Neurologice manifestations in Lyme borreliosis

Neurologic Manifestations in Lyme Borreliosis WOLFGANG KRISTOFERITSCH, MD

N ‘eurologic manifestations may occur in early disseminated or late chronic Lyme borreliosis. Signs and symptoms of peripheral neuropathy had already been reported in patients

with acrodermatitis chronica atrophicans (ACA), the principal dermatologic manifestation of late chronic Lyme borreliosis, at the turn of this century1,2 (see review in Ref 3). The first case report of a patient with Bann- warth’s syndrome, a painful radiculoneuritis that follows tick bite and erythema migrans (EM), was published in 1922 by Garin and Bujadoux.‘Unfortunately, the authors were not aware that the enlarging erythema they observed was virtually identical to the EM described in 1909 by Afzelius5 and in 19 13 by Lipschiitz.6 A case report on EM followed by meningitis was first published in 1930 by Hellerstriim.’ In the 196Os, Schaltenbranda and other Eu- ropean neurologists - 9 l3 studied large cohorts of patients, all of whom developed painful radiculoneuritis, cranial neuritis, or lymphocytic meningoencephalitis as a sequela of tick bite and EM. Although the pathogenesis was un- known, it seemed clear that these patients suffered from a clinically characteristic disease, which was named meningopolyneuritis Garin - Bujadoux- Bannwarth14 or Bann- warth’s syndrome. l3 Despite reports that showed a benefi- cial effect of penicillin on EM-meni~@tis,‘~,‘~ most European neurologists thought an arbovirus was the cause of Bannwarth’s syndrome.*-10~1*~13 This concept was drawn from the knowledge of the viral etiology of central European encephalitis, another tick-transmitted neurologic disease observed in Europe. Yet dermatolo- gists, familiar with the long-known therapeutic effect of antibiotics in EM and ACA, continued to postulate that

From the Department of Neurology, SMZ-OST Krankenhaus, Vienna, Austria.

Address correspondence to: Wolfgang Kristoferitsch, Department of Neurology, Sh4Z-OST Krankenhaus, Langobardenstrasse 122, A-1220 Vienna, Austria.

bacterial agents caused Bannwarth’s syndrome.16 In the 196Os, Hopf found signs and symptoms of peripheral neuropathy in 40% of 92 patients with ACA.3J7 This particular feature is known as ACA-associated neuropathy and represents a characteristic neurologic manifestation of late chronic Lyme borreliosis.18-20

Neurologic abnormalities in Lyme disease were also observed in the United States. Eleven percent of patients with EM or Lyme arthritis were found to suffer from radiculoneuritis similar to Bannwarth’s syndrome or from encephalitis. 21,22 Shortly after Borrelia burgdorferi was identified to be the causative agent of Lyme disease,23*24 the pathogenesis of Bannwarth’s syndrome25~26 as well as of ACA and ACA-associated neuropathy20,27 could also be disclosed. Subsequently, neurologic syndromes such as a chronic debilitating encephalomyelitis,19,2**29 cerebral vasculitis,30-33 and focal myositis34-36 could reliably be linked to borrelial infection by several investigators. On the other hand, the frequent and “defensive” use of serodiagnostic tests to “rule out” Lyme borreliosis in patients with unclear neurologic phenomena has led to an increasing amount of anecdotal reports, which ascribe a large variety of neurologic conditions to Lyme borreliosis. Many of these reports lack evidence of borrelial infection except for the demonstration of serum antibodies to B. burgdorferi. It must be kept in mind that in endemic areas, as much as 10 to 30% of the clinical normal popu- lation have been found to be seropositive.37-40 The increasing number of patients who undergo serodiagnostic testing for uncharacteristic symptoms of presumed Lyme borreliosis will subsequently lead to an increasing number of false-positive results. The overabundance of such “atypical” - in many instances, probably “false- positive“ - cases in the literature has led to a misconcep- tion of the clinical picture of neuroborreliosis. This has also led to potentially dangerous or useless extended therapeutic trials. 41-43 If the diagnosis is based on reliable criteria44-46 neuroborreliosis will generally present with

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characteristic manifestations. A carefully performed prospective study has proven that atypical neurologic cases play no role in a large cohort of patients with neuroborreliosis.47

Early Disseminated Lyme Borreliosis

Bannwarth’s Syndrome

Bannwarth’s syndrome is the principal neurologic manifestation of early disseminated Lyme borreliosis. It had been well characterized even decades prior to identifica- tion of its etiologic agent. a-i3~15~47-50 Bannwarth’s syn_

drome can be defined by the presence of both migrating pain and cerebrospinal fluid (CSF) lymphocytic pleocytosis, with or without peripheral nerve paresis (eg, polytopic radiculoneuritis), with or without cranial nerve affection (eg, facial palsy), as sequelae to tick bite in B. burgdorferi endemic areas or to EM.45

Pain caused by radiculoneuritis is the first and, in 20 to 25% of patients, the only neurologic symptom of Bann- warth’s syndrome. It usually starts 1 to 18 (median 3) weeks after the tick bite. The majority of European authors found a topical association between the location of initial pain and the site of tick bite or EM.8*9J5,47-50 This association was not observed by American investigators.*l,** Pain starts acutely or subacutely and has been described by most patients to be severe, burning, and migrating, with typical exacerbations at night. It is refrac- tory to analgesics, but will decrease dramatically within the first days of antibiotic therapy in the majority of patients. Over the course of the disease pain will frequently migrate to other regions of the body. Some patients describe a beltlike tightness around the trunk. Areas hyper- pathic to mild touch can be observed. Also, dermatomal sensory loss in the region of pain can be detected occasionally; however, sensory loss is not a prominent feature of Bannwarth’s syndrome.

Pareses of the extremities occur in about 50 to 60% of patients with Bannwarth’s syndrome13*49 and, in most cases, display the asymmetric pattern of polytopic radiculitis. The radicular lesion clinically overshadows a more distally located neuritis, which could be demonstrated in nerve biopsy studies. 51-53 Pareses are usually asymmetric at the onset, but may become more symmetric over the course of the disease. Occasionally, paresis of the abdom- inal muscles or of the phrenic nerve can be observed. As with pain the initial peripheral paresis was found in a topical association with the site of the tick bite or of EM. This observation may point to a transneural centripedal migration of the borrelia, in addition to the well-known hematogenous route.

Cranial nerve affection has been found in 47 to 82% of

patients with Bannwarth’s syndrome. It occurs as an iso- lated sign or in combination with extremity or trunk pareses. In 80 to 95% of patients with cranial neuritis the facial nerve is affected, bilaterally in about half of the cases.49 Apart from the facial nerve, the third and sixth cranial nerves seem to be the next most frequently affected. Involvement of other cranial nerves has been described on rare occasions. Multiple cranial neuritis may also occur in patients with Bannwarth’s syndrome.

Severe headache and clinical signs of meningitis are not common among European patients with Bannwarth’s syndrome. When neck stiffness occurs, it usually is described as mild and not very pronounced. In the United States, however, headache and mild meningism seem to be predominant symptoms in early disseminated Lyme borreliosis.*l,**

Approximately 10% of patients with Bannwarth’s syndrome show signs of myeloradiculitis.47,50*54 Spinal cord involvement usually starts when the signs of meningoradiculitis are already present and seems to result from an extension of the meningeal inflammatory process. A bilateral Babinski sign, spastic paraparesis, sensory loss with a sensory level, and urinary retention have also been described.55

Vegetative syndromes as manifestations of an affected autonomic peripheral nervous system have been reported occasionally. Symptoms such as hyperhidrosis, constipation, and disturbances of micturition have been associated with involvement of the autonomic nervous system.49 On rare occasions, sympathetic reflex dys- trophy followed Bannwarth’s syndrome.56

Neuropsychologic symptoms such as agitated mental state, irritability, and sleeplessness are frequent in Bann- warth’s syndrome. Severe fatigue and lethargy have been seen more frequently in the United States than in Eu- rope. 21,22,46 Still open to discussion is whether the irritability is due to a subtle encephalitis or to a secondary reaction to the severe pain. Severe encephalitis following Bannwarth’s syndrome is an extremely rare complica- f.jon.57,58

Focal myositis has been associated with Bannwarth’s syndrome. y 34 M ositis without any other associated neurologic signs or symptoms was also observed in early disseminated and late chronic Lyme borreliosis.35*36

Cerebrospinal fluid alterations are essential to the definitive diagnosis of Bannwarth’s syndrome. The lymphocytic pleocytosis ranges from a slight elevation to more then 1000 elements/mm3. The average seems to be around 150 elements/mm3. A large proportion of plasma cells is characteristic. CSF protein content is frequently found to be elevated (on the average, around 1 g/L), in light of the blood-brain barrier disturbance and intrathecal immunoglobulin synthesis. Intrathecal synthesis

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of IgG and IgM, as well as the presence of oligoclonal bands in CSF electrophoresis, is characteristic but may be absent in the first weeks of the disease.47,49

Typical Bannwarth’s syndrome, as defined previously, can be diagnosed on mere clinical grounds without the aid of serodiagnostic tests. The demonstration of intrathecally synthesized IgM or IgG antibodies to B. burgdorferi is necessary for a definitive diagnosis in patients who do not recall previous EM. During the early stages of the disease results of serodiagnostic tests may still be negative in 8 to 30% of patients.47,49

The natural course of Bannwarth’s syndrome is self- limiting in almost all cases and lasts about half a year. Pain and pareses show a spontaneous remission within this period, but mild motor or sensory residual symptoms may persist in 40 or 50% of all patients. Also, CSF alterations show spontaneous normalization, although B. burgdorferi-specific CSF antibodies and oligoclonal bands may persist for years even in antibiotic-treated patients.49,54,59 The persistence of antibodies or oligoclonal bands in CSF was interpreted as “immunologic scar syndrome” and not seen as an expression of an ongoing disease.19*54 Even though Bannwarth’s syndrome is characterized by a self-limiting course in almost all cases, ade- quate antibiotic treatment is still necessary. This signifi- cantly shortens the period of pain,47,49*60 may prevent severe sequalae, and eliminates any potential risk for the development of chronic neuroborreliosis.

Sural nerve biopsy findings point to axonal degeneration as a result of loss of myelinated fibers of variable degree. Perivascular infiltration with lymphocytes and plasma cells was observed around the epi- and perineur- ial vessels. Some of the vessels displayed evidence of occlusion, which indicates that vasculopathy may be an important pathogenic mechanism.49-51 Autopsy of a patient diagnosed with Bannwarth’s syndrome and additional signs of myelitis showed mononuclear perivascular infiltrations in the meninges as well as in the white and gray matter; however, infiltration of spinal ganglia and the dorsal nerve routes was parenchymal. The alterations were found to be limited to three spinal segments corre- sponding to the clinical presentation. The brain was not affected at a11.61

Lymphocytic meningitis with prominent headache with or without meningeal signs, but no radicular pain or pareses, has frequently been observed in patients with neurologic manifestations of Lyme borreliosis in North America. Recurrent attacks of severe meningeal symptoms lasting weeks and alternating with periods of mild symptoms are common. 21,2*,46 In Europe, however, the percentage of patients presenting with plain meningitis is less than 10% of all patients with stage 2 Lyme neuroborreliosis. Hansen and Lebeche described general

symptoms like weight loss, nausea, and a tendency for chronicity in patients with meningitis.” Plain meningitis is much more commonly seen in children than in adults.62 In patients with meningitis who lack other symptoms of Bannwarth’s syndrome, demonstration of intrathecal B. burgdorferi-specific antibody synthesis will help establish the correct diagnosis.

Facial Palsy and Meningitis in Children

Children may present with the same clinical disorders as adults, but in different frequencies. In a prospective study, Christen found typical Bannwarth’s syndrome in only 3.6% of 196 children with neuroborreliosis;62 27.2% showed signs and symptoms of plain meningitis that could not be differentiated clinically from viral meningitis. Most frequently, monosymptomatic peripheral facial palsy was observed (55%). Among the children with peripheral facial palsy, all but three showed CSF pleocytosis, but only 25% showed meningeal symptoms.

Facial palsy in European adults with Lyme borreliosis, however, was found not to be monosymptomatic, but to be associated with other symptoms of Bannwarth’s syndrome.47*49,63,6P In North American patients with Lyme borreliosis, facial palsy in the absence of other neurologic symptoms and even with normal CSF findings seems to occur more frequently.65,66

Christen found CSF pleocytosis in 97% of children with facial palsy resulting from Lyme borreliosis, but in only 11.7% of children with facial palsy of another etiology. CSF pleocytosis might therefore be a better marker of Lyme borreliosis than the search for specific serum antibodies.62

Facial palsy and meningitis had also been found to be the most frequent neurologic manifestations of Lyme borreliosis in American children.67 As in adults, facial palsy and meningitis are usually self-limiting and a chronic course has rarely been observed.62

Rare and Atypical Neurologic Manifestations

Acute encephalitis and myelitis without additional signs of Bannwarth’s syndrome have been reported on several occasions.57,68 Yet the overall frequency of these manifestations seems to be low and they could not be detected in a large prospective Danish study.47 In a different prospective study on German children, subacute encephalitis could be detected in 3.6% and focal encephalitis in only 1 of 165 patients. 62 Pseudotumor cerebri is another rare condition found in children with Lyme borreliosis.62,69 On extremely rare occasions subacute encephalitis may present as parkinsonian syndrome.‘O Subacute dementia or psychosis-like syndromes have been linked to the early stage of Lyme borreliosis. ‘l*‘* A well-documented case of


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myelitis presented as partial stiff man syndrome.73 Hy- drocephalus is another rare condition associated with Lyme borreliosis.30

Strokelike disorders with suspected cerebral vasculitis with a predilection for the posterior circulation have been reported in cases of early Lyme borreliosis.32~74~75 Yet the overall incidence of strokelike disorders in Lyme borreliosis is extremely low and serodiagnostic screening of patients with stroke seems to be of little value.76 Lastly, Guillain - Barr&like syndromes have been observed, yet a connection between true Guillain - Barre syndrome and Lyme borreliosis has not been proven so far.62*77

All these disorders are extremely rare and atypical for Lyme borreliosis. To provide solid evidence of an association between such atypical disorders and Lyme borreliosis, both inflammatory CSF alterations and intrathecally synthesized B. burgdorferi-specific antibodies should be demons~ated.‘9,28,4S,47,S4

Late-Chronic Lyme Borreliosis

Chronic Progressive Encephalomyelitis

In 1985 Ackermann and co-workers reported on a chronic progressive and debilitating encephalomyelitis in eight patients. The CSF of all patients showed inflammatory alterations and signs of intrathecal B. burgdorferi- specific antibody synthesis. The neurologic defects improved on parenteral antibiotic treatment.19 Later, a group of 44 patients was studied, and predominant cerebral manifestations resembling multifocal encephalitis could be differentiated from predominant spinal symptoms mimicking chronic spinal multiple sclerosis.28 The principal clinical symptoms included spastic para- and tetrapareses, ataxia, organic mental disorder, lesions of the seventh or eighth cranial nerve, as well as bladder dysfunction. Characteristic CSF alterations include lymphocytic pleocytosis, elevated total protein content, and intrathecal synthesis of IgG, IgM, and IgA as well as oligoclonal bands. Demonstration of B. burgdorferi-specific intrathecal antibody synthesis is considered essential to the correct diagnosis. 192829#K’S4 On the other hand, in-

trathecal specific antibody synthesis without other signs of CSF inflammation does not necessarily prove active infection; such synthesis has also been observed in clinical healthy persons and may represent latent infection or prior exposure to B. burgdorferi.2*,54 A few patients developed chronic encephalomyelitis following chronic headache with pronounced general symptoms, in particular nausea and weight loss, with no signs of meningism.47 Most patients did not remember preceding EM or Bann- warth’s syndrome. These findings could be confirmed by other European authors. 29,30,33,47,54,68,78,79 me overall inci_

dence of chronic progressive borrelia encephalomyelitis, however, seems to be low: only 4 to 13% of patients with neuroborreliosis.47,54*68

Most cases of progressive borrelia encephalomyelitis had been treated for multiple sclerosis, tubercular or fun- gal meningitis, or chronic viral encephalitis before the correct diagnosis was established.28 These disorders are the primary differential diagnoses. The demonstration of intrathecally synthesized B. burgdorferi-specific antibodies, a CSF total protein content of more than 1 g/L, synthesis of three classes of immunoglobulins (IgG, IgA and IgM), and lymphocytic pleocytosis greater than 50 elements/mm3 help to differentiate progressive borrelia encephalomyelitis from chronic multiple sclerosis.28,63,79

At least one autopsy study of a patient with chronic progressive borrelia encephalomyelitis has been published. Basal chronic leptomeningitis, ependymitis and leptomeningeal obliterative inflammatory vasculopathy with infarctions in the myelencephalon, similar to findings in tertiary neurosyphilis, were observed.33

Lyme Encephalopathy

Very few reports from North America seem to correspond to the well-defined progressive borrelia encephalomyelitis, although lack of specific, intrathecal antibody synthesis in some of these cases makes this association problem- atic.44*57 On the other hand, North American investigators have stressed a condition with mild defects in memory and cognition, mood changes, sleep disorders, and word- finding difficulties without any signs of focal neurologic deficits in patients with late Lyme borreliosis or with previous symptoms of Lyme disease.57~80-85 In about half of these patients, intrathecal B. burgdorferi-specific antibody synthesis has been postulated, although in such low ratios that this has not remained uncontradicted.47,54,a6,*7 Some of the patients showed subtle magnetic resonance imaging abnormalities. After antibiotic therapy, improvement of these mild deficits was documented by neuropsychologic testing in the majority of patients. It was concluded that this condition reflects either a mild encephalitis caused by direct central nervous system infection or an indirect “toxic-metabolic” effect of a sys- temic infection.*0-85 But it has also been stated that symptoms persisting after Lyme borreliosis may be caused by a mild defectious state and not an ongoing disease,54,86 or may be caused by a secondary depressive disorder.84 Dif- ferentiation of these conditions may be extremely diffi- cult.

Acrodermatitis Chronica Atrophicans- Associated Neuropa thy

A mild chronic peripheral neuropathy can be observed in about 40 to 60% of patients with ACA. The characteristic

Clinics in Dermatology KRISTOFERITSCH 397 1993;21:393-400 NEUROLOGIC MANIFESTATIONS IN LYME BORRELIOSIS

pattern of this ACA-associated neuropathy had been well defined in the first systematic neurologic study of patients with ACA by Hopf in 1966.3 Clinical symptoms and signs are usually mild but of a chronic nature. Patients describe mild pain, paresthesia, or weakness. The distribution of sensory deficits may be patchlike and located within the region involved by ACA or of a distal asymmetric or more symmetric type. Extremities without ACA may also be involved. Loss or diminution of tendon reflexes or pareses usually occur on the lower extremities in a distal distribution. Pareses are mild and occur in about 20% of patients with ACA-associated neuropathy. Electroneurographic results were found to be consistent with axonal neuropathy. The CSF was found to be normal in most patients with ACA or ACA-associated peripheral neuropathy. 3~17,49,*8 In the majority of patients, pain and paresthesia disappeared or improved after antibiotic therapy, whereas sensory or motor deficits and electroneurographic results remained unchanged.45,89 Sural nerve biop- sies showed perivascular infiltration with lymphocytes and plasma cells, distributed around small and medium- sized epineurial vessels and in epineurial soft tissue. In addition, disseminated loss of myelinated fibers as a result of axonal degeneration was observed. There is a striking similarity between nerve biopsy findings in ACA-associated neuropathy and those reported in Bann- warth’s syndrome.18

Chronic Neuropathy Without Acrodermatitis Chronica Atrophicans

Several studies performed in the United States have reported a mild chronic neuropathy in conditions associated with late Lyme borreliosis other than ACA. With the exception of a subgroup of patients with radicular pain, symptoms and clinical signs were similar to those found in Europe in ACA-associated neuropathy.*2~85~90-92 The results of electroneurographic investigations indi- cated mild axonal damage and are compatible with those described in ACA-associated neuropathy. Signs of para- spinal denervation were also found and interpreted as radiculoneuropathy. In the majority of patients clinical and electrophysiologic improvement was achieved after antibiotic therapy.

In up to 25% of patients with late Lyme borreliosis neurophysiologic evidence of carpal tunnel syndrome has been reported .93 On the other hand, routine serologic screening for Lyme borreliosis has not been found to be justified in patients with carpal tunnel syndrome.94

Rare and Atypical Disorders

Contrary to the chronic neuropathy found in late Lyme borreliosis in the United States and in ACA in Europe is the case report on a patient with painless, chronic weak-

ness of the lower extremities, caused by inflammation of ventral nerve roots. Serodiagnostic tests were positive for B. burgdorferi and spirochetes could be demonstrated in the CSF, which showed a mononuclear pleocytosis. Prior to establishment of the correct diagnosis the patient was thought to suffer from lower motor neuron disease.95

In an anecdotal report a disorder mimicking primary lateral sclerosis was connected to chronic B. burgdorferi infection.96 Case reports on patients with amyotropic lateral sclerosis (ALS) plus suspected Lyme borreliosis did not convincingly fulfill diagnostic criteria.97 The results of serologic screening in patients with ALS showed conflict- ing data.98,99

In another anecdotal report chronic neuromyopathy was linked with Lyme borreliosis.loO Focal nodular myositis has been observed in a few patients with ACA.3,36 Cerebral vasculitis,31,33,75J“0 psychiatric disorders,101J02 and presenile dementia lo3 have all been associated with chronic Lyme borreliosis.

Many of these reports lack clear evidence of a causal association between the underlying disorder and infection with B. burgdorferi.

Conclusions

Most patients with neurologic manifestations of Lyme borreliosis present with clinically characteristic symptoms. These include Bannwarth’s syndrome, with or without additional signs of mild myelitis, and lymphocytic meningitis; the latter seems to be more frequent in North America. In children, monosymptomatic facial palsy with lymphocytic pleocytosis and plain meningitis are the characteristic neurologic manifestations of early disseminated Lyme borreliosis.

Typical syndromes of late and chronic Lyme borreliosis are progressive borrelia encephalomyelitis and mild neuropathy in patients with ACA. Mild, chronic encephalitis or encephalopathy as well as chronic neuropathy without ACA has been reported in larger groups of patients with late Lyme borreliosis in North America.

A broad variety of distinct neurologic conditions that according to anecdotal reports were associated with Lyme borreliosis occur rarely, if at all, and their importance has been overestimated. Although prior to the availability of serodiagnostic tests neurologic conditions indicative of Lyme borreliosis frequently remained underdiagnosed, there now exists a tendency to overdiagnose. This tendency should be avoided by the use of clear clinical and diagnostic criteria.

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Neurologice manifestations in Lyme borreliosis