Symptoms of LNB & ‘Post-Lyme Disease’

Acute & Chronic LNB

In Europe, the most frequent manifestation of LNB is meningoradiculitis, also known as Bannwarth’s syndrome. It is characterized by intense, lancinating pain, typically exacerbated by night. The dynamic of the pain during the course of the day is still unexplained. A reason might be the increased alertness to pain during the night time, or the supine position with more warmth in the spine region during bed rest.^[121] However, studies on this topic are lacking. Meningeal signs or headache are mostly mild and less common. In particular, if left untreated, the pain is followed by focal neurological signs, such as paresis or paresthesia.^[122] The paresis is mostly linked to the location of maximal pain and might affect the limbs, the trunk or the cranial nerves. Typical for LNB are, for example, paresis of the abdominal muscles or bilateral facial palsy. By contrast, an isolated polyneuropathy in LNB without acrodermatitis chronica atrophicans has not been reliably documented in Europe so far. Polyneuropathy in the context of acrodermatitis chronica atrophicans (an isolated polyneuropathy in LNB without an affection of the skin has not been reliably documented in Europe so far) or encephalomyelitis are rare manifestations of LNB and belong to the typical clinical picture of chronic LNB.^{[69,122–124]} In addition, case reports have proposed further CNS manifestations, such as cerebellitis^[125] or carpal tunnel syndrome,^[126] but based on such rare cases, it is difficult to discriminate an incidential coincidence from a real association or cause.

In North America, the manifestation of LNB is less characteristic, with headache and neck stiffness (due to meningitis), subtle sensory polyneuropathy or mild cognitive disturbances in the context of encephalopathy.^[69,70] The reason for the different clinical pictures between the continents is most probably the different genospecies, as B. garinii and the recently separated B. bavariensis (as the typical species found in Bannwarth’s syndrome^[2]) are only endemic in Europe and not in North America.^[69] Even within Europe, there appear to be different forms of LNB depending on the responsible Borrelia species. While LNB patients infected with B. garinii report radicular pain more often and express meningeal signs, those infected with B. afzelii complain more about dizziness.^[71] Taken together, LNB should be recognized as a more heterogeneous disease, and it might even be of use to stratify LNB according to the underlying borrelial genospecies.

‘Post-Lyme Disease Syndrome’

There is still an ongoing discussion as to whether PLD really exists. According to proposed diagnostic criteria, it encompasses patients following a treated Lyme disease who suffer from persisting, mostly mild and nonspecific symptoms, in whom other causes have been excluded.^[127,128] The onset of the symptoms should be no later than 6–12 months after Lyme disease. On the one hand, there is a large, well-designed American study that did not find an increased incidence of such symptoms in patients after treated Lyme borreliosis compared with the general population.^[129] By contrast, a meta-analysis documented persisting symptoms significantly more often – in approximately 5% of patients after Lyme borreliosis^[130] – but there may have been a publication bias, as positive studies are often easier to publish. An additional argument against the existence of PLD might be an increased sensitivity to nonspecific symptoms with the knowledge of a borrelial infection in the past, especially as persisting symptoms were found more frequently in those who were misdiagnosed with Lyme disease than in those that had definitely been infected by B. burgdorferi in the past.^[129] A European study approached this bias problem in a rather innovative way. A large population (n = 505) of young military recruits was screened for B. burgdorferi-specific antibodies. After exclusion of those who remembered a subsided case of borrelial infection, or suffered from an active infection with Borrelia, the recruits had to fill out a questionnaire without knowledge of the results from the serology. Antibody-positive individuals reported fatigue, general malaise and limb pain significantly more often.^[131] This might be an important argument for the existence of PLD. Finally, as already described for LNB, there might be a difference between American and European PLD, and results from either continent are not easily transferred to the other. A study from Norway compared patients who were treated for LNB 30 months ago with a healthy control group and found – besides objective neurological findings – poorer quality of life and, in particular, more fatigue in the treated LNB patients.^[132] However, an important drawback of this European study was the selection of the control group, as patients with other inflammatory diseases of the CNS in the past might be more suitable for such a comparison.

The pathogenesis of PLD – if it really exists – is unknown. An ongoing, active borrelial infection is very unlikely, for the following reasons: Borrelia have not been cultivated or even identified by PCR from the CSF in PLD patients; the CSF displays no inflammatory changes in these patients; and a resistance of B. burgdorferi to the typically applied antibiotics has not been documented to date.^[127] Based on these pathogenic considerations, there is no indication for antibiotic treatment of PLD. This is further substantiated by appropriate clinical trials. A large, controlled-treatment trial clearly demonstrated that treatment of PLD (both seropositive and seronegative cases) for 30 days with intravenous ceftriaxone followed by oral doxycycline for 60 days is not more effective than placebo.^[133] If only scientifically sound studies that fulfill certain methodological criteria are considered, all other studies on this topic could reproduce these findings.^[128] Recently, it was demonstrated that even 10 days of antibiotics are sufficient to treat early Lyme disease, with a 2-year treatment failure-free survival rate of 99%.^[134] Therefore, there is no indication for antibiotic treatment beyond the 10–21-day regimen. It must be remembered that a prolonged course of antibiotics leads to increased bacterial resistance and also eliminates the physiological bacterial flora. In addition, there are reports on severe complications, including death, from a prolonged, nonindicated antibiotic therapy for ‘chronic’ Lyme disease.^[127]

But what other pathogenic mechanism could account for PLD? In a recent study, antineuronal antibodies against motor neurons and dorsal root ganglia cells have been found in nearly half of patients with PLD, but only in 18.5% of patients after a subsided infection without persisting symptoms.^[120] In addition, as described previously, it has been shown that antibodies in LNB are not only directed against the spirochetes themselves, but also against the CNS parenchyma.^[135] This would suggest an autoimmune phenomenon triggered by the Borrelia, possibly due to molecular mimicry. Another interesting theory is that persisting symptoms after treated LNB are due to disturbances of the hormone axis, as suggested recently, but arguments for an endocrine dysfunction remain very sparse.^[136] Nevertheless, PLD has to be distinguished from persisting symptoms due to the harmful effects of the initial borrelial infection (e.g., direct cytotoxicity of the spirochetes). It has to be assumed that remaining complaints after a subsided LNB, which can be found in up to 48% 1 year after the infection,^[137] are at least in part the result of damage that the Borrelia have left behind. An evident example is a remaining facial palsy after cranial neuritis. In addition, other differential diagnoses have to be considered (e.g., chronic fatigue, fibromyalgia or depression).^[138]

Taken together, PLD as a disease entity is not yet well defined and its pathophysiology is far from clear. Further studies on this topic are urgently needed, as those patients with persisting symptoms are a diagnostic and therapeutic problem in everyday practice. Often, those patients feel that they are not taken seriously and, due to the unclear diagnosis, therapeutic options are poor.