Neurological symptoms of Lyme disease

Lyme borreliosis is the most common vector-borne infection in Europe and North America, with a significant proportion of cases presenting with neurological manifestations, involving a wide range of the central and peripheral nervous system. This is explained by the neurotropic properties of the Borrelia burgdorferi sensu lato complex: in Europe, the B. garinii and B. afzelii strains are particularly common, of which B. garinii has been shown to be neurotropic. Neurological symptoms may appear in the early stages, but also in the late stages of infection, which may have been present for months or years. The clinical picture differs significantly between Europe and North America, which can be explained by the differences between the dominant Borrelia strains.

Pathophysiological background and affected structures

After the bite, the pathogen multiplies and spreads locally. It reaches the bloodstream by crossing the walls of the capillaries in the skin tissue, but within 4-6 hours of the tick bite, direct contact is established between the tick’s digestive system and the blood vessels, allowing a much larger amount of the pathogen to enter the bloodstream directly. The most likely method of neurotropism is that Borrelia reaches the nervous system through haematogenous dissemination. In some cases, the complications of Lyme disease affecting the nervous system are accompanied by characteristic lymphocytic pleiocytosis in the cerebrospinal fluid, a moderate increase in protein levels, and the presence of intrathecal Borrelia-specific antibody production, which is not observed in all cases. Most of the clinical symptoms are related to immune-mediated mechanisms, inflammation of the roots and nerves, and involvement of the meninges and, less frequently, the brain or spinal cord parenchyma. The guidelines of the EFNS/EAN (European Federation of Neurological Societies) and the German Neurological Society traditionally distinguish between acute (<6 months) and chronic neurological involvement based on neurological manifestations.

The classic triad: meningitis, cranial neuropathy, radiculoneuritis

The “classic triad” – lymphocytic meningitis, cranial neuropathy (primarily facial paresis) and radiculoneuritis – are the three most common forms of neurological complications of Lyme disease, especially in Europe. The elements of the triad may appear in isolation or in various combinations, and the temporal course of symptoms may also be characteristic: radicular pain often precedes headache, which is later accompanied by cranial nerve palsy.

Lymphocytic meningitis may be clinically associated with subacute onset of headache, neck stiffness, photophobia, nausea and fever, but the symptoms are often milder than in viral meningitis and the patient’s general condition may remain relatively good. Neurological physical examination often reveals only mild meningeal signs, possibly papilledema. Although cerebrospinal fluid (CSF) examination is included in many protocols as a criterion of decisive diagnostic significance, in practice it is not always used due to its invasiveness and unknown sensitivity. Several different tests can be performed on CSF samples:

Confirmation of the presence and number of white blood cells, which indicates inflammation, but this is not always present or significant in cases of Lyme disease with neurological symptoms.
Detection of intrathecal antibodies, which some guidelines accept as diagnostically significant if the presence of antibodies is also detectable in serum samples taken at the same time. A known problem is the generally low sensitivity of serum antibody tests (below 50%) and the persistence of antibodies in treated patients even after recovery. For this reason, the combined sensitivity of parallel testing and combined testing is unknown and cannot be estimated. In the literature, studies that do not define neuroborreliosis based on this method show a higher prevalence of the disease.
Many renowned Lyme disease experts do not recommend testing for intrathecal antibodies because the disease can be adequately treated with antibiotics, thus posing less risk than diagnostic intervention. However, it should be noted that:
In Europe, the most common Borrelia strain is Garinii, which is more resistant than the sensu stricto strain that is almost exclusive to North America.
The garinii strain is sensitive to beta-lactam and penicillin agents, but less sensitive to doxycycline-type agents, so it may be necessary to identify the strain causing the infection in advance.
In the case of neuroborreliosis, IV ceftriaxone, which is particularly effective, is still linked to cerebrospinal fluid testing in protocols – which is unjustified in some respects.
It is also possible to detect the CXCL13 chemokine, which has been studied in numerous recent clinical trials, because the pathogen, especially in the early stages, causes symptoms not only through its direct presence, but also through chemokines and cytokines that bypass the blood-brain barrier.

Of the cranial neuropathies, involvement of the VII cranial nerve is by far the most common. Facial paralysis can be unilateral or bilateral, sudden or developing over a few days in the form of peripheral facial paresis. In children and young adults, Lyme disease should be considered even in cases of isolated facial paresis occurring during the tick exposure season, especially if the patient reports erythema migrans or flu-like symptoms. In addition to the facial nerve, the vestibulocochlear nerve, oculomotor nerve, abducens nerve or trigeminal nerve may also be affected, albeit less frequently; in cases of multiple cranial neuropathy, Lyme borreliosis is an important differential diagnosis.

Radiculoneuritis is an inflammatory involvement of the sensory or sensory-motor roots, which is associated with pronounced, often worsening at night, dermatomal radicular pain, paresis and sensory deficits. In Europe, Bannwarth syndrome – painful radiculitis, often with cranial neuropathy and lymphocytic pleiocytosis of the cerebrospinal fluid – is the most common form of neurological complications of Lyme disease in adults. Patients often complain of burning, cutting pain at night, which is not easily relieved by movement, and is often followed by radicular paresis. Patients often complain of nocturnal, burning-cutting pain that is not greatly affected by movement and is often followed by radicular paresis.

Central nervous system manifestations

Although the vast majority of neurological Lyme disease is meningoradicular in nature, parenchymal involvement of the central nervous system (CNS) is also significant. Late neurological complications may include encephalomyelitis, myelitis, meningoencephalitis or leukoencephalitis, most commonly with subacute, focal neurological symptoms and progressive gait disturbance.

Encephalomyelitis may manifest clinically as spastic-ataxic gait, lower limb paraparesis, bladder dysfunction, sensory ataxia, and pyramidal tract signs. Neuroimaging – primarily MRI – may show multifocal T2 hyperintensities in the white matter, involvement of the corpus callosum, and occasionally contrast-enhancing lesions, which may mimic multiple sclerosis, causing a diagnostic dilemma.

Spinal cord involvement (myelitis) is associated with slowly progressive paraparesis, sensory disturbances and sphincter dysfunction. MRI often shows lesions affecting long segments, located centrally or dorsally. From a differential diagnostic point of view, it is important to distinguish between inflammatory myelopathies, neuromyelitis optica spectrum disorders and paraneoplastic conditions.

Cerebral vasculitis may also occur in rare cases, manifesting as ischaemic stroke or TIA, mainly in younger patients without cardiovascular risk factors. In such cases, multiple lacunar infarcts, intracranial artery stenoses or aneurysms are often seen, and the cerebrospinal fluid is inflammatory in nature. Vasculitis should be suspected especially when stroke is accompanied by symptoms of meningitis or radiculitis.

Early observations suggest that some patients may develop subacute-chronic encephalopathy, which is associated with slowly progressive cognitive complaints (memory and concentration disorders), fatigue, sleep disturbances and mood instability. These symptoms are non-specific and often difficult to distinguish from other psychiatric or somatic conditions, so proof of Lyme origin can only be considered valid if there is a well-documented history of infection and objective neurological/cerebrospinal fluid abnormalities.

Peripheral nervous system symptoms

Peripheral nervous system involvement is a common component of Lyme disease. In addition to radiculitis, sensory, sensory-motor or, less commonly, purely motor polyneuropathy may also develop. The clinical picture is mostly characterised by distal, symmetrical, “sock-glove” type paraesthesia, burning dysaesthesia, loss of sensation, mild distal paresis and decreased reflexes. Electrophysiology can confirm chronic polyneuropathy with axonal predominance.

European studies have also described a form of multiplex mononeuropathy, in which asymmetric sensory or motor deficits predominate, with involvement of different nerve trunks. From a clinical point of view, it is particularly important to consider Lyme borreliosis in cases of painful polyneuropathy or multiplex mononeuropathy of unknown origin, especially if tick exposure, erythema migrans or other symptoms suggestive of Lyme disease are present in the medical history.

Plexopathy involving the brachial or lumbosacral plexus is also rare, but it is a described form that has an acute or subacute onset and is combined with severe limb pain and paresis. The possible association of Guillain-Barré syndrome-like acute inflammatory polyneuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP) with Lyme disease has not yet been confirmed, its frequency has not been studied, and for the time being it is only supported by individual case reports.

Neurocognitive symptoms and psychiatric implications

The spectrum of cognitive and psychiatric symptoms associated with Lyme disease is broad, but it is difficult to distinguish Lyme-specific central nervous system damage from functional or co-morbid psychiatric disorders. Clinical studies have described chronic encephalopathy associated with slowly progressive memory and attention deficits, deterioration of executive functions, sleep disturbances, and affective symptoms. In this condition, neuropsychological tests reveal a moderate, heterogeneous pattern of deficits, while MRI often shows only mild, non-specific white matter abnormalities.

Psychiatric symptoms – depressive mood, anxiety, irritability – are often secondary to the burden of chronic illness, pain, and sleep disturbances, so caution is needed from an aetiological perspective when assessing the causal relationship between Lyme disease and mental disorders. The leading guidelines do not recommend Lyme screening based solely on psychiatric symptoms in the absence of objective neurological abnormalities confirmed by a detailed Lyme symptom assessment.

Imaging and electrophysiological tests in diagnostics

In addition to cerebrospinal fluid testing, imaging and neurophysiological methods play an important complementary role in the diagnosis of neurological complications of Lyme disease. MRI often reveals leptomeningeal contrast enhancement, root or cranial nerve involvement, and the aforementioned white matter and spinal cord lesions. Facial nerve involvement may manifest as contrast enhancement in the intracanalicular or intraparotid segments. In cases of cerebrovascular complications, MR or CT angiography may reveal narrowing, aneurysmal dilation, or dissection of the affected arteries.

Electroneurography and EMG can be used to confirm root lesions associated with radiculoneuritis, the axonal or demyelinating nature of polyneuropathy, and the extent of cranial neuropathies.

Differential diagnosis

The neurological symptoms of Lyme disease can mimic many other conditions, so differential diagnosis is crucial. Lymphocytic meningitis may be caused by enterovirus, HSV, VZV infection, tuberculosis, autoimmune or paraneoplastic meningitis. Radiculoneuritis must be differentiated from disc herniation, degenerative spinal disease, herpes zoster radiculitis and neoplastic root involvement.

In patients with KIR white matter lesions, multiple sclerosis, ADEM, vasculitis, sarcoidosis, and other infectious encephalomyelitis (HIV, HTLV, syphilis) may also be considered. In the differential diagnosis of polyneuropathy, diabetes, alcohol abuse, vitamin B12 deficiency, paraneoplastic and other autoimmune neuropathies are at the forefront.

Summary

The neurological manifestations of Lyme disease are extremely diverse, ranging from radicular or polyneuropathic involvement of the peripheral nerves to cranial neuropathies, meningitis and Bannwarth syndrome to the rarer encephalomyelitis, vasculitis-associated stroke and neurocognitive disorders. It is crucial for clinicians to consider Lyme aetiology in neurological conditions where the medical history includes tick exposure, erythema migrans or seasonal occurrence, or where the clinical picture is characteristic, for example, facial nerve palsy associated with radicular pain.

The guidelines emphasise that diagnosis cannot be based solely on serology: a combined assessment of the clinical picture, cerebrospinal fluid findings and epidemiological background may be necessary. In line with the EU Lyme position statement, physicians specialising in Lyme disease often initiate treatment based on a diagnosis of “borreliosis with neurological symptoms” based on positive results from newly developed blood or serum tests and clinical symptoms. The vast majority of neurological symptoms regress with appropriate, timely antibiotic treatment, although in some cases residual deficits may persist, particularly after polyneuropathy or severe radiculoneuritis.

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