Stroke and Infection: Tuberculosis, Brucellosis, Syphilis, Lyme Disease and Listeriosis

Neurological complications may occur as sequelae of systemic infection, but can be a presenting feature with certain pathogens. An association exists between ischemic strokes and infection, with a number of proposed mechanisms by which vascular disease develops into central nervous system (CNS) infections. The pathophysiological mechanisms may involve vasculitis, affecting primarily the vessels at the base of the brain in the setting of meningitis, an immune-mediated parainfectious process leading to vasospasm or thrombosis, or a hypercoagulable state in combination with endothelial dysfunction resulting from activation of inflammatory and procoagulant cascades .

Patients with neurotuberculosis, neurosyphilis, neurobrucellosis, and neuroinvasive listeriosis can initially have meningitis which may be asymptomatic, but can progress to a chronic form. Cerebrospinal fluid (CSF) analysis is notable for lymphocytic pleocytosis, high protein content, and low glucose levels, and hence is a more sensitive guide in diagnosis, treatment, and cure of the disease.

Stroke is a serious complication with CNS infections and is clinically indistinguishable from a noninfectious etiology. Proper management requires a high index of suspicion, prompt recognition and early initiation of appropriate therapy, given progression to devastating neurologic outcomes.

Neurosyphilis

Neurosyphilis is a globally endemic disease caused by the spirochete Treponema pallidum . With the development of penicillin, there was a decline in the incidence of syphilis, followed by a resurgence since 2000. T.pallidum rapidly invades the CNS early in the course of infection, though most patients remain asymptomatic and the infection is cleared from the CNS. Symptomatic neurosyphilis may occur at any stage of disease.

Pathogenesis

T. pallidum invades, usually following sexual activity through small breaks in the skin or intact mucosa, manifesting later as a chancre at the site of infection. The bacteria then rapidly disseminate to virtually every organ system. CNS invasion occurs quickly, though the majority of patients remain asymptomatic. Infection produces a vasculitis, leading to endarteritis of the large- and medium-sized vessels. Obliterative endarteritis is characterized by fibroblast proliferation in the intima, a thinning of the media, and fibrosis of the adventitia. This inflammation leads to thrombosis and infarction. Infection with T. pallidum may also directly involve the brain parenchyma, causing frontal and temporal lobe atrophy .

Clinical Features

Early symptoms of neurosyphilis include headache, vertigo, and insomnia, typically with a sudden onset. Stroke symptoms are directly related to the areas of infarction, with the middle cerebral artery (MCA) and basilar artery (BA) commonly involved. Patients may develop hemiplegia, hemianesthesia, homonymous hemianopia, and aphasia. If the vessels of the spinal cord are involved, syphilitic meningomyelitis presents as spastic weakness of the legs, loss of sphincter control, and sensory loss. Parenchymal involvement in the brain manifests as general paresis with features of dementia and psychosis or in the spinal cord as tabes dorsalis with loss of proprioception and vibratory sense .

Diagnosis

Diagnosis of neurosyphilis is based on CSF analysis that shows an elevated white blood cell (WBC) count ≥5 cells/mL with lymphocyte predominance, elevated protein, and a reactive CSF Venereal Disease Research Laboratory (VDRL) test. The sensitivity of CSF VDRL has not been clearly established, and while a positive CSF VDRL confirms neurosyphilis, a negative test does not exclude it. There are no pathognomonic radiological findings, and imaging is of little diagnostic value.

Treatment

Penicillin is the treatment of choice for neurosyphilis. If the patient is penicillin allergic, desensitization should be performed. Treatment is with aqueous crystalline penicillin G 18–24 million units per day intravenously (IV), given either by continuous infusion or as 3–4 million units IV every 4 h for 10–14 days. If penicillin cannot be used, then ceftriaxone 2 g IV or intramuscularly (IM) every 24 h may be used in nonpregnant patients for 10–14 days, although the data on efficacy are limited.

Neurobrucellosis

Neurobrucellosis is rarely seen in most developed countries, but remains endemic in the Middle East, India, and Latin America. Brucella spp. are aerobic, intracellular gram-negative coccobacilli. Four pathogenic species, Brucella abortus , Brucella suis , Brucella canis , and Brucella melitensis infect humans. B. melitensis is the most pathogenic. Most infections occur secondary to direct exposure to animals or consumption of contaminated animal products including unpasteurized milk.

Pathogenesis

Brucellosis occurs following contact with infected animals, unpasteurized milk products, or by inhalation. The bacteria then migrate to lymph nodes and survive intracellularly within macrophages. CNS involvement is mediated both by the direct effect of the bacteria and the resulting immune response. CNS invasion occurs either via transport within macrophages or direct endothelial cell invasion. Brucella invades and replicates within astrocytes and microglia. Activation of the innate immune system triggers an inflammatory response which leads to astrogliosis, a characteristic feature of neurobrucellosis. This inflammatory response is primarily responsible for the clinical features of neurobrucellosis. Ischemic stroke results from vascular and perivascular inflammation leading to lacunar infarcts, microhemorrhages, and venous thrombosis. A second mechanism by which stroke may occur is rupture of a mycotic aneurysm. Hydrocephalus may be seen if granulomatous inflammation within the CSF blocks reuptake by the arachnoid villi .

Clinical Features

Acute neurobrucellosis presents with high fever, malaise, headaches, and arthralgias. Meningeal signs, confusion, papilledema, hepatosplenomegaly, back pain, ataxia, paresthesias, paraplegia, and urinary or fecal incontinence may also be present. Patients may develop stroke, acute or chronic meningoencephalitis, myelitis, radiculitis, isolated cranial or peripheral nerve involvement, brain abscess, subarachnoid bleeding, or neuropsychiatric symptoms. While mortality is low at less than 1%, morbidity may be significant .

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