Neurological sequelae following LYMErix vaccination.
Journal of the Peripheral Nervous System Volume 9 Issue 3 Page 165 - September 2004
Norman Latov, Anita T. Wu, Russell L. Chin, Howard W. Sander, Armin Alaedini, Thomas H. Brannagan III (2004)
Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi
Journal of the Peripheral Nervous System 9 (3), 165-167. doi:10.1111/j.1085-9489.2004.09306.x
Neurological syndromes that follow vaccination or infection are often attributed to autoimmune mechanisms. We report six patients who developed neuropathy or cognitive impairment, within several days to 2 months, following vaccination with the OspA antigen of Borrelia burgdorferi.
Two of the patients developed cognitive impairment, one chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy, one both cognitive impairment and CIDP, and one cognitive impairment and sensory axonal neuropathy. The patients with cognitive impairment had T2 hyperintense white matter lesions on magnetic resonance imaging. The similarity between the neurological sequelae observed in the OspA-vaccinated patients and those with chronic Lyme disease suggests a possible role for immune mechanisms in some of the manifestations of chronic Lyme disease that are resistant to antibiotic treatment.
Neurological sequelae of vaccination are often acute and fulminate as in the Guillain-Barr� syndrome or acute disseminated encephalomyelitis (Tselis and Lisak, 1998) but can also be chronic and indolent, or involve both the central and peripheral nervous systems (Poser, 1982;Vital et al., 2002). We report the development of chronic neuropathies or cognitive impairment in six patients, following vaccination with the LYMErix vaccine, which contains the OspA protein of Borrelia burgdorferi coated onto aluminum hydroxide.
Patients The medical records of six patients seen at our center over a 2-year period, who reported developing neurological sequelae after vaccination with the OspA protein in the form of the LYMErix vaccine, were reviewed.
Patients with clinical evidence for peripheral neuropathy underwent electromyography and nerve conduction studies or skin biopsies to assess for intradermal nerve fiber density, and those that had cognitive impairment underwent brain magnetic resonance imaging (MRI), with and without gadolinium. Vaccination was typically given in three doses, the second dose 1 month following the first, and the third dose 1 year later. Some of the patients received the full three doses, but others developed neurological syndromes after only one or two doses. They were not tested for Lyme antibodies before vaccination.
Results of neurological evaluation and ancillary investigations of the six patients are summarized in Table 1. Two of the patients had cognitive impairment, two had demyelinating neuropathies, one had both cognitive impairment and demyelinating neuropathy, and one had cognitive impairment and sensory axonal neuropathy. In all cases, onset of symptoms was hours to 8 weeks after vaccination.
One of the patients (patient 2) with demyelinating neuropathy also had diabetes mellitus, but it is unlikely that the diabetes was responsible, as it was controlled with diet, the neuropathy responded to IVIg, and there were no symptoms of neuropathy before vaccination in contrast to the severe neuropathy which followed. No other causes for cognitive impairment or neuropathy were found in any of the patients.
All four patients with cognitive impairment had difficulty with concentration, short- and long-term memory impairment, and chronic fatigue. All four had evidence on MRI of subcortical white matter lesions (Table 1).
Patients 2 and 3, with CIDP, and patient 1 with multifocal motor neuropathy, partly improved following treatment with IVIg, but relapsed, and required repeated or maintenance therapy. The cognitive impairment in patients 3, 4, 5, and 6 persisted but stabilized, both in those that were treated with IVIg for their demyelinating neuropathy and those that were not treated. The cognitive impairment was sufficiently severe, so that the patients could no longer carry out their usual work-related functions.
Neurological syndromes that follow vaccination or infection are often considered to be immune-mediated and result from molecular mimicry or non-specific activation of pre-existing autoreactive lymphocytes (Wraith et al., 2003).
Neurocognitive dysfunction with musculoskeletal pain and chronic fatigue was also previously reported in another 15 patients who received the OspA vaccine, but the patients were not neurologically evaluated and the symptoms were attributed to reactivation of Lyme disease, although some of the patients had no history of exposure (Donta, 2001). Of interest, the only two patients (patients 4 and 5) in this study to develop symptoms following the first vaccine gave a history of previously treated Lyme disease, which might have primed their immune system to a subsequent challenge.
The incidence of neurological sequelae following LYMErix vaccination is unknown. No increase in neurological disease was noted in the original efficacy studies of the vaccine (Steere et al., 1998) or by the Vaccine Adverse Event Reporting System (Lathrop et al., 2002).
However, a subsequent comparison to the adult tetanus-diphtheria vaccine indicated a higher incidence of 'neuropathy and paralysis' in the LYMErix-vaccinated patients, although the diagnoses were not verified (Geier and Geier, 2002). The vaccine has since been withdrawn from the market.
OspA is a lipoprotein with immuno-stimulatory properties that can activate pro-inflammatory toll-like receptors of the innate immune system (Bulut et al., 2001).
Such receptors are also found on Schwann cells, microglia, astrocytes, and oligodendroglia (Bsibsi et al., 2002;Oliveira et al., 2003), possibly contributing to the development of the autoimmune response. It has also been reported to induce proliferation and apoptosis of astrocytes (Ramesh et al., 2003) and implicated in the pathogenesis of Lyme arthritis, possibly through its immune-activating mechanisms (Steere and Glickstein, 2004).
Of interest, neuropathy and cognitive impairment, as seen in the vaccinated patients, are also common manifestations of chronic Lyme disease that are resistant to antibiotic treatment (Duray, 1989;Steiner, 2003). The cognitive impairment, in particular, that is manifested by forgetfulness, inability to focus, disorganization of thought, and chronic fatigue, without focal neurological signs, is not commonly seen in other conditions (Caudino et al., 1997;Krupp et al., 1991;Morgen et al., 2001).
Brain white matter lesions, as were seen in some of our patients, can be non-specific in the elderly but were more numerous or larger than that which would be expected in our patients' age group and are commonly seen in patients with chronic Lyme encephalopathy (Morgen et al., 2001).
Neuropathies in patients with chronic Lyme disease commonly present as nonvasculitic mononeuritis multiplex (Logigian, 1997;Kindstrand et al., 2000;Halperin, 2003), but demyelinating neuropathies, including those with multifocal conduction block, have also been reported (Oey et al., 1991;Zifko et al., 1995).
The neurological manifestations of chronic Lyme disease are often attributed to persistent infection, although autoimmunity has also been suggested because of the resistance to antibiotics (Halperin, 2003;Steiner, 2003).
The observed similarities between the neurological manifestations of chronic Lyme disease and those following vaccination with the OspA protein suggest that some of the manifestations may result from autoimmune mechanisms that can be triggered by infection or vaccination.
Similar mechanisms have been proposed to explain antibiotic-resistant arthritis in chronic Lyme disease (Steere and Glickstein, 2004). These observations warrant further investigation.
This article is cited by:
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Medline This article is cited by the following articles in Blackwell Synergy and CrossRef Praful Kelkar. (2006) Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) With Rapid Progression After Influenza Vaccination: A Report of Three Cases. Journal of Clinical Neuromuscular Disease 8:1, 20
By author Norman Latov Anita T. Wu Russell L. Chin Howard W. Sander Armin Alaedini
Anita T. Wu11Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
Russell L. Chin11Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
Howard W. Sander11Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
Armin Alaedini11Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
Thomas H. Brannagan, III
Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA1Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA
*Norman Latov, MD, PhD, The Peripheral Neuropathy Center, Weill Medical College of Cornell University, New York, NY 10022, USA. Tel: +1-212-888-8516; Fax: +1-212-888-9206; Email: [email protected]
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