Neurological Complications of Lyme Disease
MEDICINE & HEALTH/RHODE ISLAND
VOLUME 91 NO.7 JULY 2008
Syed Rizvi, MD, and Amanda Diamond, MD
A tick-bite associated rash with later neurological manifestations, including paralysis and meningitis, had been documented in Europe for several years before Lyme arthritis was recognized in the 1970s.1-4 The illness was later understood to be part of a multisystem disease caused by spirochetae and transmitted by Ixodes ticks. 5,6 Borrelia burgdorferi, although initially thought to be a single species, has been found to have several sub-species. These subgroups may be responsible for the variation in clinical symptoms observed in different parts of the world.7
The pathophysiology of neuroborreliosis is difficult to demonstrate, but mimics other spirochetal infections. Infection is local with subsequent dissemination. During this time spirochete numbers are high. B. burgdorferi components that induce cytokine production by T and B cells produce immune activation and indirect cell damage. Central nervous system involvement is common and clinical syndromes tend to occur in stages.7
Lyme disease has been implicated in a variety of peripheral and central nervous system disorders. The neurological syndromes are often accompanied by more general complaints (arthralgias, fatigue, myalgias). Earlier neurological symptoms, or those occurring during dissemination within weeks to months, tend to be more clinically obvious and develop in an estimated 15% to 20% of patients.4 Several late syndromes seem to follow a more insidious course.8 For purposes of simplification, disorders of the peripheral and central nervous systems will be reviewed separately.
NEUROBORRELIOSIS OF THE PERIPHERAL NERVOUS SYSTEM
The most common peripheral manifestations of Lyme disease are cranial neuropathies, peripheral neuropathies and radicultis. However, many other syndromes, including a "Guillian Barre-like" syndrome, motor neuron disease, axonopathies, brachial and lumbar plexopathies, mononeuropathy multiplex and even myositis have been described. 7
Radiculoneuropathy. Painful radiculitis is one of the most common early neurologic symptoms of Lyme disease in Europe. Incidentally, it was also part of the symptom-complex described in the first patient reported with the syndrome.1 Usually occurring within the first weeks to months in the infection, the radiculoneuropathies of Lyme disease have included motor, sensory and mixed symptoms. They are usually self-limited and may be easily mistaken for nerve-impingement syndromes, with segmental symptoms of weakness, sensory or reflex changes.9 The symptoms may not occur in the region of the tick bite. Electrodiagnostic testing usually shows multifocal mild sensorimotor involvement. 10, 11
Cranial neuropathies. Involvement of cranial nerves, particularly the seventh nerve, may be present in up to 50%-75% of all patients experiencing neurologic syrnptoms.4 Multiple cranial nerves may be involved simultaneously.9 Reports include symptoms of every cranial nerve except the olfactory nerve. The facial nerve involvement is reported to be bilateral in up to one third of cases. II Facial nerve symptoms may not affect taste or hearing, indicating that involvement may be outside the subarachnoid space. Additionally, CSF analysis in isolated Lyme disease facial palsy may be normal. Complete recovery occurs in 80-90% of patients within weeks to months.
"Guillain Barre-like" syndrome. Although rare, an acute and severe syndrome of diffuse polyneuropathy, including bifacial weakness, may mimic the symptoms of Guillan Barre. A CSF lymphocytic pleocytosis and/or neurophysiologic testing may help differentiate between the syndromes.7
Peripheral neuropathy. Symptoms of peripheral neuropathies in patients with Lyme disease tend to be primarily sensory, occurring in a stocking-glove fashion, although patchy paresthesias may also be noted. In some European patients, a dermatologic manifestation is often associated with the neuropathy. Labeled acrodermatitis atrophicans, the skin becomes tissue-thin and discolored.
The same patients have been discovered to develop an axonal neuropathy* in the affected limb.9. In the case of chronic infection, it has been estimated that one in four patients may have peripheral nerve involvement. These patients may present with mainly sensory symptoms. 10,11
NEUROBORRELIOSIS OF THE CENTRAL NERVOUS SYSTEM
Meningitis. Although many syndromes involving the central nervous system remain controversial, several have been well-defined. Certainly, the early appearance of lymphocytic meningitis is well recognized. Mildly increased CSF pressure with headache and papiledema may occur. The lymphocytic pleocytosis usually includes tens to hundreds of lymphocytic cells per mL. A mild elevation of protein may also be seen, with CSF glucose usually remaining within a normal range to minimally decreased. 12 The 'typical' symptoms that usually occur with 'aseptic' meningitis, such as photophobia, headache and neck stiffness, are extremely variable with Lyme meningitis. 11,12
Intracranial hypertension syndrome. A rare complication of Lyme disease resulting in headache and potential papilledema, this syndrome seems to be associated more often with children and adolescents. CSF abnormalities may occur. There does not appear to be a correlation with female sex or obesity, as with pseudotumor cerebri. 11,13
Encephalomyelitis. A chronic manifestation of Lyme disease, encephalitis is rare in North American (nearly all cases have been reported in Europe). On MRI there is evidence of parenchymal involvement. This can include hemispheric or brainstem abnormalities and is usually nonspecific, although may mimic ischemic patterns. 11
Myelopathy. Patients may present with symptoms of transverse myelitis so that Lyme disease should be considered in the diagnosis of these patients. 11, 14 Rarely, a transverse myelopathy may accompany Lyme radiculoneuritis. This typically occurs at the same level as radicular involvement and may be preceded by a leptomeningitis.12
Lyme encephalopathy. This may be the most common late neurologic manifestation of Lyme disease. Patients express difficulties with concentration, sleep disturbance, emotional lability, memory and attention. 11,15,16 Despite studies including requirements for CSF abnormalities and SPECT imaging, the definitive diagnosis of Lyme encephalopathy remains elusive. 16 In the consideration of acute encephalopathy, one should note that persons with Lyme-induced cognitive changes likely have a mild encephalitis; these patients should not be confused with mental status changes associated with systemic symptoms. 17 Such patients are likely to have objective findings on neuropsychiatric testing and such a diagnosis should only be made in the presence of appropriate findings after testing has been performed by a qualified professional. This is distinct from the more subjective symptoms patients often experience for weeks to months following an episode of acute infection with B. burgdorferi (discussed below).
DIAGNOSIS OF NEUROLOGIC LYME DISEASE
The crucial element for the consideration of neurologic Lyme disease is the presence of an indicative neurologic symptom. Laboratory data should be complimentary and supportive of clinical findings. In evaluating response to therapy, the clinician must remember that many neurologic illnesses improve with time, regardless of treatment. 17 Unfortunately, sensitivity of culture in nervous system infections is low (only about 10% in CSF in Lyme meningitis). The sensitivity of PCR testing appears to be low as well. Confirmation of the diagnosis, therefore, relies largely on serologic testing. Spinal fluid can, however, be tested for the presence of anti-B. burgdorferi antibodies. 19
Researchers have also described a B-cell-tropic chemokine, CXCLl3, which appears abnormally elevated in CSF of patients with Lyme neuroborreliosis. If confirmed, this cytokine might serve as a marker to assist in the confirmation of the diagnosis of neuroborreliosis.23
TREATMENT OF NEUROBORRELIOSIS
Although the general recommendation in the US is to use parenteral antibiotics whenever the nervous system is involved, there is considerable evidence in the European literature suggesting oral doxycycline (200-400mg/day) may be equally effective in most patients. At the recommended doses it appears that the CSF concentrations of doxycycline exceed minimum inhibitory concentration for most strains. Although there are strain differences between United States and Europe, there probably is not a significant difference in antimicrobial susceptibility. 24
Syed Rizvi, MD, is Director, Rhode Island Hospital Multiple Sclerosis Center, and Assistant Professor of Clinical Neurosciences, Warren Alpert Medical School of Brown University.
Amanda Diamond, MD, is a Neurology Fellow, Warren Alpert Medical School of Brown University.