Autoimmune encephalitis: Epidemiology, pathophysiology and clinical spectrum (part 2).

Autoimmune encephalitis (AE) represents a growing number of severe autoimmune-inflammatory diseases affecting both the white and grey matter of the brain. In part 1 of this series we focused on the epidemiology, pathophysiology and clinical presentation of this condition, with two illustrative cases. In this part, we will introduce the clinical criteria for AE, particularly for the diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, which were developed to facilitate immune treatment in suspected cases before antibody results are available. We subsequently discuss the work up, differential diagnosis and treatment options for patients with this disease.

TOR1A mutation-related isolated childhood-onset generalised dystonia in South Africa.

BACKGROUND: Childhood-onset generalised dystonia is commonly caused by TOR1A mutations and is known to respond well to pallidal deep-brain stimulation (DBS) surgery. The incidence and prevalence of monogenic dystonia in individuals from Africa and specifically of African ancestry are unknown, and no local cases of TOR1A mutation dystonia are found in the literature. OBJECTIVES: To describe our experience with the outcome of TOR1A mutation-positive patients with isolated generalised dystonia (IGD) of childhood onset who were treated with pallidal DBS. METHODS: All patients with TOR1A mutations from Steve Biko Academic Hospital and the Pretoria Neurology Institute in Pretoria, South Africa (SA), who underwent DBS for IGD of childhood onset were identified. We conducted a retrospective analysis of their demographics, clinical presentation and time to generalisation, genetic status and family history, and response to DBS treatment of the internal segment of the globus pallidus (GPi), utilising pre- and post-surgical scores of the United Dystonia Rating Scale (UDRS). RESULTS: Three patients, all of black African ancestry, were identified. The median age at onset was 12 years and the median time to surgery from dystonia generalisation was 3 years. Two children presented with cervical-onset dystonia. Two patients were related, representing the only two with a positive family history. All three patients had a positive outcome after surgery, with improvement of 67 - 90% on the UDRS recorded at last follow-up. CONCLUSIONS: TOR1A mutations are found in SA patients of black African ancestry, with age of onset and generalisation comparable to those described in international studies. However, onset with cervical dystonia was more common than previously reported. Response to GPi DBS was excellent in all patients.

Life-threatening Listeria meningitis: Need for revision of South African acute bacterial meningitis treatment guidelines.

BACKGROUND: The recent listeriosis outbreak in South Africa (SA) received widespread attention in the media. More than 1 000 laboratory-confirmed cases of listeriosis occurred during an 18-month period, with a case fatality rate of 28%. Acute bacterial meningitis due to listeriosis was extremely rare at Steve Biko Academic Hospital in Pretoria until 2017/18, when we saw two very sick adults with this condition during the listeriosis outbreak. OBJECTIVES: To describe the presentation, treatment and outcome of these patients to raise awareness of this potentially fatal but treatable infection that does not respond to empirical third-generation cephalosporins. CASE REPORTS: Case 1: A 60-year-old man collapsed at home after being discharged from hospital for treatment of Listeria meningitis. On readmission he had neck stiffness and a depressed level of consciousness with right-sided hemiparesis. A computed tomography (CT) scan of the brain showed possible subarachnoid haemorrhage, but on CT angio- and venograms, extensive thrombosis of the superior sagittal, right transverse and bilateral sigmoid sinuses extending into the right internal jugular vein was noted. Patient 2: A 55-year-old HIV-positive hypertensive man on highly active antiretroviral therapy and antihypertensives visited the emergency department complaining of a new-onset headache. He was discharged on pain medication, but was readmitted the next day with a depressed level of consciousness, neck stiffness, low-grade fever and generalised tonic-clonic convulsions. A lumbar puncture revealed active cerebrospinal fluid that was culture-positive for L. monocytogenes. The patients received ampicillin and gentamicin for 3 weeks; the cerebral venous thrombosis was treated with unfractionated heparin. In both cases, the course of the disease was complicated. The first patient remained confused and suffered from psychotic episodes for 5 weeks. He was finally discharged after 6 weeks in hospital and continued to improve to the extent that he was able to return to work. The second patient needed intubation and ventilation and was treated in the intensive care unit. He improved over the next week and was finally discharged home with no residual neurological sequelae. CONCLUSIONS: Our two cases demonstrate that the listeriosis outbreak should change the way we view bacterial meningitis in SA: according to the National Institute for Communicable Diseases, empirical treatment for meningitis should include ampicillin and gentamicin in all adult patients with features of meningitis. There may be a need for an updated meningitis treatment guideline in SA.

Clinical Findings and Genetic Screening for Copy Number Variation Mutations in a Cohort of South African Patients with Parkinson's Disease

BACKGROUND:Parkinson's disease (PD); with a prevalence of up to 4% in Western countries; appears to be less common in Africa; possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. OBJECTIVE:To describe the clinical and genetic findings in a group of black South African patients with PD.METHODS:All black African patients with PD from a tertiary hospital neurology clinic were examined. Symptoms were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS); and patients were classified according to motor features. Genomic DNA was extracted and multiplex ligation-dependent probe amplification was used for detection of copy number variation (CNV) mutations in the known PD-causing genes.RESULTS:Sixteen patients were identified (ages 56 - 82 years). Three had a family history of PD. Classification into motor subtypes showed 44% mixed; 31% akinetic-rigid; and 25% tremor-dominant subtypes. UPDRS scores ranged from 7 to 88; with dementia in 20%. No patient had G2019S LRRK2 and A30P SNCA mutations; and all except one had no CNV mutations in the known PD-causing genes. A female patient (age of onset 50 years; no family history) had a parkin gene heterozygous deletion of exon 4. She had hyperreflexia; bilateral Hoffmann's reflexes; normal plantar responses and no dystonia.CONCLUSION:This group of black African patients showed similar characteristics to patients in Western studies; possibly with a higher proportion having tremor-dominant disease. Genetic analysis showed one parkin gene mutation. The limited knowledge on PD-causing genes and mutations in black populations warrants further studies involving next-generation sequencing approaches

Basedow paraplegia: A possible misnomer.

Thyrotoxic myopathy frequently occurs in clinical practice; however, the association of hyperthyroidism with a flaccid, areflexic paraplegia, so-called Basedow paraplegia, appears to represent a controversial and doubtful entity. An 18-year-old female with undiagnosed and untreated Graves' disease presented with acute onset of global weakness predominantly in the lower limbs, but also affecting the upper limbs. The weakness was accompanied by hypotonia and areflexia. Clinically, the patient had a goitre and signs of thyroid ocular disease. Laboratory testing confirmed the presence of hyperthyroidism, and thyroid-stimulating hormone receptor antibodies were positive. The cerebrospinal fluid protein level was raised. The electroneuronographic and needle examinations were compatible with a clear denervation process, such as acute motor axonal neuropathy, a variant of Guillain-Barre syndrome. Intravenous immunoglobulin therapy, carbimazole and propranolol were administered. The occurrence of hyperthyroidism with a flaccid, areflexic paraplegia appears to represent more of a fortuitous than a causative association. It is important to consider and treat other causes, such as acute idiopathic polyneuritis.

AIDS-related progressive multifocal leukoencephalopathy (PML): a retrospective study from Pretoria, South Africa.

INTRODUCTION AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, results from lytic infection of predominantly oligodendrocytes. Following the HIV pandemic, the incidence of PML has risen sharply, but has rarely been reported in Africa. An increasing number of PML cases were seen recently in a tertiary South African hospital, and this study describes their clinical and radiological features. METHODS: Patients with positive cerebrospinal fluid (CSF) JC virus confirmed by real-time polymerase chain reaction (PCR) were retrospectively identified from January 2008 to June 2012. Adults seen at Neurology with PML were identified, and clinical features, laboratory findings and imaging studies were analysed. RESULTS: Of 121 specimens, 19 were positive; records of 17 patients were available (ages 27 - 64; CD4 counts 11 - 328 x106/µl); clinical manifestations included focal weakness (47%), impaired co-ordination (41%), and speech disturbances (12%), and CSF analysis showed high protein in 76%, and pleocytosis in 35%. Fifteen patients had CT brain scans, showing white matter involvement in 12; MRI studies in 13 patients showed typical PML lesions. CONCLUSION: This report is the first case series of patients with PML from a South African neurology unit, emphasising the fact that PML occurs commonly in South African patients with HIV infection.

Comparison of HTLV-associated myelopathy (HAM) in HIV-positive and HIV-negative patients at a tertiary South African hospital.

BACKGROUND: HTLV-1 associated myelopathy (HAM), or tropical spastic paraparesis, is caused by a retrovirus, the human T-cell lymphotropic virus (HTLV). Although patients with HAM and HIV infection have been described, to our knowledge no direct comparison has been made between patients who are HIV positive and suffering from HAM (HHAM) v. those who are HIV negative and suffering from HAM. AIM: We aimed to compare clinical and radiological findings in HIV-positive and -negative patients with HAM. METHODS: Adult patients who presented to the Neurology Unit at the Steve Biko Academic Hospital from May 2005 to June 2012 with a progressive myelopathy and HTLV seropositivity were retrospectively identified and their clinical and radiological data were collected and reviewed. RESULTS: 21 patients with HAM were identified, of whom 9 were HIV-positive and 11 HIV-negative. One patient, whose HIV status had not been established, was not included in the study. Although the trend did not reach statistical significance, co-infected patients tended to present at an earlier age (HHAM 6/9 (66%) <40 years old; HAM 2/11 (18%) <40 years old) and presented to hospital earlier (HHAM 6/9 (66%) < 3 years symptomatic; HAM 7/11 (63%) > 3 years symptomatic). Cord atrophy occurred in 7/8 dually infected patients and 8/10 HIV-negative patients. CONCLUSION: Although the study is limited by the small number of patients, co-infected patients tended to have a younger age of onset and to present to hospital sooner, and thoracic cord atrophy was very common.

Significance of cerebrospinal fluid adenosine deaminase isoenzymes in tuberculous (TB) meningitis.

Adenosine deaminase (ADA) exists as two isoenzymes, ADA(1) and ADA(2). It appears that the ADA(2) isoenzyme originates mainly from monocytes and macrophages. In tuberculous pleural effusions most of the ADA activity consists of ADA(2). The aim of this prospective study was to analyse ADA isoenzymes in the CSF of patients with meningitis to investigate whether the expected rise of the ADA(2) isoenzyme would occur in tuberculous meningitis. ADA isoenzyme analysis was performed on the CSF of 15 patients with tuberculous and 11 patients with bacterial meningitis by an automated kinetic enzyme coupled assay in the presence and absence of a specific ADA inhibitor. The ratio of ADA(2)/ADA(Total) was > 0.8 in 14/15 patients with tuberculous meningitis. In bacterial meningitis the ratio was > or =0.8 in 10/11 patients. The ADA(2) isoenzyme is the major contributor to increased ADA activity in the CSF of patients with tuberculous meningitis, probably reflecting the monocyte-macrophage origin of the ADA.

Clinical, cerebrospinal fluid and pathological findings and outcomes in HIV-positive and HIV-negative patients with tuberculous meningitis.

BACKGROUND: The early diagnosis of tuberculous (TB) meningitis remains difficult. In South Africa, the HIV epidemic has shifted the spectrum of meningitis towards chronic infections (mainly tuberculosis [TB] and cryptococcosis). This study aimed to analyze clinical, cerebrospinal fluid (CSF) and pathological findings and outcomes in TB meningitis to evaluate whether HIV infection significantly influences the characteristic findings. PATIENTS AND METHODS: 40 consecutive patients with TB meningitis presenting at the Pretoria Academic Hospital were evaluated clinically and chest X-rays (CXR), computerized tomography (CT) brain scans, CSF profiles, HIV and routine blood tests were analyzed. Postmortem examinations (PM) were performed in seven patients and outcomes were assessed after treatment. RESULTS: 20 patients were HIV-positive and 17 were negative (three not tested). History and clinical findings were similar in both groups. The mean Glasgow Coma Scale (GCS) value on admission was 13 in both groups, while CXR showed abnormalities consistent with TB in 9/17 with HIV and 7/15 without, with abnormal CT brain scans in 15/19 patients with HIV and 12/16 without. Dilated ventricles and infarcts occurred more commonly in HIV-positive patients. The CSF results showed similar results in both groups. PM in three HIV-positive patients showed weakly formed granulomas and extensive endarteritis and infarcts. Outcomes were similar in the two groups, but a low GCS value on admission was a better prognostic indicator than the CD4-count in HIV-positive patients. CONCLUSION: HIV infection does not significantly alter clinical and CSF findings in TB meningitis in South Africa, but ventricular dilatation and infarcts are more frequent in HIV-positive patients. The GCS gives a better indicator of prognosis than the CD4-count.

The impact of HIV on meningitis as seen at a South African Academic Hospital (1994 to 1998).

BACKGROUND: The increase in HIV infections in South Africa is alarming. The aim of this prospective 4-year study was to evaluate the rising incidence of HIV-related admissions due to meningitis at the Pretoria Academic Hospital (PAH) adult neurology ward and to investigate the spectrum of meningitis during this time. PATIENTS AND METHODS: Adults with meningitis presenting at the PAH neurology ward from March 1994 through February 1998 were included. HIV antibody status was determined and patients were assigned to five categories: bacterial, tuberculous, viral and cryptococcal meningitis, as well as an uncertain category. RESULTS: Over the 4-year study period 141 patients with meningitis were seen. Of these, 44 were HIV-positive (31%), with TB meningitis occurring in 16 (36%), cryptococcal meningitis in 22 (50%) and acute bacterial meningitis in three (7%). In the first 2 years of the study, 14% of patients were HIV positive; this figure rose to 44% in the 3rd year, and 57% in the final year. The spectrum of meningitis also changed: bacterial meningitis remained relatively stable at about 25% of the total; TB meningitis almost doubled from 16% in the 1st year to 31% in the last year of the study; viral meningitis initially occurred in 8% of patients and later in 3% of cases, while cryptococcal meningitis showed the most significant increase from 6% of cases in 1994/5 to 31 and 26% respectively in the last 2 years of the study. CONCLUSION: Over a 4-year period the HIV epidemic was responsible for a marked shift in the spectrum of meningitis towards chronic infections such as TB and cryptococcal meningitis at the PAH.

Discrimination between viral and nonviral meningitis by visually analyzed and quantitative electroencephalography.

A prospective study was conducted to assess the ability of the visually analyzed electroencephalogram (VEEG), the quantitative EEG (QEEG) and the Glasgow Coma Scale (GCS) to discriminate between patients with viral and nonviral meningitis. The 55 subjects, aged 14-75 years, fell into one of the following categories: viral (n = 12), bacterial (n = 19), tuberculous (n = 16) or cryptococcal (n = 8) meningitis. EEG recordings and Glasgow Coma Scale (GCS) scores were obtained within 48 hours of admission to hospital. The sensitivity of the VEEG and QEEG for the prediction of patients with nonviral meningitis (true positives in this context) attained reasonably high values of 70% and 80%, respectively. In contrast, the sensitivity of the GCS was only 38%. Each of the three tests achieved high degrees of consistency in this regard with positive predictive values of 94% or better. The specificity for each of the three tests was high, 100% for the VEEG and the GCS and 82% for the QEEG indicating a high probability for the correct prediction of viral meningitis (true negatives). The consistency of this prediction was, however, poor due to negative predictive values of only 53% for the QEEG, 48% for the VEEG and 32% for the GCS. The QEEG results did not reveal any obvious advantages over the VEEG. Rather the assessment of the occurrence of particular VEEG abnormalities showed that patients with delta abnormalities had a very high probability of nonviral meningitis. At the other end of the spectrum, all normal VEEGs occurred in viral meningitis. In important respects the predictive ability of the EEG was superior to that of the GCS. While there was statistically significant agreement between the VEEG and GCS, the degree of agreement was poor. This study indicates that the EEG is a valuable and probably underestimated test in the acute phase of meningitis and provides complementary information to the GCS.

A prospective study of Glasgow Coma Scale (GCS), age, CSF-neutrophil count, and CSF-protein and glucose levels as prognostic indicators in 100 adult patients with meningitis.

BACKGROUND: The Glasgow coma scale (GCS) is an objective measurement of a patient's level of consciousness and has prognostic implications in traumatic head injuries. Morbidity and mortality of patients with meningitis have been related amongst others to level of consciousness, hypoglycorrhachia, extremes of age, and high CSF protein values. In this prospective study of 100 patients the correlation between the GCS, age, CSF-neutrophil count and CSF-glucose and protein levels and the eventual outcome of the patients was assessed. METHODS: In 100 consecutive patients with meningitis (bacterial, viral, tuberculous, cryptococcal and other) the GCS, age, CSF-neutrophil count and CSF-protein and glucose levels were determined at admission. After treatment the outcome of the patient was assigned to one of four categories: healthy, minor and severe neurological deficits and death. RESULTS: From a non-parametric one-way analysis of variance it was found that with respect to mean GCS-values significant differences were present among the outcome categories (P < 0.0001). The outcome categories did not differ significantly with respect to age, CSF-neutrophil count or CSF-glucose level, but did differ significantly with respect to the CSF-protein level (P < 0.0025). Additionally, 88% of patients with a GCS value of > 12 had a good neurological outcome, while 88% of those with a GCS value of < or = 8 had a poor outcome. CONCLUSION: A good correlation between both the GCS and CSF-protein level at admission and the outcome of patients with meningitis was found, with the GCS value being a better prognostic indicator than high CSF protein levels.

Lymph node biopsy as an aid in the diagnosis of intracranial tuberculosis.

This report describes five patients with intracranial tuberculosis (TB): four with tuberculous meningitis and one with intracranial tuberculomas. In all cases the diagnosis was confirmed by excision biopsy of an enlarged cervical or axillary lymph node. The biopsies showed caseating granulomas and acid fast bacilli, confirming the diagnosis of TB within 48 h of admission. Lymphnode biopsies may be an effective and practical aid in diagnosing intracranial TB.

Recurrent attacks of unconsciousness with diffuse EEG alpha activity.

A 45-year-old patient presented with recurrent attacks of unconsciousness, which resembled sleep. However, EEG recordings during these attacks showed diffuse, frontal-dominant 10-Hz alpha activity. Both the attacks and EEG changes reversed promptly with intravenous flumazenil, but not with methylphenidate, atropine or placebo. The attacks could not be prevented with methysergide, flumazenil, clonidine, piracetam or phenytoin. Laboratory investigations revealed a temporal lobe arachnoid cyst, a distal motor and sensory polyneuropathy, abnormal auditory evoked responses during the attack, an abnormal silent period latency and abnormal melatonin regulation. Similar attacks were reported by history in two siblings and in the proband's late father. It is postulated that the attacks of unconsciousness could involve gamma-aminobutyric acid- (GABA)-mediated mechanisms.

Sneddon's syndrome with anticardiolipin antibodies--complications and treatment.

We investigated 2 patients with Sneddon's syndrome, elevated anticardiolipin antibodies and systemic complications, which included stroke, habitual abortions, cardiac valvular lesions, acrocyanosis, hypertension and renal insufficiency. Treatment with a combination of immunosuppressive agents and warfarin or aspirin prevented further complications and improved renal function. It is important for those in different specialties to be aware of this potentially treatable disorder.