Katarzyna Gustaw
Introduction
Institute of Agricultural Medicine Lublin
Occurence, Prevalence, Incidence of Tics and tics transmitted diseases in Lublin Region
Neurological and psychological symptoms after the Borreliosis with nervous system involvement
PCR –diagnosis of relapses in
chronic Neuroborreliosis
Neuroborreliosis or/and MS Cases
Katarzyna Gustaw MD, PhD
Neurologist
Department of Neurodegenerative Diseases
Institute of Agricultural Medicine
Lublin
Poland
Lubin ~ 500,000 inhabitants
Lublin Region (agricultural, forestry),~ 2,5 m. people,
Is a national institution;
Deals with all health problems of the Polish rural population
Ocupational diseases
Neuroinfections
Aging related diseases
Investigates the conditioning of human health, having adopted a holistic and interdisciplinary approach;
Conducts
scientific research, expertise, projects for practical implementation and services;
Carries out educational, diagnostic, therapeutic, rehabilitation and judicial activities;
Department of Environmental Hygiene, Department of Pathomorphology
Department of Toxicology , Department of Public Health
Independent Laboratory for Socio-Medical Studies
Section for Statistics and Medical Services Documentation
Outpatient Department for Rural Occupational
Diseases
Department of Neurodegenerative Diseases
Clinic of Internal and Occupational Diseases
Department of Laboratory Diagnostics
Department of Occupational Biohazard (Microbiology)
Based on epidemiological data collected 1995-2001
The incidence of borreliosis was estimated to be :
9,710 /100 000 /year in the farmers and
6,580 / 100 000 /year in urban citizens.
The biggest incidence was observed in the 1996-11,800 / 100 000 / year.
It is decreasing !
The incidence is significantly higher (+Kruskal-Wallise) as compared to Poland and Europe in general. It is similar to „forestry” regions in Poland and Europe
Occurence of Borrelia and TBEV in ticks see -
STUDY ON THE OCCURRENCE OF BORRELIA BURGDORFERI SENSU LATO AND TICK-BORNE ENCEPHALITIS VIRUS (TBEV) IN
TICKS COLLECTED IN LUBLIN REGION (EASTERN POLAND)
Occurence of borrelia in ticks
Lublin Region in total 1,8%; Zamość 9,6%
The highest infection rate-females tics
Prevalence of tics infection was significantly higher in Zamosc as compered with whole Region (p=0.003)
6 genospecies in Poland
In Lublin Region Borrelia burgdorferi s.s., (55%)
Borrelia garinii (35%)
Borrelia afzelii~
Study Protocol: Observational Retrospective Study, Cohort study
The study was supported by the Polish Committee for Scientific Research (KBN), Project KBN P05 G22/01
Cases from 1995-2000
Examination carried out 2001-2003
Because of may suggestions and growing body of evidence that:
Lyme disease can mimic many neurological disease
Fallon BA, Nields JA, Parsons B, Liebowitz MR, Klein DF: Psychiatric manifestations of Lyme borreliosis. J Clin Psychiatry 1993. 54(7), 263-268.
Pachner AR.
Neurological manifestations of Lyme disease, the new Great Imitator. Rev Inf Dis 1989, 11, 1482-1486.
Pachner AR, Steere AC: Neurological findings of Lyme disease. Yale Journal of Biology & Medicine 1984, 57, 481-483.
Pachner AR, Steere AC: The triad of neurologic
manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology 1985, 35, 47-53. etc..
Because of still high incidence of borreliosis especially in our region
We design the study
To explore the character of neuroborreliosis and to try to check convictions and facts about Lyme disease based on our own experience.
Population 2 milion
The first cohort, 669 people. The group of 669 patients who were diagnosed with borreliosis in years 1995-2000 in Lublin’s Region.
547 people responded.
People with co-existence of Borreliosis and TBE, SLE, alergies, other neuroinfections and any type
of vasculitis and liver diseases were excluded.
MS excludes as well but MS/Borreliosis cases were selected … Link to MS…..more
Second cohort consisted of 345 people
Two groups selected according to the type of symptoms in the beginning of the process
Neuroborreliosis group, 124 people. People who suffered from borreliosis with central and/or peripheral nervous system involvement.
Control, 60 people. Healthy people. Age and sex as Neuroborreliosis. Borrelia infection excluded serological method –ELISA, didn’t remember tick bite episode.
Erythrema C. Migrans group, 60 people. People with Erythema Chronicum Migrans as the only symptom of borreliosis- comparison!!!
One point stratification:
Treatment during the acute phase of the disease (no later then 72 h after the occurence of symptoms).
86 people - nT Neuroborreliosis group
38 people - T Neuroborreliosis group
Second point stratification
recall the tick bite episode
tick removal etc.
One point stratification:
Treatment during the acute phase of the disease (no later then 72 h after the occurence of symptoms).
38 people - T Neuroborreliosis group
86 people - nT Neuroborreliosis group
Second point stratification
the tick bite episode recall
Occurence of ECM etc.
38 people/124 – Treated since the beginning of the disease.
Only 30.6 % from Neuroborreliosis group were treated
compared to 67% in ECM group (+ Kruskal-Walis)
Data are being collected…. Physical Rating Scale (1-7) to assess the impairment …..correlates with treatment
The severity of impairment doesn’t depend on the type of the treatment (type of the antybiotic used)
Time period from beginning of the symptoms to may be
positivelly correlated with scale of impairment
Time length of the treatment may correspond negatively with severity of the treatment
Medical history- key point. List of questions was tested in a preliminary study.
Neurological examination.
Psychological examination.
Variety of consultations
Serological test (blood,ELISA).
Neurophysiological cognitive Evoked Potentials study P100, P300.
Neuroimaging MRI/T1/T2/FLAIR, CT, SPECT
PCR.
Physical Rating Scale.
See Neurological and psychological symptoms after the severe acute neuroborreliosis.
Ig G class, against antigens Borrelia burgdorferi sensu lato
p 100
Osp C
Osp 17
p 41
P 18
Ig M class against antigens Borrelia burgdorferi sensu lato
Osp C
P 41
Results expressed as BBU/ml
9 to 10 –border line
11 to 20 –positive
21 to 30 –highly positive
>30 to – extremely highly positive
T Neuroborreliosis group vs Control vs nT Neuroborreliosis group (p<0,05)
| T Neuroborreliosis | IgG Borelioza BBU/ml | IgM Borelioza BBU/ml |
| Mean | 17.7 | 66.5 |
| SD | 12.4 | 13.4 |
| nT Neuroborreliosis | IgG Borelioza BBU/ml | IgM Borelioza BBU/ml |
| Mean | 99.1 | 133.5 |
| SD | 46.8 | 54.4 |
| Control | IgG Borelioza BBU/ml | IgM Borelioza BBU/ml |
| Mean | 15.1 | 21.5 |
| SD | 5.1 | 12.4 |
Multifocal Disseminated Neurological Deficite …….Link to MS
Neuroborreliosis is similar to MS in its clinical picture or v.v MS may be simillar to some forms of Neroborreliosis
Overlap, Ethiopathogenesis?
Neurophysiological methods – p100 and p300 potentials latency was measured
May correspond with cognitive functions
Limitations: Cases with vision and hearing difficulties were excluded
Latency of p300 was significantly higher as compared both to ECM group and to Control
(p<0, 001)
Difference in latencies between sides (L/R) was significant in Neuroborreliosis group as compared to control. Comment:The same pattern was noticed in Schizophenia and Depression and in Vascular Dementia
WMC (vascular) dominated as a pathological symptom in MRI of Neuroborreliosis group and their occurence was significantly higher as compared to Control but not to ECM patients!! (ECM vs Control not significant).
Moreove, WMC didn’t correlate with hypertention or diabetes. - Might
have been of borrelia induced vasculitis.
We didn’t find any specific pattern of MRI characteristic to neuroborreliosis in the brain.
Demyelinisation and dysmyelinisation in MRI (FLAIR) may occur in course of neuroborreliosis 21%.
Only 10% of chronic Neuroborreliosis cases met the
MRI criteria for MS.
Brain athrophy was noticed in 43,4% of all the Neuroborreliosis cases. Didn’t corresspond with dementia in course of Neuroborreliosis
MRI changes location correspoded well with the clinical neurological symptoms.
Significantly more people with Neuroborreliosis had a cognitive dysfunction or even fulfilled a criteria for dementia as compared to Control and to ECM group
Despite a discussion in the literature of a possible link between Neuroborreliosis and Alzheimers Disease
Cognitive
dysfunction and dementia in our group was rather simillar to Vascular Dementia (VaD) in the character of cognitive dysfunctions
Over the course of six months of observation…
Nt Neuroborreliosis group-86
48/56% had relapses
10/12% had reversible relapses
28/32% had episodes of relapses with a new neurological symptoms – the clinical course secondary progressive
10/12% the clinical course was primary progressive
T Neuroborreliosis group-38
16/42% had „relapses” almost exclusively reversible; severity of existing symptoms were changing
The clinical courses of both Neuroborreliosis and MS can be simillar
Skotarczyk et al. (2002): PCR sensitivity in detection of DNA of Borrelia burgdorferi sensu lato in different isolates.
no Borrelia DNA in particular blood sample risk for fals negativ eresults
PCR results depends on genetic markers employed to DNA detection or DNA isolation risk
for false negative results
One ml of blood from peripheral elbow veine collected to tubes with EDTA
DNA was isolated using kits (Qiagen)
DNA encoding flageline (fla) was amplified using PCR kits (DNA Gdańsk)
Amplified DNA fragment 442 pairs of nucleotides
Compleate set of primers for „fla” gene
Isolated DNA (from the blood)
Polymerase Delta 2 (thermostable) (DNA Gdańsk)
Mixture of nucleotides (DNA Gdańsk)
DNA pattern 53-1031 pairs of nucleotides (FERMENTAS)
Positive control
(B. Burgdorferi s.s.) (DNA Gdańsk)
Negative control- redestilated water
Buffer for electroforesis ( FERMENTAS)
Carried out in thermocycler (Hot Shot 25, DNA Gdańsk)
The course was as follows:
initial denaturation 2 min., temp. 93 C, 40 cycles
denaturation 30 sec., temp. 93 C
incorporation of primers 60 sec., temp. 52 C
elongation 60 sec., temp. 72 C
terminal elongation
60 sec., temp. 72 C
Amplified DNA fragment- 442 pars of nucleotides
Nt Neuroborreliosis group-86 - 7/8%
T Neuroborreliosis group-38 - 5/13%
12 patient/124/9.6%
Control 1 person - ECM group 3%
12 PCR positive patients
The occurence of relapses was higher in Neuroborreliosis group as compared to ECM group and Control
PCR turned into negative after treatment
Despite limitations PCR may be of a diagnostic value in chronic cases of Neuroborreliosis and to monitor its clinical outcome
A positive PCR resuts corelated positivelly with the level of IgM
More positive PCR results were noticed in patients where positive both IgG and IgM were noticed.
See Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study
People with MS. We recruited as control for our cohort (22 people).
They didn’t remember the tick bite!
Examined during relapses.
Serological ELISA was significantly lower than in Neuroborreliosis cases (relapses)
No PCR positive cases
Different character of MRI
changes
Serological ELISA tests may be false positive in MS
MS cases diagnosed as a neuroborreliosis
The same cases - serological results
MA a 57, veterinary doctor
Late 70’ research worker she work with Ixodes ricinus -
1989, Multifocal neurological syptoms, cerebellar ataxia, right extremities weekness. MRI-did’t meet critera for MS -She was treated with steroids
1992 toxoplasmosis /miscarriage Treated
(Fansidar/Rovamycine)
1993 clumsiness of left hand
Apraxia of left hand-focal sign?
Fig. MRI/FLAIR of the patient with neuroborreliosis. Horizontal image
Wasn’t typical for MS Apraxia didn’t correspond with MS MRI changes
Fig. MRI/T1 image saggital image with a cyst (toxoplasmosis?)
Neuroborreliosis ELISA IgM. Western B., PCR positive (CSF)
See Dysarthria as the isolated clinical symptom of borreliosis--a case report.
64 y.o. man
Tongue flaccid palsy
XII cranial nerve n. hypoglossus dysfunction
Interesting !!!-Both L/R
He was diagnosed as MND-excluded
Probable neuritis in. n. hypoglossus
IgG, IgM ELISA positive, WB positive
PCR negative, CSF (all positive)
35 year old man was seen by Speech terapist who suggested non fluent aphasia
Progressive character, PNFA
MND symptoms-one site?
FTD/MND
Developed arthritis
IgM positive, PCR positive
34 y.o. woman,
„Proximal” muscles of lower (upper less) extremities fatigue.
She wasn’t able to stand up from a sitting position. She wasn’t able to climbed the stairs…Symptomes lasted 6 months.
In neurological examination: pure motor symptoms.
Weekness, no flaccidity, no pathological signs
Weekness was stable, not increasing during movement.
Spinal diseases excluded
No familly history of polineuropathy. Other forms of polineuropathy were excluded. EMG and fEMG slowness of muscle constricton. Biopsy( left m. vastus medialis)
inflamation?
Chronic Fatigue Syndrome…..
Inspiration - cholinergic disfunction in CFS
Lyme disease?
During the next visit she complained of joint pain (elbows, knees)
She was ELISA IgG and IgM and PCR positive
After a second month of antibiotic therapy with improvement
On behalf of:
Dr Ewa Cisak
Dr Jolanta Chmielewska-Badora
Professor Jacek Dutkiewicz
Lyme Disease Action, Registered Charity Number 1100448, Registered Company Number 4839410
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