General paresis (also known as paretic neurosyphilis, dementia paralytica, and general paralysis of the insane) is a meningoencephalitis associated with direct invasion of the cerebrum by T. pallidum. The clinical illness is a chronic process that evolves over many years and declares itself in middle to-late adult life. This form of late syphilis develops 15-20 years after initial infection. Prior to World War II, patients with this disease made up 5-10% of all first admissions of psychotic patients to psychiatric hospitals. Although this disease is now rare, it accounted for 10% of cases of neurosyphilis in the first two decades of penicillin therapy.
The clinical picture is that a combination of psychiatric manifestations and neurologic findings that may mimic almost any type of psychiatric or neurological disorder. The illness is commonly insidious in onset but may occasionally become suddenly evident. The early features are usually of a psychiatric nature, and the course of illness is that of a dementing process. As the disease progresses, these symtpoms are magnified and others appear, including defects in judgment, emotional lability, delusions, and inappropriate social and or moral behavior. Grandiose delusions and megalomania, although dramatic manifestations, occur in only 10-20% of cases. Depression may be the predominant presenting feature and the most common initial diagnosis in patients with paresis. Adult-onset seizures, noted in 15-20% of patients, may be the initial manifestation of paresis. Although rare, congenital syphilis may present with a paresis-like picture in adolescence, resulting in poor performance in school and behavioral abnormalities.
The most common neurologic findings in general paresis are pupillary abnormalities; flattening of the facial lines, tremors of the lips, tongue facial muscles, and fingers; and impaired handwriting and speech. Pupillary abnormalities are common in paresis and may be present in other forms of neurosyphilis. The pupils may be large, unequal, and sluggishly reactive to light and accommodation. Over the course of months, normal pupils may change in the Argyll Robertson type defined by the following characteristics: 1) retina is sensitive (i.e., the eye is not blind); 2) the pupils are small and fixed and do not react to strong light; 3) the pupils react normally to convergence accommodation; 4) mydriatics (atropine) fail to dilate the pupils fully; and 5) the pupils do not dilate on painful stimuli. Argyll Robertson pupils are observed more frequently in tabes than in paresis.
The duration of untreated paresis range from a few months, in cases of sudden onset, to 4 or 5 years until death. Uncommonly, spontaneous but transitory remissions have occurred. The shorter the duration and the milder the symptoms at the institution of therapy, the better is the prognosis.
Communicating hydrocephalus has complicated a few cases of general paresis and may account for either lack of clinical improvement or progressive deterioration after treatment. The patients have had gait apraxia, akinetic mutism, incontinence, and pyramidal tract signs along with severe dementia. Isotope cisternograms have shown early ventricular entry of the radionuclide and absence of parasgittal radioactivity. CSF shunting has produced immediate improvement in several cases.
Nontreponemal serologic tests of blood and CSF are usually but not invariably positive in cases of paresis. Other CSF findings are typical of those in neurosyphilis. The CSF may be normal in a patient whose neurosyphilis has been arrested by treatment.
Specific antitreponemal antibody tests of CSF, such as FTA-ABS or micro-hemagglutination assay for T. pallidum (MHA-TP), have been studied as a tool to diagnose neurosyphilis in cases in which the CSF VDRL is nonreactive. These tests are more sensitive, but they may be reactive as a result of diffusion of serum immunglobulins into the CSF; for this reason they should probably not be done routinely, although some advocate their use of these to help rule out neurosyphilis.
Another approach is to examine intrathecal antibody synthesis of antitreponemal antibodies using the CSF-IgG index, obtained by dividing the CSF to serum IgG ratio by the CSF to serum albumin ratio. As a result >0.7 is indicative of IgG synthesis within the CNS, but this finding is consistent with a variety of infectious or inflammatory processes. Better evidence for intrathecal antitreponemal antibody synthesis may be obtained if the CSF: serum ratio of T. pallidum hemagglutination assay (TPHA) is at least four times higher than the corresponding ratio for some other unrelated but ubiquitous antibody, such as adenovirus hemagglutinating antibody. CSF T. pallidum-specific IgM antibody levels have been studied for their utility in diagnosing CNS syphilis but have not found widespread use in practice. An increase in proportions of B cells in CSF may help diagnose neurosyphilis. A PCR test oc CSF for T. pallidum has been reported to be modestly sensitive and specific diagnosing neurosyphilis but, to date, has not been applied in clinical practice.
Computerized tomography in parenchymatous neurosyphilis may show extensive regions of decreased attenuation of the cerebral white matter, particularly in the frontal lobes and paraventricular areas of the parietal lobes, together with enlargement of cortical sulci and associated ventricular dilation; such changes are similar to those seen in demyelinating disorders. Cortical atrophy and multilpe areas of hypodensity in both cerebellar hemispheres are in the brainstem consistent with infaractions, may also be seen. Multiple nodular enhancing lesions were observed at the base the brain in one patient with meningovascular syphilis and cleared completely within 3 months after a 10-day course of intravenous penicillin. Both enhancing lesions (gummas) and generalized cortical and subcortical atrophy have been observed in patients with neurosyphilis.
What should the physician conclude concerning an older adult with a history of prior treated early syphilis who years later has a reactive serum treponemal test, atypical neurologic or psychiatric findings, and CSF abnormalities such as minimal pleocytosis and slightly elevated protein with a negative CSF VDRL? Is this a patient whose treponemal test reactivity merely represents prior infection and whose current neurologic syndrome has a non syphilitic etiology, or does he/she have active neurosyphilis in the absence of serum and CSF VDRL reactivity. This may be a very difficult diagnostic dilemma.
Grossly, the brain in general paresis shows varying degrees of thickening of the meninges, consistent with chronic meningitis and fibrosis. Cerebral atrophy is prominent, particularly in the frontal pole and the tips of the temporal lobes. Demyelination of cerebral white matter is often present. Granular ependymitis, formed of whorls of subependymal astrocytes, is characteristic.
Diagnosis and differential diagnosis
The diagnosis is based on the clinical picture, which is readily recognizable in its full blown form but is more difficult to define when atypical or incomplete, together with characteristic spinal fluid abnormalities. Moreover, other diseases including alcoholic brain disease may mimic paresis, and if they occur in patient with positive serologies for syphilis, a mistaken diagnosis of paresis may be made. The findings on CT scan, the presence of pupillary changes, and a history of alcohol abuse are helpful in correct diagnosis. Hallucinations are prominent in delirium tremens but are rare in general paresis.