the nervous system. The CSF laboratory profile presented here could be useful in the differential diagnosis between MS and NB.
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and oligoclonal immune response in multiple
sclerosis. Mult Scler 1998;4:111?7.
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fluid variables for early diagnosis of neuroborreliosis.
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11. Reiber H, Lange P. Quantification of virus-specific antibodies
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Tsekkiläisessä tutkimuksessa selvitettiin mm. borrelioosin ja MS-taudin eroja. Borreliavasta-aineita tavataan n. 5 - 10 %:lla ihmisistä mutta noin 1 - 4 sadasta henkilöstä saa oireita.
MS-potilaillla (88 %) esiintyi tyypillisesti korkeita vasta-ainepitoisuuksia tuhkarokkoa, vihurirokkoa ja vesirokkoa (MRZ) vastaan. Suurimmalla osalla neuroborrelioosia sairastavista selkäydinnesteen/seerumin albumiini oli koholla. MS-tautia sairastavista se oli koholla noin kolmasosalla.
Kummassakin sairaudessa on myös yhteisiä piirteitä kuten fatiikki, tominnallisia häiriöitä, selkäydinnesteessä samantyyppisiä muutoksia jne.
Relevance of immunological variables in neuroborreliosis and multiple sclerosis
Bednarova´ J, Stourac P, Adam P.
Acta Neurol Scand 2005: 112: 97?102.
Blackwell Munksgaard 2005.
P. tourac?, Department of Neurology, Faculty Hospital,
Jihlavsk 20, 625 00 Brno, Czech Republic
Tel.: +420-5-3223 3396
Fax: +420-5-3223 2249
e-mail: pstourac@fnbrno.cz
Objectives ? The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities.
Methods ? Three cohorts of patients were investigated: MS (n ¼ 42), NB (n ¼ 27) and other neurological diseases (OND) (n ¼ 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Qalb (CSF/ serum albumin ratio) as a marker of blood?CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining.
Results ? Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually antimeasles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Qalb in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Qalb in 81.5% and normal cell count in 7.4%.
Conclusion ? MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.
Borreliosis is caused by the tick-borne spirochete Borrelia burgdorferi. The spirochetes may invade different organs including the nervous system,
heart, joints and skin. Involvement of the nervous system called neuroborreliosis (NB) is an inflammatory disease manifesting with meningitis, cranial neuritis, radiculoneuritis and other symptoms often reported as Bannwarth syndrome (1). Various encephalomyelitic forms of the disease can also occur posing the tendency to chronicity (2?4). The Czech Republic is an area of borreliosis endemicity with an estimated incidence of 61 cases per 100,000 inhabitants (5). According to different sources at least 20% of cases of borreliosis develop neurologic complications (6).
The high prevalence of borrelia antibodies in the population (5?10%) indicates that the risk of getting an infection is quite high (7). However, only in one to four out of 100 tick bites, symptoms consistent with the disease occur (8 ). The diagnosis of the acute stage of NB seems to be relatively easier when compared with the potential chronic course of NB and other chronic autoimmune diseases of the nervous system.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease with polysymptomatic clinical pattern and the most common cause of
neurologic disability in young adults. The prevalence of MS is about 60 per 100,000 in the Czech Republic. In spite of fast evolution of paraclinical
methods like magnetic resonance and electrophysiology, MS diagnosis is still based on clinical pattern and course, supported by cerebrospinal
fluid (CSF) analysis confirming inflammatory origin of the disease.
Because of some clinical similarities and differential diagnostical difficulties during the clinical course of MS and NB and considering the theory that chronic form of NB can be of an autoimmune origin, we decided to investigate selected parameters of CSF which are considered as characteristics for nervous diseases of autoimmune origin, i.e. intrathecal synthesis of antiviral antibodies called MRZ reaction (M ? measles, R ? rubella, Z ? varicella zoster) in the context of additional relevant parameters [Qalb as a marker of blood?CSF barrier function, specific B. burgdorferi antibody index (AI), cytology]. As MRZ reaction and oligoclonal bands (OB) are expressed in IgG class only, we focused on IgG antibodies in NB and omitted IgM synthesis in order to keep the consistency among examined parameters. Intrathecal synthesis of both specific and non-specific antibodies is expressed in the form of AI reflecting the status of blood/CSF barrier and determining the portion of antibodies synthetized intrathecally. The AI solely cannot differentiate among acute, chronic or past infection with B. burgdorferi.
There is only an exceptional report that MRZ reaction can be present in a chronic course of NB till now (9).
Both diseases share some common clinical features especially in chronic course as fatigue, transient or residual motor and sensory symptoms. There are some similarities in CSF variables between NB and MS. The main similarities include predominantly slight lymphocytic pleocytosis and presence of oligoclonal IgG bands. Considering different immunological regulations in CSF vs blood (no classical switch from IgM to IgG phase during the course of the disease, long persistence of antibodies of different classes, equivocal interpretation of the presence of specific antibodies in endemic areas), the differential diagnosis between NB and MS especially in subacute and chronic course could be improved by using some additional CSF and blood variables.
In order to further improve the differential diagnosis between MS and NB we asked the following questions:
a) How often is the MRZ reaction positive in NB?
b) What is the typical CSF variables profile in NB?
c) How often is the MRZ reaction positive in MS?
d) What is the typical CSF variables profile in MS?
e) Can we use the MRZ reaction as reliable CSF parameter especially in equivocal cases between MS and NB?
Results:
Intrathecal synthesis
The intrathecal synthesis of specific IgG antibodies against measles (M), rubella (R), varicella zoster (Z) viruses and B. burgdorferi (Bb) was evaluated by calculating the AI for each species. The frequencies of positive intrathecal synthesis in patients with MS are reported in Table 1. Eighty-eight percent of MS patients had a combined intrathecal synthesis against one, two or three of the M, R and Z viruses. The most frequent intrathecal synthesis was observed for measles antibodies in 73.8% MS patients with AI in the range 1.5?20.2 and AI median 2.6. Positive intrathecal synthesis of rubella antibodies was observed in 40.5% MS patients with AI in the range 1.5?51.0 and AI median 2.9. Positive intrathecal synthesis of varicella zoster antibodies was detected in 35.7% MS patients with AI in the range 1.5?10.6 and AI median 2.2. Combination of positive intrathecal synthesis of M + R was observed in 11.9%, M + Z in 14.3%, R + Z in 7.1% and M + R + Z in 14.3% patients with MS. The intrathecal synthesis against B. burgdorferi was observed in 26.2% MS patients with AI in the range 2.1?9.3 with AI median 3.5. The CSF AU of antibodies against B. burgdorferi of these patients were in the range 0.5?65.0 with AU median 1.8 and AU mean 8.5 (Table 2).
Table 1 Frequencies (%) of positive intrathecal synthesis in MS, NB and OND patients
Table 2 Frequencies and intensity of positive anti-borrelia intrathecal synthesis in MS and NB patients
The frequencies of positive intrathecal synthesis in patients with NB are reported in Table 1. Eighty-nine percent of NB patients had positive intrathecal synthesis against B. burgdorferi with AI in the range 1.5?33.0 with AI median 4.1. The CSF AU of antibodies against B. burgdorferi of these patients were in the range 4.0?100.0 with AU median 100.0 and AU mean 78.9. The frequencies, AI and AU of MS and NB patients with positive intrathecal synthesis against B. burgdorferi are summarized in Table 2. One NB patient (3.7%) had positive intrathecal synthesis against measles with AI ¼ 2.5 and one patient (3.7%) had positive intrathecal synthesis against rubella with AI ¼ 3.2. The AI against M, R and Z were negative in all patients with OND. One OND patient (6.7%) had positive intrathecal synthesis against B. burgdorferi with AI ¼ 2.5. The serum IgG and IgM titers for borrelia antibodies were negative in this patient.
Oligoclonal IgG bands
Positive oligoclonal IgG bands were detected in 81% MS patients, 74% NB patients and 6.7% OND patients.
Blood?CSF barrier function
Function of blood?CSF barrier is expressed by albumin CSF/serum concentration quotient, Qalb. Increased values of Qalb indicate dysfunction of blood?CSF barrier, because albumin originates exclusively from blood (12). In MS patients, Qalb was increased by 31% mostly lightly, in NB patients by 81.5% and in OND patients by 66.7%.
Cellular immune response
Values of total cell count are reported in Table 3. In the MS subgroup 66.7% patients had normal cell count (<5/ll), only 4.8% patients had values >40/ll and the highest value was 81/ll. In NB 7.4% patients had normal cell count, 74% patients had values >40/ll and the highest value was 450/ll. In OND 33.3% patients had normal cell count.
Table 3 Total cell count, oligoclonal IgG bands (OB) and Qalb in CSF in MS, NB and OND patients
Figure 1. The profiles of antibody indices against measles, rubella, varicella zoster (MRZ reaction) and Borrelia burgdorferi (anti-borrelia AI) in MS, NB and OND patients. In MRZ positivity statistically significant differences (P < 0.001) are between MS and NB, MS and OND groups. In antiborrelia AI statistically significant differences (P < 0.001) are between MS and NB, NB and OND groups, respectively.
Statistical analysis
Statistical evaluation first using Pearson?s chisquare test was positive and subsequent paired testing by Fisher?s exact test revealed statistically
significant differences (P < 0.001) in MRZ positivity between MS and NB, MS and OND groups, respectively, but non-significant difference between
NB and OND groups. As far as positivity of intrathecal synthesis against B. burgdorferi (AI) was concerned, significant differences on statistical level (P < 0.001) were confirmed between MS and NB, NB and OND groups, respectively, and nonsignificant difference between MS and OND groups. Calculated sensitivity of MRZ reaction was 88% in MS patients and 7.4% in NB patients. Specificity of MRZ reaction was 100% in both groups. Calculated sensitivity of anti-borrelia AI was 26% in MS group and 89% in NB group. Specificity of anti-borrelia AI was 93% in both groups (Fig. 1).
Discussion:
Multiple sclerosis
A high percentage of MS patients (84?94%) were previously reported having intrathecal antibody synthesis against one, two or three of the M, R,
and Z viruses (MRZ antibodies or MRZ reaction) (9). CombinationsM + R,M + Z or R + Z that are rarely seen in other diseases (e.g. acute infections) are clues to the presence of a chronic, autoimmune disease. In OND the frequency of MRZ reaction is below 1% for the single species and far below 0.1% for M + R + Z, except for very rare instances in which the disease follows a chronic course (12).
MRZ reaction in MS reflects a polyclonal activation of plasma cells with low values of antibody titers compared with specific plasma cell activation in infectious diseases including NB which is reflected by high values of antibody titers against causative antigens (13).
Our present data of MRZ reaction is positive in 88% MS patients and the frequencies of AI correspond to these findings. However, the MRZ reaction is not specific for MS alone, it is also detected in other autoimmune diseases with CNS involvement such as lupus erythematosus, Sjogren?s syndrome or Wegener?s granulomatosis (14).
As a part of oligoclonal, polyspecific immune intrathecal reaction in MS, anti-toxoplasma and anti-dsDNA antibodies are also reported. We also
found specific anti-borrelia antibodies intrathecal production in approximately 26% of patients in our MS cohort. According to previous clinical course and data we do not suppose that these patients had clinically active NB nor they were immunized by contact with borrelia antigen in endemic area. The latter is unlikely because in the OND group only one patient had positive intrathecal anti-borrelia-specific antibody synthesis.
False positivity of anti-borrelia antibodies was excluded according to the results in the OND group. Lower anti-borrelia AU (median, mean) in MS patients compared with high anti-borrelia AU in NB patients reflect polyspecific immune response in MS vs immune response against B. burgdorferi, as the causative antigen in NB. These results correspond to similar findings in Fuchs heterochromic cyclitis (13).
Oligoclonal IgG bands are normally present in 95% patients with clinically definite MS. However, the frequency is lower at the time of first clinical
symptoms and increases during the course of the disease. Presence of OB is important in the diagnosis of early MS, particularly in those with normal brain MRI scans (15). The frequency of OB in patients with optic neuritis, one of the earliest manifestations of MS, is between 34 and 72% depending on the detection technique used (16).
Another report also confirms gradually increasing positivity of OB during MS course, e.g. the statement that MS-like lesions or OB of clinically
isolated syndrome (CIS) are positive only in 50?70% of cases (17). We observed positive oligoclonal IgG bands in 81% MS patients. This lower
number is caused by the above discussed fact that our subgroup of MS patients contained five patients (12%) at the time of first clinical symptoms.
Cellular immune response in MS presents normal cell count or slight pleocytosis with the presence of plasma cells or activated lymphocytes and total cell count usually not exceeding 40 cells/ll. Large cell count (>90 ll) rules out the diagnosis of MS. Blood?CSF barrier function is commonly intact or slightly impaired in MS patients. Large values of Qalb (>20 · 10)3) are not consistent with the diagnosis of MS (12).
According to our results the typical CSF variables profile in MS includes normal and slightly elevated cell count, normal blood?CSF barrier, high percentage of IgG OB in CSF (about 90?95%) and highly specific MRZ reaction (84?94%).
Neuroborreliosis
In our NB subgroup 89% had positive intrathecal anti-borrelia IgG synthesis. In parallel one patient with positive anti-borrelia IgG antibodies and corresponding history of illness had positive intrathecal anti-measles IgG antibodies. Clinically he suffered from aseptic meningitis with pleocytosis in CSF. One patient with positive anti-borrelia IgG antibodies had positive intrathecal synthesis of anti-rubella IgG antibodies and suffered from meningoradiculoneuritis (Bannwarth syndrome) with pleocytosis in CSF. In both cases M, R positivity was due to unspecific stimulation without clinical symptoms of measles or rubella.
Oligoclonal IgG bands are reported in 63% NB cases (18 ). In our cohort 74% NB patients had positive oligoclonal IgG bands either in CSF or both in serum and CSF.
Cellular immune response in NB patients consists of elevated cell count with the presence of plasma cells, activated lymphocytes, neutrophils and total cell count usually exceeding 90 elements per 1 ll. Blood?CSF barrier in NB is usually disturbed in almost all cases (10). Our 81.5% positivity of
elevated Qalb is in consent with this observation.
According to our results the typical CSF variables profile in NB includes mixed pleocytosis, disturbed blood?CSF barrier, high percentage of oligoclonal IgG bands and anti-borrelia-specific intrathecal synthesis and negative MRZ reaction. Concerning OND subgroup, one patient with positive AI-Bb was diagnosed as purulent meningitis with prevailing neutrophil pleocytosis of bacterial origin in CSF. NB was excluded in this patient according to diagnostic criteria. Positive intrathecal synthesis of anti-borrelia antibodies was due to polyspecific immune response accompanying an inflammatory process in the brain. .....................................
Conclusions
Based on our data we confirmed that the MRZ reaction is statistically highly significant (P < 0.001) between MS and NB, respectively, in wider sense among autoimmune and infectious diseases of the nervous system. The CSF laboratory profile presented here could be useful in the differential diagnosis between MS and NB.
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