Utility of 18F FDG-PET in Parkinsonism in an African population.

Parkinson's Disease remains a diagnostic challenge. Misdiagnosis during life is approximately 25%. Diseases that resemble PD clinically, such as the Parkinsonianplus disorders usually have a poorer prognosis. A diagnostic biomarker is needed to differentiate PD from PPS. Geographical differences in PD prevalence, genetics and environmental factors may suggest a different pathogenesis of PD in Africa which may affect metabolic changes seen on 18F-FDG-PET. We investigated the utility of 18FFDG-PET in differentiating PD from PPS in a real-life clinical setting. The study was conducted at the Movement Disorder Clinic, South Africa. 81 patients with Parkinsonism had fluorine-18-labelled-fluorodeoxyglucose-PET; 53 PD and 28 PPS. Six persons living with HIV and Parkinsonism were included. Of the 22 Black African patients, 21 had PD and only one had a PPS. Image-based diagnosis was made by visual interpretation aided by statistical parametric mapping (SPM) analysis by a Nuclear Medicine Physician blinded to the clinical diagnosis. This was compared to the final clinical diagnosis made by two Movement disorder Neurologists blinded to the 18F-FDG-PET diagnosis. Patients were followed up for a median of 4 years. 18F-FDGPET diagnosis was in agreement with final clinical diagnosis in 91% of all subjects (90% PD, 93% all PPS). Our paper reports the clinically realistic sample of patients seen with Parkinsonism in Africa. The present data shows that 18F-FDG-PET can distinguish PD from PPS with good accuracy. Few Black Africans present with an Atypical Parkinsonian syndrome. The pattern of metabolism in PLH-PD is similar to PD patients without HIV.

The association between headache presentation, normal examination and neuroimaging findings: a retrospective analysis of patients presenting to a tertiary referral centre.

Background: There is a high worldwide burden of headaches. Selection of patients with headaches for neuroimaging, in the absence of traditional red flags, is imperative in guiding further management. Objectives: Determine the yield of neuroimaging findings in patients with headache and normal examination; and potentially identifying additional red flags. Methods: A retrospective consecutive chart review of patients with a main complaint of headaches and normal clinical examination were assessed at a tertiary hospital, over a 10-year period. Results: Cohort consisted of 114 patients. Unexpected or normal variants found in 20.2% of patients (23/114) and 11.4% (13/114) required change in management. The absence of nausea and vomiting (p=0.009) and absence of sharp type headaches in unexpected or normal variants group (p=0.03) were statistically significant. There was a higher chance of an abnormal neuroimaging study in men and HIV seropositive patients. Conclusions: Decision to neuroimage should be determined on an individual basis (demographic factors, history of headache and examination) as normal examination cannot preclude patients from unexpected findings on neuroimaging. Headache with nausea and vomiting in isolation may be associated with normal neuroimaging reflecting primary type headaches. Findings support a lower threshold to neuroimage men and HIV seropositive patients with headaches despite normal clinical examination.

Does antiretroviral therapy alter the course of Parkinson's disease in people living with HIV?

South Africa has the world's largest antiretroviral programme which has resulted in an increase in life expectancy in persons living with HIV. Parkinson's disease (PD) is an age-related neurodegenerative disorder. No data has been published in this setting with regards to the interaction between PD and people infected with HIV. This was a retrospective study which matched two HIV non-infected PD patients to one HIV-infected patient with PD. Patients with secondary causes of Parkinsonism were excluded. Demographic, clinical and laboratory data were extracted from the charts. Hoehn and Yahr scale was used to assess PD severity. Twenty PD patients were recruited from 1 January 2008 to 31 October 2020 and were diagnosed with HIV for a median of 72 months. The median age at onset of PD was 52 years. All patients were on antiretroviral therapy. There were no statistically significant differences in the levodopa equivalent daily dose, clinical phenotype, impulse control disorders (ICDs) and frequency of a positive family history between the two groups. HIV-infected patients had a higher frequency of dopamine dysregulation syndrome. At the end of follow-up, 3 (15%) PLH-PD had moderate to severe PD compared to 16 (40%) of PD controls. The OR of having moderate to severe PD in HIV non-infected PD patients was 4. Persons living with HIV and Parkinson's disease present with PD symptoms at a younger age, progress slower to a severe stage and respond well to dopaminergic replacement therapy.

The spectrum of functional neurological disorders: A retrospective analysis at a tertiary hospital in South Africa.

BACKGROUND: Functional neurological disorders (FNDs) are commonly encountered in practice; however, there is a paucity of data in Africa. AIM: To identify and describe the clinical profile of patients presenting with FNDs, underlying medical and psychiatric diagnoses and review the investigation and management of these patients. SETTING: Inkosi Albert Luthuli Central Hospital (IALCH), a tertiary-level hospital in Durban, South Africa. METHODS: A retrospective chart review and descriptive analysis were performed over a 14-year period (2003-2017) on cases meeting the study criteria. RESULTS: Of 158 subjects, the majority were female (72.8%), had a mean age of 32.8 years, were single (63.3%), unemployed (56.3%) and of black African ethnicity (64.6%). The most common clinical presentation was sensory impairment (57%) followed by weakness (53.2%) and seizures (38.6%). Inconsistency was the most frequent examination finding (16.5%). Medical conditions were identified in half of the study population (51.3%), with hypertension (22.2%) and human immunodeficiency virus (HIV) (17.2%) being most common. Of patients with a psychiatric diagnosis (55.1%), 25.3% had depression. Magnetic resonance imaging (MRI) was the most frequently performed investigation (36.1%). The majority of patients received psychotherapy (72%) and most had not shown improvement (55.3%) at a median follow-up of 2 months, whilst 17% had deteriorated. CONCLUSION: Functional neurological disorders were most frequently diagnosed in young unmarried females, of black African ethnicity. Family history, personal exposure to a neurological illness and certain socioeconomic factors may be potential risk factors. Sensory impairment was the most common clinical phenotype. Further studies are needed to better understand and manage FNDs in the South African context.

Review of the neurological aspects of HIV infection.

There are almost 40 million people in the world who live with the human immunodeficiency virus (HIV). The neurological manifestations associated with HIV contribute to significant morbidity and mortality despite the advances made with anti-retroviral therapy (ART). This review presents an approach to classification of neurological disorders in HIV, differentiating diseases due to the virus itself and those due to opportunistic infection. The effects of antiretroviral therapy are also discussed. The emphasis is on the developing world where advanced complications of HIV itself and infections such as tuberculosis (TB), toxoplasmosis and cryptococcal meningitis remain prevalent.

Laboratory diagnosis of tuberculous meningitis in human immunodeficiency virus-seropositive patients: Correlation with the uniform case definition.

BACKGROUND: Laboratory confirmation of the diagnosis of tuberculous meningitis (TBM) has always been problematic. Using the uniform case definition suggested by Marais et al., we determined the sensitivity of a variety of laboratory tests. METHODS: Human immunodeficiency virus (HIV)-seropositive patients suspected of having subacute meningitis were included in the study. Using the uniform case definition, patients were divided into possible and probable cases of TBM. The following specific tests were done on the cerebrospinal fluid (CSF): layered Ziehl-Neelsen (ZN) staining, CSF culture and a panel of nucleic acid amplification tests (NAAT) consisting of the GenoType MTBDRplus assay, Cepheid Xpert MTB/RIF, the MTB Q-PCR Alert (Q-PCR) and the loop-mediated isothermal amplification (LAMP) assay. The sensitivity of each test was compared to the case definition and to each other. RESULTS: A total of 68 patients were evaluated. Using the uniform case definition only, without any of the specific laboratory tests, there were 15 probable cases (scores > 12) and 53 possible cases (scores 6-11) of TBM. When the uniform case definition was tested against any laboratory test, 12 of the 15 (80%) probable cases and 26 of the 53 (49.1%) possible cases had laboratory confirmation. When each test was compared to any other test, the sensitivities for the Xpert MTB/RIF, GenoType MTBDRplus, CSF culture, Q-PCR, LAMP and ZN layering were 63.2 (46.0-78.2), 76.3 (59.8-88.6), 65.7 (47.8-80.9), 81.1 (64.8-92.0), 70.3 (53.0-84.1) and 55.6 (38.1-72.1), respectively. CONCLUSION: In this study, the GenoType MTBDRplus and the Q-PCR tests performed better than the Xpert MTB/RIF. Because the Xpert MTB/RIF is not good enough to 'rule out' TBM, a negative result should be followed up by another NAAT, such as the GenoType MTBDRplus or Q-PCR. The LAMP assay may be considered as the first test in resource-poor settings. At the time of the study, we did not have access to the Xpert MTB/RIF Ultra, which has now been recommended by the World Health Organization as the test of first choice. However, even this test has a similar limitation as the Xpert MTB/RIF, with two recent studies showing variable results.

Clinical series of Parkinson's disease in KwaZulu-Natal, South Africa: Retrospective chart review.

BACKGROUND: There is limited data on Parkinson's disease (PD) in South Africa. METHODS: Demographic and clinical information was extracted from the hospital records of patients who were coded as PD (International Classification of Diseases, 10th revision, G20) from 2002 to 2016.PD was diagnosed using the United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria (UKBBC). RESULTS: 414 patients met the criteria, 194 Indian, 130 Black, 16 Mixed Ancestry and 74 White patients. Median age at onset was 60 years, 53% were male and 20% had early onset PD (EOPD). There were no differences between the ethnic groups for the male: female ratio, age at onset, frequency of EOPD, family history, clinical phenotype and disease severity. Dyskinesia and neuropsychiatric symptoms were more frequent in Indian and White patients (p < 0.001). PD referral centre prevalence was 23/1000 neurological cases for the period 2002-2016. Referral centre prevalence of PD was 2.8 times higher in White compared to Black patients. Our study demonstrates an increase in referral centre prevalence of PD since the last clinical series in 1988 and an age related increase in prevalence. CONCLUSIONS: PD prevalence is increasing. The clinical profile of PD in Black patients is similar to the other ethnic groups. This study highlights the need for health care resource allocation to neurodegenerative disorders in an ageing African continent.

A comparative study of motor neuron disease in HIV-infected and HIV-uninfected patients.

BACKGROUND: This study is a descriptive review of the clinical and treatment outcome differences in HIV-infected patients with motor neuron syndrome (MNS) and HIV-uninfected patients with motor neuron disease (MND). METHODS: A retrospective analysis of patients with MND/S was performed at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa between 2003 and 2017. RESULTS: One hundred and thirty six patients were included in the study, 101 (76%) were HIV-uninfected and 35 (26%) were HIV-infected. Ninety four percent of the HIV-infected cohort were <50 years, median 41, IQR (33-45), p < 0.001, had median ALS functional rating scale revised (ALSFRS-R) score of 28, IQR [24-30] and 40% of these patients on anti-retroviral therapy (ART) survived longer than 10 years. Ninety one percent of the HIV-uninfected cohort were >50 years, median 66, IQR(57-74), P < 0.001, had median ALSFRS-R score of 44 (IQR 42-45) and 93% died within 5 years of their illness. CONCLUSION: HIV-infected MNS patients were younger, had more severe disease at presentation and survived longer if treated with ART with possible reversal of the disease process, compared to patients with MND.

Posttubercular syringomyelia in HIV-infected patients: A report of 10 cases and literature review.

OBJECTIVES: To describe the clinical presentation, spinal magnetic resonance imaging (MRI) findings and outcome of HIV-infected patients with tuberculosis (TB)-associated syringomyelia and to compare these findings between all HIV-infected and -uninfected cases published in the literature. METHODS: A retrospective observational study conducted over a 12.5-year period at a public-sector referral hospital in South Africa. HIV-infected adults with neurological TB in whom MRI confirmed a syrinx were included. We searched PubMed to identify all published syringomyelia cases. RESULTS: Ten patients were enrolled. Syringomyelia complicated neurological TB within four years of initial diagnosis in all patients (median: 21 months, range: 0-39) after initial diagnosis. Six patients were treated conservatively (TB treatment = 5, no treatment = 1); four improved, but only one was ambulant during follow-up. Four patients underwent syringoperitoneal shunting; three improved and one died three months later. Our literature review identified 50 additional cases (HIV-infected = 2, HIV-uninfected = 9, HIV status not documented = 39 [presumed HIV-uninfected]). Clinical and imaging findings and outcomes were similar between HIV-infected and -uninfected cases, except for time of presentation following neurological TB diagnosis, which was delayed (>4 years) in 46% of HIV-uninfected cases, compared to 8% of HIV-infected cases. Conclusions Syringomyelia is a disabling complication of neurological TB that usually presents early after neurological TB diagnosis in HIV coinfected patients.

Spinal Tuberculosis: Clinicoradiological Findings in 274 Patients.

Background: Mycobacterium tuberculosis is a major cause of myelopathy and radiculopathy in settings with a high prevalence of tuberculosis/human immunodeficiency virus (HIV) coinfection. However, a paucity of publications exists on the spectrum of neurological and magnetic resonance (MR) imaging findings of spinal tuberculosis in these populations. Methods: We conducted a retrospective study of adults with spinal tuberculosis at a referral center in South Africa for patients with spinal disease without bony involvement seen at plain film radiography. We report the clinical, laboratory and spinal MR imaging findings, compare HIV-infected and HIV-uninfected patients, and correlate clinical and cerebrospinal fluid findings with those of MR imaging. Results: Of 274 patients, 209 (76%) were HIV infected and 49 (18%) were HIV uninfected. Radiculomyelitis occurred in 77% (n = 210), and spondylitis in 39% (n = 106). Subdural abscess (n = 42) and intramedullary tuberculoma (n = 33) were common. In 24% of HIV-infected and 14% of HIV-uninfected patients, spinal disease manifested as a paradoxical tuberculosis reaction, frequently following tuberculous meningitis. The triad of neurological deficit, fever, and back pain was similar in patients with spondylitis (24%), epi/subdural abscess without bony disease (14%), meningoradiculitis (17%), and isolated myelitis (17%) . Conclusions: Radiculomyelitis is a common manifestation of spinal tuberculosis in settings with high tuberculosis/HIV prevalence, often presenting as a paradoxical reaction. We describe a high frequency of rarely reported spinal tuberculosis manifestations, suggesting that these are more common than implied by the literature.

The neuromyelitis optica presentation and the aquaporin-4 antibody in HIV-seropositive and seronegative patients in KwaZulu-Natal, South Africa.

BACKGROUND: The association of the anti-aquaporin-4 (AQP-4) water channel antibody with neuromyelitis optica (NMO) syndrome has been described from various parts of the world. There has been no large study describing this association from southern Africa, an HIV endemic area. HIV patients often present with visual disturbance or features of a myelopathy but seldom both either simultaneously or consecutively. We report our experience of NMO in the era of AQP-4 testing in HIV-positive and HIV-negative patients seen in KwaZulu-Natal, South Africa. METHODS: A retrospective chart review was undertaken of NMO cases seen from January 2005 to April 2016 in two neurology units serving a population of 7.1 million adults. The clinical, radiological and relevant laboratory data were extracted from the files and analysed. RESULTS: There were 12 HIV-positive patients (mean age 33 years), 9 (75%) were women and all 12 were black patients. Of the 17 HIV-negative patients (mean age 32 years), 15 (88%) were women and 10 (59%) were black people. The clinical features in the two groups ranged from isolated optic neuritis, isolated longitudinally extensive myelitis or combinations. Recurrent attacks were noted in six HIV-positive patients and six HIV-negative patients. The AQP-4 antibody was positive in 4/10 (40%) HIV-positive patients and 11/13 (85%) HIV-negative patients. The radiological changes ranged from longitudinal hyperintense spinal cord lesions and long segment enhancing lesions of the optic nerves. Three patients, all HIV-positive, had tumefactive lesions with incomplete ring enhancement. CONCLUSION: This study confirms the presence of AQP-4-positive NMO in southern Africa in both HIV-positive and HIV-negative patients. The simultaneous or consecutive occurrence of optic neuritis and myelitis in an HIV-positive patient should alert the clinician to test for the AQP-4 antibody. It is important to recognise this clinical syndrome as specific therapy is available. We further postulate that HIV itself may act as a trigger for an autoimmune process.

Visual loss in HIV-associated cryptococcal meningitis: A case series and review of the mechanisms involved.

Permanent visual loss is a devastating yet preventable complication of cryptococcal meningitis. Early and aggressive management of cerebrospinal fluid pressure in conjunction with antifungal therapy is required. Historically, the mechanisms of visual loss in cryptococcal meningitis have included optic neuritis and papilloedema. Hence, the basis of visual loss therapy has been steroid therapy and intracranial pressure lowering without clear guidelines. With the use of high-resolution magnetic resonance imaging of the optic nerve, an additional mechanism has emerged, namely an optic nerve sheath compartment syndrome (ONSCS) caused by severely elevated intracranial pressure and fungal loading in the peri-optic space. An improved understanding of these mechanisms and recognition of the important role played by raised intracranial pressure allows for more targeted treatment measures and better outcomes. In the present case series of 90 HIV co-infected patients with cryptococcal meningitis, we present the clinical and electrophysiological manifestations of Cryptococcus-induced visual loss and review the mechanisms involved.

Visual Loss in HIV-Associated Cryptococcal Meningitis: A Case Series and Review of the Mechanisms Involved

Permanent visual loss is a devastating yet preventable complication of cryptococcal meningitis. Early and aggressive management of cerebrospinal fluid pressure in conjunction with antifungal therapy is required. Historically; the mechanisms of visual loss in cryptococcal meningitis have included optic neuritis and papilloedema. Hence; the basis of visual loss therapy has been steroid therapy and intracranial pressure lowering without clear guidelines. With the use of high-resolution magnetic resonance imaging of the optic nerve; an additional mechanism has emerged; namely an optic nerve sheath compartment syndrome (ONSCS) caused by severely elevated intracranial pressure and fungal loading in the peri-optic space. An improved understanding of these mechanisms and recognition of the important role played by raised intracranial pressure allows for more targeted treatment measures and better outcomes. In the present case series of 90 HIV co-infected patients with cryptococcal meningitis; we present the clinical and electrophysiological manifestations of Cryptococcus-induced visual loss and review the mechanisms involved

Human T cell lymphotropic virus type 1- associated infective dermatitis in KwaZulu Natal, South Africa.

BACKGROUND: The Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (IDH), is a chronic relapsing dermatitis which usually presents in children older than 2 years. A total of 300 cases have been reported worldwide (Latin America, the Caribbean and only 5 from Senegal). Neither IDH, nor its complications have been reported from the rest of Africa. We aimed to examine the clinical and aetiological characteristics of IDH in a cohort of South African children. METHODS: Attendees at the dermatology clinic at King Edward VIII Hospital, Durban underwent clinical examination. After obtaining consent those suspected of IDH had specimens taken for blood counts, immunoglobulins, serum protein electrophoresis, viral studies (including genotyping), skin swabs and stool examinations. RESULTS: Nineteen of 60 suspected cases recruited over 3 years met the diagnostic criteria for IDH. The male-to-female ratio was 1:2; mean age 8 years (range 0.7 to 15). Dermatitis mostly affected the scalp (78.9%) and axilla (73.7%); fewer children had nasal crusting (47.4%). Mean Ig A, IgG and IgM were raised, at 3.52 g/l, 22.6 g/l and 1.38 g/l, respectively. The median CD4 cell count was 1958 cells/mm3. Viral genotyping of all tested samples were positive for the Cosmopolitan, Subtype A (HTLV-1a). CONCLUSIONS: IDH is a distinct entity which also affects South Africans. Our patients were older at presentation and the majority did not present with nasal crusting as has been described in other countries.

Early clinical and subclinical visual evoked potential and Humphrey's visual field defects in cryptococcal meningitis.

Cryptococcal induced visual loss is a devastating complication in survivors of cryptococcal meningitis (CM). Early detection is paramount in prevention and treatment. Subclinical optic nerve dysfunction in CM has not hitherto been investigated by electrophysiological means. We undertook a prospective study on 90 HIV sero-positive patients with culture confirmed CM. Seventy-four patients underwent visual evoked potential (VEP) testing and 47 patients underwent Humphrey's visual field (HVF) testing. Decreased best corrected visual acuity (BCVA) was detected in 46.5% of patients. VEP was abnormal in 51/74 (68.9%) right eyes and 50/74 (67.6%) left eyes. VEP P100 latency was the main abnormality with mean latency values of 118.9 (±16.5) ms and 119.8 (±15.7) ms for the right and left eyes respectively, mildly prolonged when compared to our laboratory references of 104 (±10) ms (p<0.001). Subclinical VEP abnormality was detected in 56.5% of normal eyes and constituted mostly latency abnormality. VEP amplitude was also significantly reduced in this cohort but minimally so in the visually unimpaired. HVF was abnormal in 36/47 (76.6%) right eyes and 32/45 (71.1%) left eyes. The predominant field defect was peripheral constriction with an enlarged blind spot suggesting the greater impact by raised intracranial pressure over that of optic neuritis. Whether this was due to papilloedema or a compartment syndrome is open to further investigation. Subclinical HVF abnormalities were minimal and therefore a poor screening test for early optic nerve dysfunction. However, early optic nerve dysfunction can be detected by testing of VEP P100 latency, which may precede the onset of visual loss in CM.

Sodium valproate and highly active antiretroviral therapy in HIV positive patients who develop new onset seizures.

Recurrent seizures may occur in up to 11% of HIV positive patients. The aetiology of the seizures includes opportunistic infections, neoplasia, HIV itself, metabolic derangements and drugs. Apart from treating the cause of the seizures, the challenge is to use the appropriate anticonvulsant drug (AED) to avoid potentially adverse drug-drug interactions in patients who are on concurrent highly active antiretroviral therapy (HAART). Initial recommendations were that the newer AEDs should preferably be used because of their simpler pharmacokinetics. We report on our experience with the use sodium valproate (SV) in eight patients who were on concurrent HAART. There were two males and six females with a mean age of 34.1 years. The mean dose of SV was 1075 mg per day. Seizure control was excellent, the CD4 count improved and there was successful viral suppression in all patients. This small study showed that SV was safe and effective. It is also relatively inexpensive compared to the newer AEDs - an important consideration in resource poor settings.

Utility of a novel lipoarabinomannan assay for the diagnosis of tuberculous meningitis in a resource-poor high-HIV prevalence setting.

BACKGROUND: In Africa, tuberculous meningitis (TBM) is an important opportunistic infection in HIV-positive patients. Current diagnostic tools for TBM perform sub-optimally. In particular, the rapid diagnosis of TBM is challenging because smear microscopy has a low yield and PCR is not widely available in resource-poor settings. METHODS: We evaluated the performance outcome of a novel standardized lipoarabinomannan (LAM) antigen-detection assay, using archived cerebrospinal fluid samples, in 50 African TBM suspects of whom 68% were HIV-positive. RESULTS: Of the 50 participants 14, 23 and 13 patients had definite, probable and non-TBM, respectively. In the non-TB group there were 5 HIV positive patients who were lost to follow-up and in whom concomitant infection with Mycobacterium tuberculosis could not be definitively excluded. The test sensitivities and specificities were as follows: LAM assay 64% and 69% (cut-point 0.22), smear microscopy 0% and 100% and PCR 93% and 77%, respectively. CONCLUSION: In this preliminary proof-of-concept study, a rapid diagnosis of TBM could be achieved using LAM antigen detection. Although specificity was sub-optimal, the estimates provided here may be unreliable because of a classification bias inherent in the study design where it was not possible to exclude TBM in the presumed non-TBM cases owing to a lack of clinical follow-up. As PCR is largely unavailable, the LAM assay may well prove to be a useful adjunct for the rapid diagnosis of TBM in high HIV-incidence settings. These preliminary results justify further enquiry and prospective studies are now required to definitively establish the place of this technology for the diagnosis of TBM.