Neurology -- Correspondence for Blanc et al., 69 (10) 953-958

Correspondence published:

Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients: Unn Ljøstad, Åse Mygland (27 December 2007)

Reply from the authors: Frederic Blanc, Benoit Jaulhac, Jerome de Seze, Yves Hansmann, Christine Tranchant (27 December 2007)

Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients: Douglas J. Lanska (4 December 2007)

Reply from the author/ Lanska: Frederic Blanc, B. Jaulhac, MD, PhD; M. Fleury, MD; J. de Seze, MD, PhD; S.J. de Martino, MD; G. Blaison, MD; Y. Hansmann, MD; D. Christmann, MD, PhD; and C. Tranchant, MD, PhD. (4 December 2007)

Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients 27 December 2007

Unn Ljøstad,
Department of Neurology
Serviceboks 416, 4604 Kristiansand, Norway,
Åse Mygland
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Re: Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients

unn.ljostad{at}sshf.no Unn Ljøstad, et al.

Blanc et al. found that a positive intrathecal anti-Borrelia antibody index (AI) had a low diagnostic sensitivity of 75% and a high specificity of 97% in Lyme neuroborreliosis. [1] Based on this they suggest new diagnostic criteria, according to which patients with any neurologic symptom and a normal CSF lymphocyte count can be diagnosed with Lyme neuroborreliosis if they have either a postive AI or a response to antibiotic treatment given a negative history of neuroborreliosis and no differential diagnosis.
We have some concerns about both the reference standard used for definite neuroborreliosis, and the suggested new diagnostic criteria. Our first concern is that 22 of the 40 patients classified as definite neuroborreliosis had a normal CSF lymphocyte count. Their clinical syndromes were cranial neuropathy, neuropathy, spinal radiculitis, acute delusion, cognitive impairment, lower motor neuron syndrome and chronic polyradiculoneuritis. Could some of these syndromes be idiopathic with spontaneous recovery or placebo response to treatment? If Blanc et al. had used a stricter reference standard including presence of CSF pleocytosis, it would give a lower AI test specificity and higher test sensitivity with following implication for interpretation and diagnostic criteria.
In addition, previous studies have shown that AI may be negative in early disease due to a delayed immune response, but that it becomes positive in nearly 100% of untreated neuroborreliosis patients with over six weeks duration of symptoms. [2,3] How long was the disease duration in the four AI negative patients in this study?
In conclusion, we appreciate the initiative to revise existing diagnostic criteria, but in accordance with existing criteria, CSF pleocytosis should be required. A better way of achieving liberalization of diagnostic criteria would be to discriminate between definite, probable and possible neuroborreliosis.
References
1. Blanc F, Jaulhac B, Fleury M, et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology. 2007;69:953-958.
2. Hansen K, Lebech AM. Lyme neuroborreliosis: a new sensitive diagnostic assay for intrathecal synthesis of Borrelia burgdorferi-- specific immunoglobulin G, A, and M. Ann.Neurol. 1991;30:197-205.
3. Ljostad U, Skarpaas T, Mygland A. Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur.J.Neurol. 2007;14:873-876.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 27 December 2007

Frederic Blanc,
Department of Neurology, University Hospital of Strasbourg and Louis Pasteur University
67091 Strasbourg Cedex, France,
Benoit Jaulhac, Jerome de Seze, Yves Hansmann, Christine Tranchant
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Re: Reply from the authors

blanc.frdrc{at}free.fr Frederic Blanc, et al.

We thank Drs. Ljostad and Mygland for their comments on our article where we studied 123 consecutive patients with neurological involvement and CSF anti-Borrelia antibodies. [1]
In analyzing these patients, we found that a positive intrathecal anti-Borrelia antibody index (AI) had a diagnostic sensitivity of 75% and a specificity of 97% in Lyme neuroborreliosis. [1] We chose to include all patients with CSF anti-Borrelia antibodies and not only patients with pleocytosis and CSF antibodies for several reasons.
First, we did not want to exclude any neuroborreliosis diagnosis, second because establishing the Lyme etiology of patients with pleocytosis and anti-Borrelia antibodies in CSF is generally not a diagnostic problem, and third because pleocytosis is no longer an obligatory criterion for European diagnosis of neuroborreliosis.
Initially, in 1996, European criteria for neuroborreliosis (EUCALB criteria) included pleocytosis [4] but it is not currently a necessary criterion for early neuroborreliosis as mentioned on the EUCALB website. [5] Moreover, several papers reported some cases in Europe for which neuroborreliosis was diagnosed without any pleocytosis. [6-7]
Drs. Ljostad and Mygland have some concerns about the etiological diagnosis of the 22 of 40 patients with definite neuroborreliosis and normal CSF count. All these patients presented symptoms already described in neuroborreliosis literature. Some patients had acute delusion, cognitive impairment or lower motor neuron syndrome; such symptoms recover rarely spontaneously, particularly the lower motor neuron syndrome.
Moreover, in our study, none of the patients have relapsed more than two years after the end of the antibiotic treatment. Three of the four patients with spinal radiculitis had bilateral sciatalgia without disk herniation. Such symptoms are rarely “idiopathic with spontaneous recovery” but are frequent in neuroborreliosis. A higher sensitivity of the Borrelia AI was observed when tested only on patients with pleocytosis in our study since 16 out of 18 patients (89%) with neuroborreliosis and pleocytosis had a positive AI. Specificity was not calculable because there was no other patient in our cohort with pleocytosis but patients with neuroborreliosis. The specificity was also not calculated in the study of Drs. Ljostad and Mygland. [3]
Finally, we agree with Drs. Ljostad and Mygland who reported that the Borrelia AI is more frequently positive after 6 weeks of clinical evolution. [3] In our study, the four patients with negative AI had lumbar puncture for CSF analysis between 2 to 4 weeks after the osnet of symptoms.
References
4. Stanek G, O'Connell S, Cimmino M, et al. European Union Concerted Action on Risk Assessment in Lyme Borreliosis: clinical case definitions for Lyme borreliosis. Wien Klin Wochenschr 1996;108:741-747.
5. http://meduni09.edis.at/eucalb/diagnosis_case-definition-outline.html
6. Dhôte R, Basse-Guerineau AL, Beaumesnil V, Christoforov B, Assous MV. Full spectrum of clinical, serological, and epidemiological features of complicated forms of Lyme borreliosis in the Paris, France, area. Eur J Clin Microbiol Infect Dis 2000;19:809-815.
7. Roux F, Boyer E, Jaulhac B, Dernis E, Closs-Prophette F, Puechal X. Lyme meningoradiculitis: prospective evaluation of biological diagnosis methods. Eur J Clin Microbiol Infect Dis 2007;26:685-693.
Disclosure: The authors report no conflicts of interest.

Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients 4 December 2007

Douglas J. Lanska,
Veterans Affairs Medical Center,
500 E. Veterans St., Tomah, WI 54660
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Re: Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients

Douglas.Lanska{at}med.va.gov Douglas J. Lanska

Blanc et al note that in Europe an anti-Borrelia CSF-serum antibody index is used as an indicator of intrathecal synthesis for diagnosis of Lyme neuroborreliosis. [1] However, they incorrectly indicate that this is not the case in the US, citing surveillance criteria of the Centers for Disease Control (CDC). [2]
An accompanying editorial surprisingly concurs. CDC surveillance criteria state that they are “not intended to be used in clinical diagnosis” and that encephalomyelitis must be confirmed for surveillance purposes by demonstrating production of anti-B. burgdorferi antibodies in CSF (i.e., intrathecal synthesis), as shown “by a higher titer of antibody in CSF than in serum.” [2]
Several US research groups have published methods of determining intrathecal antibody synthesis based on indices of specific antibodies in CSF and serum. Also, CSF-serum antibody indices of intrathecal synthesis of anti-B. burgdorferi antibodies are commercially available in the US.
Furthermore, practice parameters for diagnosis of Lyme neuroborreliosis supported by the American Academy of Neurology state that proper assessment of intrathecal antibody production needs to correct “for immunoglobulin leakage into the CSF because of blood-brain barrier disruption. ...When CNS involvement is suspected, demonstration of intrathecal antibody production is highly specific and quite sensitive, particularly in patients with acute disease; it may even rarely be diagnostic despite negative peripheral blood serologic tests. ...Intrathecal antibody production may persist for years following successful treatment, so this does not provide a useful marker of disease activity.” [3] Even the brief summary statement by the AAN Quality Standards Subcommittee concluded that “CSF analysis for cells, protein, and intrathecal production of specific antibody is indicated if CNS infection is suspected.” [4]
Blanc et al. used a 3x3 categorization of test results (positive, intermediate, negative) and disease states (definite neuroborreliosis, possible neuroborreliosis, other conditions). Because calculation of sensitivity and specificity requires a 2x2 categorization, [5] they combined the intermediate and negative test results only for cases with definite neuroborreliosis or other conditions, while inappropriately dismissing possible neuroborreliosis cases. [1] This produces biased results (spectrum bias) as can be seen by considering such cases as either diseased or not diseased. [5]
“Possible neuroborreliosis” cases are those that pose diagnostic challenges and in whom the utility of such a diagnostic test should be evaluated. Instead, the test was given the much easier task of discriminating between clinically definite neuroborreliosis cases and controls without much suspicion of neuroborreliosis (low pre-test probability), which inflates calculated test indices.
References
1. Blanc F, Jualhac B, Fleury M, et al. Relevance of the antibody index to diagnose Lyme neuroborelliosis among seropositive patients. Neurology 2007;69:953-958.
2. Centers for Disease Control. Case definitions for infectious conditions under public health surveillance. MMWR Morbid Mortal Weekly Rep 1997;46(No. RR-10):20-21.
3. Halperin JJ, Logigian AEL, Finkel MF, Pearl RA. Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease). Neurology 1996;46:619-627.
4. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: diagnosis of patients with nerve system Lyme neuroborreliosis (Lyme disease) – summary statement. Neurology 1996;46:881-882.
5. Feinstein AR. Diagnostic and spectral markers. In, Clinical epidemiology: the architecture of clinical research. Philadelphia: W.B. Saunders Co., 1985: 597-631.
Disclosure: The author reports no conflicts of interest.

Reply from the author/ Lanska 4 December 2007

Frederic Blanc,
Department of Neurology, University Hospital and Louis pasteur University. Strasbourg. France ,
B. Jaulhac, MD, PhD; M. Fleury, MD; J. de Seze, MD, PhD; S.J. de Martino, MD; G. Blaison, MD; Y. Hansmann, MD; D. Christmann, MD, PhD; and C. Tranchant, MD, PhD.
Send Correspondence to journal:
Re: Reply from the author/ Lanska

blanc.frdrc{at}free.fr Frederic Blanc, et al.

We thank Dr. Lanska for his comments. The aim of our paper was not to oppose clinical practices of Europeans and Americans. The aim was to study the interest but also the limit of intrathecal anti-Borrelia antibody index (AI) to diagnose neuroborreliosis. [1] We also showed that positive Lyme serology in the CSF does not mean neuroborreliosis.
Among 123 consecutive patients with positive Lyme serology in the CSF, only 40 had a definite neuroborreliosis and 9 possible. Dr. Lanska specified that the CDC’s criteria of neuroborreliosis include AI to confirm encephalomyelitis. [6] Encephalomyelitis is a rare entity of neuroborreliosis, corresponding only to 4 to 6% of all the neuroborreliosis. [7,8] It would mean that to diagnose the majority of patients with neuroborreliosis, clinicians would not need to use the Borrelia AI.
Moreover, according to the CDC criteria: “Encephalomyelitis must be confirmed by demonstration of antibody production against B. burgdorferi in the CSF, evidenced by a higher titre of antibody in CSF than in serum”. This latter parameter is less precise than the AI. To establish the AI, the total non-specific IgG concentrations in CSF and serum have to be taken into account, and not just the comparison of the specific IgG levels.
In their recent review on neuroborreliosis, Drs. Pachner and Steiner specified that “In American LNB, the CSF antibody index is not commonly used, possibly because there has not been an extensive study to assess its usefulness in the American LNB setting relative to the usefulness of serum antibodies in patients with possible LNB”. [9]
In 1996, the statement of the AAN Quality Standards Subcommittee concluded that additional testing may be necessary. [4] Thus CSF analysis for cells, protein, and intrathecal production of specific antibody was indicated if CNS infection was suspected. As shown in our article and others [1,7,8], detection of anti-Borrelia intrathecal antibody production with the AI is not only useful for the diagnosis of CNS neuroborreliosis but also for meningitis, meningoradiculitis, radiculitis and probably for some cases of neuropathy.
We do agree with Dr. Lanska that possible neuroborreliosis is the diagnostic challenge. However, in our study, to validate the interest of the AI among positive Lyme serology in the CSF, only patients with definite neuroborreliosis or definite other etiology could be considered. Future studies will assess the clinical relevance of the AI test for possible neuroborreliosis cases.
References
6. CDC. Case definitions for infectious conditions under public health surveillance. Morb Mortal wkly Rep 1997;46:1-55.
7. Oschmann P, Dorndorf W, Hornig C, Schafer C, Wellensiek HJ, Pflughaupt KW. Stages and syndromes of neuroborreliosis. J Neurol 1998;245:262-272.
8. Hansen K, Lebech AM. The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985-1990. A prospective study of 187 patients with Borrelia burgdorferi specific intrathecal antibody production. Brain 1992;115 (Pt 2):399-423.
9. Pachner AR, Steiner I. Lyme neuroborreliosis: infection, immunity, and inflammation. Lancet Neurol 2007;6:544-552.
Disclosure: The authors report no conflicts of interest.