Progressive multifocal leukoencephalopathy or immune reconstitution inflammatory syndrome after fingolimod cessation? A case report.

BACKGROUND: Fingolimod is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML); however, its discontinuation may cause severe immune reconstitution inflammatory syndrome (IRIS). As both of these conditions (especially fingolimod induced PML) are rarely described in medical case reports distinguishing between PML-IRIS and MS-IRIS may be diagnostically challenging. CASE PRESENTATION: We report a patient with severe clinical decline (Expanded Disability Status Scale (EDSS) increasing from 3.5 to 7.5) and multiple, large, contrast-enhancing lesions on brain magnetic resonance imaging (MRI) a few months after fingolimod withdrawal. The diagnostic possibilities included IRIS due to fingolimod withdrawal versus PML-IRIS. The JC virus (JCV) antibody index was positive (2.56); however, cerebrospinal fluid (CSF) JCV real-time polymerase chain reaction (JCV-PCR) was negative and brain biopsy was not performed. After a long course of aggressive treatment (several pulsed methylprednisolone infusions, plasmapheresis, intravenous dexamethasone, oral mirtazapine) the patient gradually recovered (EDSS 2.5) and MRI lesions decreased. CONCLUSIONS: This case report demonstrates the importance of monitoring patients carefully after the discontinuation of fingolimod for PML-IRIS and rebound MS with IRIS as these conditions may manifest similarly.

Spinal Cord Sarcoidosis Occurring at Sites of Spondylotic Stenosis, Mimicking Spondylotic Myelopathy: A Case Series and Review of the Literature.

Sarcoidosis is a multisystem granulomatous disease, with intramedullary spinal cord involvement seen in <1% of cases. This case series illustrates the clinical presentations and imaging findings of 5 patients with intramedullary spinal neurosarcoidosis occurring at sites of spondylotic spinal canal stenosis, which can be indistinguishable from spondylotic myelopathy with cord enhancement. Both entities are most common in middle-aged men and present with weeks to months of motor and sensory symptoms. On imaging, both can have focal spinal cord enhancement and longitudinally extensive signal abnormality centered at or just below the level of spinal canal stenosis. On the basis of our experience, we suggest that in patients with cord enhancement centered at or just below a site of spinal canal stenosis, consideration should be given to chest imaging and lymph node biopsy when applicable, to assess for the possibility of underlying sarcoidosis before surgical decompression.

Dynamic expression of JC virus in urine and its relationship to serostatus.

BACKGROUND: There is limited information regarding the daily shedding of JC virus (JCV) in urine and its correlation with serum JCV antibody levels. METHODS: The dynamic expression of JCV in urine and its correlation with JCV antibody status in patients receiving disease modifying therapy for multiple sclerosis were examined in a longitudinal case-control study. JCV antibody index levels were determined using a two-step ELISA (Stratify). JCV shedding in urine samples was determined by quantitative PCR during two 30-day study periods separated by intervals of at least 6 months. RESULTS: Of 42 study subjects (57% female; ages 22-56, average age 39.6 years), 27 (64.3%) were JCV antibody positive (index >0.40) at initial urine collection. Twelve seropositive subjects (44.4%) had detectable JCV in their urine with values ranging from 290 to 5.08 × 108 copies/mL. Daily viral shedding in these patients remained fairly constant throughout the study. Urinary JCV shedding was not detected in any JCV antibody index negative or indeterminate subject. In JCV urinary shedders, the average JCV antibody index was 2.69 (range 1.67-3.57). The average anti-JCV antibody index for the remaining JCV seropositive individuals without viral urinary shedding was 1.35 (range 0.46-3.91). CONCLUSION: MS patients displayed a consistent pattern of JCV shedding over days and months in which higher levels of viruria appeared to have driven higher levels of JCV antibody index. The findings provide additional insights into the dynamic expression of JCV and host response; however, studies in larger populations and of longer duration will be needed to determine their significance to the development of progressive multifocal leukoencephalopathy (PML).

A brainstem paraneoplastic syndrome associated with prostate cancer.

BACKGROUND: Paraneoplastic syndromes are seldom observed with prostate cancer. A rare paraneoplastic brainstem syndrome associated with prostate cancer is described, and the presence of antineuronal antibodies with this syndrome is demonstrated for the first time. SETTING: Tertiary referral centre for neurological disorders. PATIENT: This 59-year-old man developed ophthalmoplegia, dysarthria, dysphagia, pruritus, ataxia, corticobulbar and corticospinal signs in association with prostate cancer. The disorder was unaffected by treatment of the underlying malignancy, but responded initially to high-dose corticosteroid administration and intravenous immunoglobulins. RESULTS: Antibody to intracellular neuronal antigens was demonstrated in both the serum and the cerebrospinal fluid. CONCLUSIONS: This unique paraneoplastic syndrome chiefly affecting the brainstem may be a diagnostic clue to the presence of unsuspected prostate adenocarcinoma. Further studies will be required to determine the precise antigenic target.

Molecular genetic analysis of the Drosophila trithorax-related gene which encodes a novel SET domain protein.

The products of the trithorax and Polycomb groups genes maintain the activity and silence, respectively, of many developmental genes including genes of the homeotic complexes. This transcriptional regulation is likely to involve modification of chromatin structure. Here, we report the cloning and characterization of a new gene, trithorax-related (trr), which shares sequence similarities with members of both the trithorax and Polycomb groups. The trr transcript is 9.6 kb in length and is present throughout development. The TRR protein, as predicted from the nucleotide sequence of the open reading frame, is 2431 amino acids in length and contains a PHD finger-like domain and a SET domain, two highly conserved protein motifs found in several trithorax and Polycomb group proteins, and in modifiers of position effect variegation. TRR is most similar in sequence to the human ALR protein, suggesting that trr is a Drosophila homologue of the ALR. TRR is also highly homologous to Drosophila TRITHORAX protein and to its human homologue, ALL-1/HRX. However, preliminary genetic analysis of a trr null allele suggests that TRR protein may not be involved in regulation of homeotic genes (i.e. not a member of the trithorax or Polycomb groups) or in position effect variegation.

Molecular targets of opiate drug abuse in neuroAIDS.

Opiate drug abuse, through selective actions at mu-opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiates drugs have some affinity for kappa (KOR) and/or delta (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS.

Diagnostic value for culture of cerebrospinal fluid from HIV-1-infected individuals for opportunistic viruses: a prospective study.

OBJECTIVE: To investigate the diagnostic value of cerebrospinal fluid (CSF) culture for opportunistic viruses from HIV-1-infected individuals. METHODS: A 4-year prospective study was conducted using a participant population consisting of 186 HIV-1-infected individuals without neurologic disease, 73 HIV-1-infected individuals with encephalopathy, myelopathy, and/or peripheral neuropathy, and 10 controls. CSF samples recovered at 1-year intervals were subjected to virus culture using technique commonly used in the clinical laboratory setting. RESULTS: CSF samples obtained from only 15 of the 269 (5.6%) participants yielded an opportunistic virus upon culture. Cytomegalovirus, herpes simplex virus types 1 and 2, adenovirus, and presumptive enteroviruses were identified. No consistent correlation was observed between the detection of an opportunistic virus within a CSF sample and the presence or future development of neurologic disease. However, a significant correlation was observed between culture of virus from CSF and the future development of abnormal CD4+ (chi 2, P = 0.0286) and CD8+ (chi 2, P = 0.0018) lymphocyte counts in HIV-1-infected participants without neurologic disease. CONCLUSION: These results show that culture of CSF to screen for opportunistic viruses is neither diagnostic nor predictive of neurologic disease in HIV-1-infected individuals. Nevertheless, the presence of virus within CSF may be an indicator of HIV-1-mediated immune dysfunction and a predictor for future development of abnormal CD4+ and/or CD8+ lymphocyte counts.

Cerebrovascular disease in AIDS: a case-control study.

The autopsy records of adult patients dying with AIDS between 1983 and 1987 at a large, metropolitan, university-affiliated hospital were reviewed to determine the incidence and spectrum of cerebrovascular and associated cardiovascular disease. The clinical records of those patients with AIDS with cerebrovascular disease were retrospectively examined in detail. All autopsied patients between the ages of 20 and 50 years dying without AIDS in 1986 and 1987 served as the control group. At autopsy, 13 (8%) of 154 adult patients with AIDS had evidence of recent cerebrovascular disease. In comparison, 25 (23%) of the 111 control patients dying without AIDS had recent cerebrovascular disease (P less than 0.04). The spectrum of cerebrovascular diseases was similar in patients both with and without AIDS; however, cerebral vasculitis was observed only in the former. Thirty-nine (40%) of 97 patients with AIDS had significant cardiac disease, and cerebral emboli were demonstrated in four of the 13 patients with stroke. Stroke must be considered in the differential diagnosis of neurological disease in patients with AIDS, although it does not appear to be more common in this group than in a control population of young adults with other terminal illnesses. The causes of stroke occurring with AIDS are diverse and include cerebral emboli secondary to cardiac disease, cerebral hemorrhage secondary to thrombocytopenia, and cerebral vasculitis.

Progressive multifocal leukoencephalopathy in HIV-1-infected children.

OBJECTIVE: To describe the clinical and pathologic features of two HIV-1-infected children with progressive multifocal leukoencephalopathy (PML). DESIGN: Case report. SETTING: University-affiliated, public-health trust hospital. METHODS: Two HIV-1-infected children with PML are described. A 13-year-old girl, presumed to be congenitally infected with HIV-1, presented with dysarthria and paresthesias of the tongue and chin that evolved rapidly to dementia, muteness and severe spastic quadriparesis. The other patient, a 10-year-old boy who developed HIV-1 infection from a blood transfusion at the age of 3 years, presented with a facial palsy with subsequent development of right hemiparesis and aphasia. RESULTS: Brain biopsy in the first child and autopsy in the second confirmed the diagnosis of PML. In both patients, the CD4 T-lymphocyte count was less than 100 x 10(6)l at the time of neurological presentation. CONCLUSION: Despite seroepidemiological studies suggesting that the majority of individuals are infected with JC virus during childhood, PML is rare in children with impaired cell-mediated immunity. Our patients illustrate that PML is among the neurological complications of HIV-1 infection in children.

Oxandrolone in AIDS-wasting myopathy.

OBJECTIVE: To evaluate oxandrolone, an oral anabolic steroid with potent anabolic activity and minimal androgenic effects, for the treatment of AIDS-associated myopathy and wasting. METHODS: In a multicenter, double-blind study, 63 HIV-seropositive men with > 10% loss of body weight were randomized to receive either placebo, 5 mg/day oxandrolone, or 15 mg/day oxandrolone for 16 weeks. Body weight, neuromuscular evaluation, and measures of well-being were repeatedly assessed. RESULTS: Patients who received 15 mg/day oxandrolone showed weight gain throughout the 16-week treatment period. Overall, the 5 mg/day oxandrolone group maintained their weight gain over the 16-week period, whereas the placebo group showed continual weight loss. At week 16, significantly more patients in the 15 mg/day dose group reported increases in appetite and activity than those receiving placebo. There were no consistent, dose-related, statistically significant differences from baseline in laboratory values or adverse events. CONCLUSION: Oxandrolone, at a dose of either 5 mg/day or 15 mg/day, in contrast to placebo, had a positive impact on the weight and well-being of HIV-seropositive patients suffering from wasting and weakness. Measurable improvement in muscle strength was not noted at the doses employed in this study. Oxandrolone was well tolerated in all the patients who were enrolled in the study. Based on the results reported here, additional studies using higher doses of oxandrolone seem warranted.

Cerebrospinal fluid dopamine in HIV-1 infection.

BACKGROUND: Increasing evidence suggests significant involvement of the basal ganglia in patients with HIV-1 infection. OBJECTIVE: To study the effect of HIV-1 infection on cerebrospinal fluid (CSF) dopamine levels. DESIGN: CSF dopamine levels were measured by high-performance liquid chromatography. SETTING: A university-based outpatient clinic in south Florida involved in clinical AIDS research. SUBJECTS: Twenty-two subjects were enrolled in a prospective, longitudinal study of the neurological complications of AIDS. Five subjects were HIV-seronegative, but at risk for HIV-1 infection, 11 were HIV-1-seropositive without neurological disease and six had HIV-1-related neurological disease. RESULTS: The CSF dopamine mean values were significantly lower in the HIV-1-seropositive group with (P < 0.0001) or without (P < 0.0001) neurological disease than in the HIV-seronegative group. There was a very strong correlation between CD4 lymphocyte counts and CSF dopamine levels (P = 0.004) in the neurologically symptomatic group (P = 0.0008), but not in the other two groups. CONCLUSION: HIV-1 infection appears to have an effect on the central nervous system dopaminergic systems, as reflected in levels of CSF dopamine.

Neurosyphilis in human immunodeficiency virus type 1-seropositive individuals. A prospective study.

The prevalence of neurosyphilis in human immunodeficiency virus type 1 (HIV-1)-seropositive (HIV+) persons was assessed during the course of a study of the neurological complications of HIV-1 infection. One hundred sixty-six asymptomatic HIV+ subjects, 63 neurologically symptomatic HIV+ subjects, and six at-risk HIV-1-seronegative (HIV-) control subjects underwent cerebrospinal fluid (CSF) analysis on entry into this longitudinal study. Three (1.8%) of the asymptomatic HIV+ subjects had both a reactive CSF VDRL test and a reactive CSF fluorescent treponemal antibody-absorption (FTA-ABS) test. Two of these three subjects had a history of appropriately treated early syphilis, and all had a reactive serum rapid plasma reagin test. Of the 63 neurologically symptomatic HIV+ subjects, one patient with dementia had both a reactive CSF VDRL test and a fluorescent treponemal antibody-absorption test. Subjective improvement in cognitive skills followed high-dose, intravenous penicillin therapy. Another subject had a penicillin-responsive myelopathy accompanied by a reactive CSF fluorescent treponemal antibody-absorption test result, but a nonreactive CSF VDRL. Unsuspected neurosyphilis is relatively common in our population of asymptomatic HIV+ subjects and may be responsible for neurological disease in a significant minority of neurologically symptomatic HIV+ persons. Cerebrospinal fluid examination should be performed in all HIV+ persons with a history of syphilis or serological evidence of syphilis, regardless of prior treatment. Additionally, neurosyphilis should be considered in the differential diagnosis of neurological disease in any HIV+ person.

Neurological complications of ethylene glycol intoxication. Report of a case.

A 29-year-old man suffered bilateral facial nerve paralysis, dysarthria, dysphagia, ataxia, visual deterioration, and internal ophthalmoplegia after ethylene glycol ingestion.

Neurosyphilis in acquired immunodeficiency syndrome.

In a retrospective study encompassing 42 months (January 1984 through July 1987), 12 patients were identified as having both neurosyphilis and acquired immunodeficiency syndrome. These patients constituted 44% of the entire group meeting rigorous diagnostic criteria for neurosyphilis and 1.5% of all patients hospitalized with acquired immunodeficiency syndrome. The typical patient with acquired immunodeficiency syndrome and neurosyphilis was young (mean age, 37 years) and male (83%). All had serological evidence of syphilis in both blood and cerebrospinal fluid. Syphilitic eye disease was surprisingly common in this group, occurring in 5 (42%). Four patients (33%) had been previously treated for syphilis. In 2, treatment for latent syphilis had been completed 3 and 5 months, respectively, before neurosyphilis was documented. Neurosyphilis is not uncommon in patients with acquired immunodeficiency syndrome in our population. In light of its diverse manifestations, syphilis should be considered in the differential diagnosis of any human immunodeficiency virus type 1-infected individual presenting with neurological, psychiatric, or ophthalmological disease.

Paroxysmal dystonia as the initial manifestation of multiple sclerosis.

Paroxysmal dystonia was the initial manifestation of multiple sclerosis (MS) in eight patients. The disorder was generally characterized by dystonic posturing of unilateral extremities, averaging less than one minute in duration. Facial grimacing and dysarthria occurred in two of the eight patients. This paroxysmal phenomenon was frequently the cause of diagnostic confusion. The time elapsing before other neurological symptoms of MS developed was as long as ten years.

Guillain-Barré syndrome complicating acute hepatitis B. A case with detailed electrophysiological and immunological studies.

A 61-year old man was seen for Guillain-Barré syndrome (GBS) complicating acute type B hepatitis. Results of detailed electrophysiological studies were characteristic of a severe peripheral neuropathy of the segmental demyelinating type. Immunological studies demonstrated cell-mediated sensitization to peripheral nerve basic protein. Twenty-six cases of GBS complicating viral hepatitis were analyzed for age, sex, temporal relationship of the onset of the hepatitis to that of the polyneuritis, and outcome.

Spinal myoclonus associated with HTLV III/LAV infection.

We describe spinal myoclonus in a 35-year-old homosexual man with concurrent human T-cell lymphotropic virus type III/lymphadenopathy--associated virus (HTLV III/LAV) infection of the central nervous system as indicated by intra-blood-brain barrier synthesis of HTLV III/LAV-specific IgG. The spinal myoclonus was characterized by asymmetric, rhythmic contractions of the abdomen with a frequency ranging between 40 and 70 per minute. The myoclonus was self-limited, resolving over the course of two months. Human T-cell lymphotropic virus type III/lymphadenopathy--associated virus should be considered among the viral causes of spinal myoclonus.

Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus.

BACKGROUND: The course of neurosyphilis has been reported to be altered by human immunodeficiency virus (HIV) infection. Prior reports of neurosyphilis occurring in association with HIV infection have been largely anecdotal and have failed to compare neurosyphilis in patients with HIV infection with an uninfected control group. This study was performed to determine if the clinical presentation encountered is different in the presence of HIV infection. DESIGN: A retrospective, hospital-based, case series study based on chart review encompassing a 64-month period. SETTING: The study was performed in a large, university-affiliated, public health trust hospital in south Florida. PATIENTS: Forty-six hospitalized patients with neurosyphilis were identified; 13 patients fulfilled Centers for Disease Control and Prevention (Atlanta, Ga) criteria for acquired immunodeficiency syndrome (AIDS), 11 were HIV seropositive only, and 22 were HIV uninfected. Neurosyphilis was determined by a reactive cerebrospinal fluid VDRL slide test. RESULTS: The HIV-infected patients (both AIDS and HIV-seropositive groups) were younger and more frequently had features of secondary syphilis, such as rash, fever, adenopathy, headache, or meningismus. Significant differences were observed in cerebrospinal fluid measurements when the HIV-infected group was compared with the HIV-uninfected group, including a higher mean white blood cell count in patients with AIDS and a higher mean protein level and a lower mean glucose level in the HIV-infected group. Syphilitic meningitis was more common in HIV-seropositive patients, although the HIV-uninfected patients presented with a greater variety of types of neurosyphilis. Ophthalmic syphilis was observed more frequently in the HIV-infected group. CONCLUSIONS: Significant differences exist between neurosyphilis occurring in the presence and absence of HIV infection.

Human T lymphotropic virus type I-associated myelopathy. A report of 10 patients born in the United States.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) (tropical spastic paraparesis/HAM) has rarely been reported in the United States. We present 10 well-documented cases with positive Western immunoblot test results and polymerase chain reactions for HTLV-I. The clinical and laboratory features of these American-born patients resemble those previously reported series of tropical spastic paraparesis and HAM from the Caribbean and Japan, but important differences were observed. In our study there were equal numbers of whites and blacks and of men and women. Age at onset was younger than that reported from the Caribbean and Japan. Rate of progression to paraparesis varied but was more rapid than previously reported. Half were transfusion recipients but six had multiple sexual partners, with one regularly interacting with prostitutes and reporting a history of drug abuse. Although more rapid progression was seen in the transfusion recipients, this did not explain the earlier age of onset in this group of patients. The HTLV-I, and the associated myelopathy, are endemic in Florida, suggesting that immigration from, and proximity, to the Caribbean basin are contributing risk factors.

Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states.

OBJECTIVE: To describe the occurrence of progressive multifocal leukoencephalopathy (PML) in association with Wiskott-Aldrich syndrome, an X-linked recessive disorder with impairment of both cellular and humoral immunity. DESIGN: A detailed analysis of this patient's clinical illness, immunologic factors, neuroradiographic findings, and brain histopathologic conditions was undertaken. The medical literature on PML complicating congenital immunodeficient states was also reviewed. SETTING: A 1500-bed, university-affiliated, public health hospital. PATIENT: A 15-year-old boy with Wiskott-Aldrich syndrome. His neurologic illness was heralded by dysarthria and right-sided weakness and the diagnosis was established by brain biopsy specimen. Survival from the time of onset of PML was 10 months. CONCLUSION: Although PML typically occurs in the setting of severe acquired cellular immunodeficiency, often as a consequence of acquired immunodeficiency syndrome, organ transplantation, and leukemia and lymphoma, it may rarely accompany inherited immunodeficiency syndromes. The reported childhood cases of PML include three patients, aged 5, 11, and 18 years, with other inherited immunodeficiency syndromes. This patient represents the first time (to our knowledge) that PML has been reported to occur in association with Wiskott-Aldrich syndrome.