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LD sufferers may present with a myriad of symptoms, which reflect disseminated infection and the affinity of Bb for certain tissue types, notably the brain and peripheral nervous system, joint space and dermal tissues. In the textbook definition, acute illness is followed in some cases by early dissemination, which is sometimes characterized by peripheral neuropathies (mononeuritis multiplex), or cranial neuropathies (e.g. Bell’s palsy). Depending on the nerve involved, the patient may complain of primarily sensory (i.e. burning, shooting pain or numbness) or motor symptoms (weakness, fatigue, tremor, etc). In persistent cases of LD, or neuroborreliosis, the neurological symptoms may wax and wane or even disappear, with or without therapy. In some individuals, however, these neurological complaints may become the predominant set of symptoms and, over time, may become severe and bizarre enough to mimic multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). In fact, many of our advanced and severely ill patients have been diagnosed with MS or ALS (primarily MS) when they come to us, but very few actually meet the diagnostic criteria for MS or ALS when expert neurologists critically examine these cases. We believe that the neurological symptoms in early disseminated and certainly persistent LD are so common and important that the absence of these symptoms may call the diagnosis of Bb infection into question. Many of our advanced and disabled patients have already had at least one extensive neurological evaluation and most have had at least one referral to a neurologist. Naturally, these workups include an MRI of the brain that invariably is non-specific for MS, but often shows non-specific enhancing “white lesions”, usually in the subcortical regions. Interestingly, these are the same lesions found in some immune dysfunction cases where they have been whimsically referred to as “unidentified bright objects”. Undoubtedly, these radiologic changes represent inflammation due to possible infection or changes in the glial cells (22,23), and perhaps the neuronal cells as well. Understanding that persistent Bb infection is capable of contributing to a diagnosis of immune dysfunction syndrome, or chronic fatigue, one has to wonder how many IDS cases have been incorrectly or incompletely diagnosed.
As stated, the vast majority of our patients describe symptoms of cranial or peripheral neuropathy. In our experience, the current protocols used by most neurologists for peripheral nerve conduction studies are relatively insensitive and fail to detect both the sublime and the obvious neurologic deficits in our LD patients. When we have had occasion to order nerve conduction studies, we have consistently found that the somatosensory modality was the most sensitive and helpful tool. Unfortunately, this modality is usually excluded in the standard exam. Clinically, we commonly encounter mononeuropathies in the thoracoabominal or pelvic distribution, the symptoms of which have led to exhaustive and unrewarding workups for gall bladder, colon, pleural, or pelvic disease by previous physicians. We usually have the benefit of these workups, of course, and so our efforts to reduce symptoms in these cases usually involve reassurance and treatment with a neurleptic agent such as gabapentin. In most cases, this approach is successful but sometimes we require assistance from physical or occupational therapists, useful and important resources greatly appreciated for difficult cases.
Other patients with neuroborreliosis may exhibit great difficulty with balance, presumably as a result of peripheral or spinal cord associated neurological involvement affecting the lower extremities. Where cord involvement is concerned, we have now had three patients with documented neurogenic bladder that almost certainly reflects sacral plexus involvement.
Where balance issues are concerned, the root cause of these difficulties may lie in abnormalities of proprioreceptive dysfunction and/or muscle wasting associated with prolonged illness. In some cases there is also clearly a CNS or vestibular component contributing to imbalance. It is not unusual for these ailments to dominate the clinical picture and a significant number or our patients have come to us in wheelchairs or with other chronic ailments requiring the use of assistive devices.
Where LD is complicated by cranial nerve disease, the classic clinical cranial nerve malady linked with Bb infection is Bell’s palsy, or 7th nerve paresis. Other common cranial neuropathies we have witnessed include direct eighth nerve (auditory) involvement causing maddening tinnitus and sometimes leading to deafness (88). Advanced neuroborreliosis can lead to brainstem pathology, which may cause optokinetic disturbances, or difficulty in tracking objects in motion. Holmes-Adie syndrome, or unilateral papillary dilatation due to 3rd nerve involvement, has been reported as well (89). Acute anosmia, or loss of smell, was the major complaint in a newly diagnosed Bb patient recently seen at the Jemsek Specialty Clinic. Possibly the most common cranial neuropathic symptoms we detect are reports of a sensation of sharp or radicular facial pain, twitching of the facial muscles, or dysesthesias described as either numbness or itching “like something crawling all over my face”. Obviously, these symptoms reflect inflammation of the 5th nerve. We always query our patients about these symptoms since many patients will fail to volunteer these complaints. They sheepishly state that the symptoms are so bizarre that no one believes them and so, out of embarrassment, they no longer discuss this issue. We believe that these cranial neuropathies, as well as other associated symptoms such as tremor, assorted tics and regional dysesthesias of the torso or extremities, are more common than realized in persistent Bb infection and reflect a generalized polyneuropathathic syndrome. Hence, we feel this supports our preference to refer to persistent LD as neuroborreliosis. Interestingly, prolonged antibiotic therapy in this population often creates a flare of the neurological symptoms, akin to the dermal “Herxheimer” phenomenon mentioned previously. This can be highly unpleasant and the patient will require a great deal of reassurance and encouragement, as well as providing symptomatic relief with the therapies just mentioned.
We have had the opportunity to identify and study at least three individuals with a narcolepsy-like syndrome associated with LD. None of these cases came to diagnosis easily. In fact, all of them had extensive cardiac and endocrinologic evaluations without a diagnosis forthcoming. It took clinicians an average of 3 to 4 years before the link between Bb brain involvement and the symptoms were connected. One of our patients was so severely affected that she began to wear a football helmet at home to prevent or minimize further skull trauma with potential brain injury. Genetic narcolepsy screening was negative in all of our subjects. In referring two of these patients to a sleep specialty clinic, after a seizure disorder had been ruled out, we learned that the differential diagnosis was either an atypical cataleptic event or post infectious idiopathic central nervous system hypersomnia (personal communication). Certainly the latter diagnosis fits well with what is known about Bb and CNS disorders. For this reason, we believe that a narcolepsy-like syndrome, perhaps best described as post infectious idiopathic hypersomnia, should be added to the litany of CNS disorders described in this disease.
We have observed that the vast majority of our patients with persistent LD have ongoing cognitive dysfunction, or chronic encephalopathy (see prior description). In some cases, this may be the only symptom, and in a significant number of patients it is the most prominent symptom and is often debilitating. Several of our persistent LD patients have undergone neuropsychiatric testing by professionals who document IQ scores well below the patient’s historical levels, or at least grossly inconsistent with the academic or professional standing the patient had accomplished prior to their illness. We regret that this testing is not commonly available. Other validating procedures for the workup of chronic encephalopathy include brain SPECT scanning, which usually indicates abnormal blood flow in the encephalopathic Bb infected brain. Since this screening procedure is now more readily available, the Jemsek Specialty Clinic has begun to utilize this procedure more often, recognizing that abnormal findings are non-specific. We look forward to the increased availability of PET scanning, which reflects metabolic activity in the brain and would be expected to offer more sensitive and specific information that brain SPECT scanning. We are hopeful that Dr. Brian Fallon’s work will provide some answers to these questions (see below).
Experiencing acute encephalitis with acute LD is by no means a prerequisite to developing cognitive difficulties. However, in our clinical experience, if initial symptoms of confusion and disorientation fail to clear promptly, the prognosis for protracted CNS symptoms is high. Many patients tend to have variable courses in this regard, too often with progressive decline in cognitive abilities over the years. Still others demonstrate a reactivation or relapsing pattern in which encephalopathic symptoms can be severe and disabling. Specific cognitive problems include decreased ability to concentrate, recent memory deficits, mood disturbances, word-finding difficulties and geographic disorientation. These disturbing symptoms are often referred to as “brain fog” by our patients. The germane concern is whether or not irreversible CNS change occurs after a period of time, and one must assume that this is the case. Nonetheless, the Jemsek Specialty Clinic feels that every patient deserves a trial of intensive treatment before all hope of improvement is abandoned.
Mundane sleep disorders (see discussion on narcolepsy above) commonly accompany persistent LD and are one of the first items addressed in the initial visit at the Jemsek Specialty Clinic. In fact, if problems are found, we attempt to deal with them prior to or in concert with the onset of LD therapy. Our philosophy is that no illness can be optimally treated until a proper sleep cycle has been restored. Our patients with LD often have severe sleep disturbances, especially if these patients happen to manifest immune dysfunction syndrome with fibromyalgia.
In addition to the role of Bb in organic CNS and peripheral nervous disease in neuroborreliosis, we firmly believe that various psychiatric and mood disorders result from Bb CNS involvement. We include a mental status evaluation in our initial and subsequent reports, along with all other symptoms and signs (90,91,92,93,94,95).
Cardiovascular manifestations of Lyme disease are seen in 5% of untreated patients and are largely described as transient mild atrio-ventricular block. However, a subset of our patients has had to undergo temporary pacing of the heart due to life threatening cardiac nerve conduction disturbances. In addition, at the Jemsek Specialty Clinic we have recognized several individuals, mostly younger women, who manifested unexplained tachycardia, with heart rates in the nineties and in whom all cardiac and metabolic studies have been normal or non-diagnostic. In our limited experience with several individuals to date, after all the medical information has been processed, we find that antibiotic treatment over time tends to be associated with resolution of this problem. We would hypothesize that the events occur as a result of direct involvement of Bb at the sinus node or an extra nodal site where excitation occurs due to pathologic neurogenic changes brought on by Bb infection.
Other reported LD associated cardiac conditions include neurocardiogenic syncope, myocarditis, myocardiomyopathy, and pericarditis (96,97,98).
We have already discussed the presence of multiple recurrent rash episodes in some patients, which can be a striking clinical feature. One of the more dramatic and interesting dermatological presentations is acrodermatitis chronica atrophicans (ACA), which was recently diagnosed in two of our patients with persistent LD (see photo).
We understand that Bb has been recovered from these lesions, according to previous reports (99). In fact, ACA was reported in Europe in the 19th century (10) and by the end of the century reported in the United States as well (100). One of our patients improved dramatically after about 4 weeks of combination IV/oral therapy, while the other is still symptomatic and waiting to begin more aggressive antimicrobial therapy.
Some less well recognized complications of LD that we have recorded at the Jemsek Specialty Clinic include TMJ disease, chronic gingivitis, erosion of enamel and other dental changes, assorted tremors and tics, pressure-related neuropathic symptoms (e.g. an arm going to “sleep” while resting on a car door while driving), intensification of migraine syndromes, and the presence of palpable nodules in a peripheral nerve distribution, which we hypothesize represents myelin sheath hypertrophy of an affected nerve, mimicking or possibly representing a neurofibroma. Several of our patients describe a burning or “icy hot” feeling extending from their neck down the spine with certain movements, such as dorsiflexion of the neck. Some cranial neuropathies mimic sinus disease or other chronic headache syndromes. Because of the frequency with which 5th nerve inflammation exists, we have found it helpful to add a novel physical test to our exam, namely tapping the pre-auricular area with the examiner’s middle digit, to elicit a response of pain, numbness or tingling in the V2 or V3 distribution of the 5th nerve. It has been surprising to note how often this maneuver yields positive results (pre-auricular tap test).
In our neuroborreliosis population, many patients have musculoskeletal complaints, and occasionally these are the major and most debilitating problems, sometimes accompanied by fever and chills. Typically, large joints are involved and the arthralgias are migratory, which in fact fits the classic description for LD. In a few cases, actual arthritis is evident, although only rarely does this persist. When it does persist and comes to joint replacement surgery, we have anecdotal reports in which orthopedic surgeons, upon opening the joint in question, discover a cheesy, fibrous exudate which is uncharacteristic for the usual bacterial infection and which proves to be negative or sterile on routine smears and cultures. This is the prototypical “Lyme joint” which almost no one in the operating arena ever recognizes. In fact, some surgeons stop there and refuse to go on, believing that their patient has an unusual and previously unrecognized infection that makes their job impossible. However, if the arthroplasty continues after these initial concerns are addressed, we have noted a high rate of success in joint replacement (personal experience).
In the past 3 years, we have treated 3 individuals who had ocular complaints as their presenting symptoms. Two of these cases presented as posterior uveitis and the other with Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE). One of the cases of uveitis was acute and the other chronic. The acute case was associated with symptoms of confusion, headache, and CSF lymphocytic pleocytosis, suggesting diffuse CNS involvement. Later, she would manifest more generalized symptoms such are arthralgias, fever, severe fatigue, and so forth. The chronic uveitis case appeared at first to have symptoms localized to the eye alone, but later systemic symptoms became prominent and included various dysesthesias, unexplained headache, photosensitivity, and arthralgias. Full testing for thyroid and connective tissue disorders, HIV and STDs, and all routine studies were negative in both cases. Both were treated with steroids initially, without clinical improvement. A diagnosis of Lyme disease was made through our clinic after referral. At this point, the ocular status is much improved on intravenous antibiotic therapy, although neither has had full resolution yet of their non-ocular complaints. The case of APMPPE is a self referred 81 y/o Caucasian male who had enjoyed excellent health until he suddenly developed problems with fatigue and “weak muscles”, “foggy brain”, and shortly thereafter developed bilateral visual problems that were ultimately diagnosed as APMPPE. In reviewing the differential diagnoses possibilities in the literature and on the internet, the patient came to the conclusion he probably had LD. He convinced a friend and local physician to commence therapy with oral antibiotics and the visual and systemic symptoms improved significantly over the next few weeks. However, whenever antibiotic therapy was withdrawn, symptoms have relapsed. Eventually a laboratory diagnosis for LD was made. He is currently stable and improving on a high dose oral combination antibiotic program, which fortunately he is able to tolerate. APMPPE is rare and was originally described by Gass in 1968 (101,102). The etiology of APMPPE is controversial and the argument basically consists of theories of direct invasion of the retinal pigment epithelium proposed by Gass versus involvement of the choriocapillaris with inflammation at this level caused by a hypersensitivity reaction to an external antigen (103). Certain HLA haplotypes have been shown to be associated with this disorder, with 56% of APMPPE patients reported to be HLA-DR2 positive in one series, whereas, in another series, 40% express HLA-B7. These MHC proteins may present viral or bacterial antigens to helper and cytotoxic T cells and activate the immune response leading to capillary and pigment epithelial cell inflammation (104). This information suggests that HLA haplotypes, and therefore individual immune makeup, may play a role in the immune response to LD, as it does in other disorders (see our previous discussion on LD and immunologic response). In fact, there was some limited data on the predisposition of certain HLA haplotypes to arthritis with LD (105), but more needs to be done.
Curiously, we have noted that several of our LD patients test positive, sometimes at high titer, for rheumatoid arthritis. We consider these to be false positive serologic epiphenomenon associated with an activated immune system. In most, but certainly not all of these cases, classic measures of inflammation, e.g. sedimentation rate and C reactive protein, are normal. In reviewing our cases where C reactive protein levels are elevated, we can find no clinical patterns that would predict either disease severity or progression, but titers do tend to fall in response to treatment. This suggests that some neuroborreliosis cases may manifest inflammatory markers and activity not found in other cases. In evaluating all possibilities, we routinely test for lupus syndromes and have found no consistent pattern. However, one measure of widespread inflammatory change has been noted in our practice, namely the measurement of the anticardiolipin antibodies. We believe that up to 40% of our patients with active persistent LD will demonstrate positive tests to either IgG or IgM anticardiolipin antibodies. We consider this to be a secondary phenomenon that occurs as a result of widespread endothelial disturbance due to LD leading to an ensuing immune response. In fact, a positive anticardiolipin antibody test has become a very useful secondary laboratory marker for us in our pursuit of an LD diagnosis, where direct Bb testing remains negative. Only rarely have we documented true thrombotic events associated with these findings, but we generally recommend two baby aspirin in this circumstance regardless. We distinguish this acquired situation from the true antiphospholipid syndrome, whose cause itself, of course, remains unknown.
Finally, pervasive fatigue, often debilitating, is almost universally present in our more severe cases of persistent LD. The similarities to the classic description of Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) are unmistakable and usually include relapsing fatigue, as well as lymphadenopathy and sore throat. Unlike CFIDS, treatment with antimicrobials should benefit the persistent LD patient, although response to these therapies is often slower and less certain in the group of patients with the longest history of symptoms. Key distinctions between persistent LD and classic CFIDS, even where LD is a cause for CFIDS, have to do with the presence or history of clinically significant neurological symptoms and/or joint pain or arthritis in those patients with LD. CFIDS is clearly often associated with fibromyalgia, which may be disabling in some cases. However, joint pain or overt arthritis are not features of CFIDS, but they are common in persistent LD. Other debilitating conditions, such as cognitive dysfunction and, to a lesser extent, CNS irritability, are present in both CFIDS and LD; these symptoms are probably mediated in similar fashion for both conditions by a dysregulated immune system (see above discussion).
In summary, as we take a complete history and physical on all new patients and constantly reevaluate all new or unexplained complaints, we focus on five symptom categories in our initial evaluation of persistent LD, or chronic neuroborreliosis. Later on, focusing on these symptom groupings during antibiotic treatment is of critical importance and benefit to patient care. These categories are 1) cognitive dysfunction, 2) CNS irritability, 3) B or musculoskeletal symptoms, 4) peripheral neurological symptoms/findings, 5) chronic fatigue state. A typical clinic chart at Jemsek Specialty Clinic will reflect periodic “grading” in these symptom/sign categories. As an example, with 1 being the worst and 10 the best or norm for the patient premorbid state, the patient is asked to grade their symptoms 1 to 10 in each category ….in this case the patient serves as their own control. In other words, a rating of 10 reflects absence of symptoms in categories 1 through 4. Where the fatigue scale is concerned, 10 reflects that patient’s usual state of well being pre-illness —as an example
Date Of Visit
1) Neurocognitive Function
5/10 (Short-term memory,word finding, etc.)
2) CNS Irritability
6/10 (Photophobia, hyperacusis)
3) B Symptoms/signs
8/10 (Muscle and joint pain)
2/10 (Mononeuritis multiplex)
4/10 (compared to pre-illness)
In this theoretical case, our patient has prominent neurological symptoms that overshadow everything else. However, the patient’s neurocognitive decline is severe enough to adversely impact job performance and interpersonal relationships to a significant extent. In almost all patients with these characteristics, one would expect major limiting fatigue and perhaps a mood disorder. The only area in which this patient is relatively spared is the absence of serious musculoskeletal complaints.
Assuming this is our baseline reading, once therapy is initiated we would periodically return to our survey and do updated comparisons. While this approach may appear overly simplistic, we have found it to be very useful in the monitoring of these complex patients.