ABSTRACT

Background

The HIV is neurotropic and clinicians need to be aware of its myriad neurologic manifestations, as these may be the only clinical presentation.

Objective

To evaluate the clinical spectrum and outcome of the neurologic manifestations in patients with HIV / AIDS over a ten year period.

Design

case – note based retrospective follow-up study.

Settings

Olabisi Onabanjo University Teaching Hospital; Nigeria.

Participants

Patients attending the HIV outpatient clinic and medical in-patients with AIDS.

Intervention

Treatment was symptomatic and specific treatment was administered for indicator diseases. Highly Active Anti-retroviral Therapy (HAART) was not used routinely.

Main Outcome Measure

Neurologic impairment related to HIV / AIDS and its sequelae within 6 months.

Results

A total of 362 patients with HIV / AIDS were reviewed over a ten-year period, of which 154 patients, (42.5%) had neurological manifestations. Forty-five (29%) patients had Herpes zoster, 40 (26%) had TB meningitis (TBM), 19 (12%) had vacuolar myelopathy (VM), another 19 (12%) had AIDS dementia complex (ADC), 15 (9.7%) had toxoplasma encephalitis, 10 (6.5%) had distal sensory polyneuropathy, 4 (2.6%) had inflammatory demyelinating polyneuropathy, and 2 (1.3%) had subacute combined degeneration of the spinal cord. An overall 6-months fatality of 45% was recorded with ADC, VM and TBM as predictors of high fatality.

Conclusion

Herpes zoster appears to be the commonest neurological manifestation while TBM is the commonest AIDS defining illness. Our experience indicates that unusual neurological manifestations could be the first manifestation of HIV/AIDS, and there is need for awareness of these entities by practising doctors for prompt diagnosis and treatment.
Screening of all patients with Herpes zoster for HIV is also advised.

RESUME

Introduction

Le VIH est neurotrophique et les praticiens doivent être vigilants compte tenu du caracère polymorphe des manifestations neurologiques cliniques.

But

Evaluer les aspects cliniques et l’évolution des manifestations cliniques chez des patients HIV/SIDA durant une période de 10 ans.

Méthodes

Il s’agit d’une étude rétrospective réalisée à l’Olabisi Onabanjo University Teaching Hospital (Nigeria) chez des patients en ambulatoire pour les séropositifs ou hospitalisés, pour les sidéens. Le traitement était symptomatique et rarement trithérapie.

Résultats

362 patients VIH / SIDA ont été étudiés sur une période de dix ans. 154 patients (42.5%), présentaient des manifestations neurologiques. Quarante cinq patients (29%) avaient un zona, 40 (26%) une méningite tuberculeuse (TBM), 19 (12%) une myéopathie vacuolaire (VM), 19 (12%) une démence (AIDS dementia complex, ADC), 15 (9.7%) une toxoplasmose cérébrale, 10 (6.5%) une polyneuropathie distale sensitive, 4 (2.6%) une polyneuropathie démyélinisante inflammatoire, and 2 (1.3%) une myélopathie subaiguë subacute.

Conclusion

Le zona apparaît comme étant la manifestation neurologique la plus commune.
Notre expérience montre que les manifestations neurologiques inhabituelles peuvent être les premières manifestations du VIH/SIDA et interpelle tout médecin en présence de tout malade atteint d’un zona.

Keywords : Africa, AIDS, HIV, Nigeria, Neurological, Afrique, neurosida, VIH, SIDA

INTRODUCTION

Neurologic disorders are among the most frequent and devastating complications of HIV infection, and this may be its only clinical manifestation (1,7). As more effective therapies allow patients with AIDS to live longer, the prevalence of neurologic complications is likely to increase.

There has been dearth of information on the neurological manifestations of HIV /AIDS amongst the African population and it is with this background that this retrospective study was carried out at the Ogun State University Teaching Hospital (OSUTH), Nigeria. The study aimed at evaluating the clinical spectrum and outcome of the neurologic manifestations amongst patients attending the HIV outpatient clinic and medical in-patients with AIDS.

METHODOLOGY

The case notes of all patients attending the HIV outpatient clinic and medical in-patients with AIDS were retrieved and reviewed from December 1992 to November 2002. Only patients living with HIV / AIDS who satisfied the under listed criteria were included in the study.

HIV screening was done by ELISA technique using Immunocomb and repeatedly reactive ELISA with 2 different kits was taken as confirmatory. Confirmatory test with Western blot, CD4 count and viral load were not done, as there were no facilities at the time of study. The results of full blood count and differentials, fasting sugar, ESR, VDRL, HBsAg, chest X-ray, sputum and stool microscopy, culture and sensitivity, mantoux test, CSF analysis, and other appropriate ancillary investigations done for indicator diseases were recorded.

Setting: OSUTH is situated in Sagamu; a semi-urban town with a population of about 200,000 (2002 census). Sagamu has a large cement factory and a major petroleum depot with its attendant vibrant trailer and tanker presence as well as a booming sex trade involving the tanker drivers and the locales. The hospital is a tertiary health facility serving all towns in Ogun state as well the adjoining parts of Lagos and Oyo states, and has 240 beds distributed amongst the various specialities with 40 in-patients beds for medical admissions; 20 for females and males apiece. The bases for admission are usually the acute care needs of patients, the need for highly skilled management and the severity of the patients’ illness as well as suitability for teaching and research. Patients are admitted mostly through the accident and emergency department and medical out patient clinics. The community medicine and primary care department also runs an HIV outpatient clinic and patients were also admitted to the medical wards from this clinic whenever the need arose. Discharged patients were followed up in either the medical or HIV outpatient clinic as appropriate. The clinic attendees were mutually exclusive.

Treatment was symptomatic and specific treatment was administered for indicator diseases. Highly Active Anti-retroviral Therapy (HAART) was not used routinely at the time of study. However, a segment of the patients living with HIV / AIDS in the HIV clinics received HAART and formed part of another study (in press).
The Criteria for diagnosis were mainly clinical. Neuro-imaging techniques were not done as there were no facilities at the time of study.

Herpes zoster: Presence of a dermatomal / segmental rash and /or post-herpetic depigmentation and / or painful dysaesthesia. Carbamazepine / Amitryptilline was administered. Acyclovir was seldom used and Capsaicin was not available.

Tuberculous Meningitis (TBM): Features of subacute / chronic meningitis in the face of multiple cranial nerve lesions; with or without laboratory / radiological evidence of TB (pulmonary / extra pulmonary) and /or positive CSF culture for AFB and / or a xanthochromic CSF; and / or significant mantoux reaction or anergy; and / or elevated ESR.

Conventional short course Quadruple regime of anti-tuberculous medications for six months with prednisolone for the first 6 weeks of therapy were administered..

Vacuolar myelopathy (VM): Normal spine X- ray and typically “normal” or non-specific csf abnormalities with evidence of non-traumatic slowly progressive affectation of the posterior (impaired vibration, joint position sensation and positive Romberg’s sign) and lateral columns (spastic paraparesis, gait disorder) with sphincteric dysfunction (erectile dysfunction in males) in the absence of a sensory level, or any other obvious cause of myelopathy. Presence of a discrete sensory level, spine tenderness or back pain, positive VDRL, or CSF pleiocytosis of greater than 30 cells / mm3 as well improvement with vitamin B 12 supplement raise suspicion of other causes. Serological test for HTLV 1, toxoplasma, serum level of B12, CSF level of S-Adenosyl Methionine (SAM) and Methionine), histopathological and neuroimaging studies (spinal MRI, CT scan myelography), and Somato-Sensory Evoked Potentials (SSEP) were not done.
Sub-acute Combined Degeneration of the spinal cord: Normal Spine X – ray with evidence of posterior and lateral column affectation, as well as peripheral neuropathy, and without sphincteric dysfunction. There could be accompanying beefy red tongue and / or anaemia and / or macrocytic blood film and possible clinical improvement with B12 supplement.
Toxoplasma encephalitis: Additional history of confusional state with irrational behaviour and seizures as well as clinical improvement with therapeutic trial of pyrimethamine and dexamethasone for medical decompression. There could be lateralising signs but usually without meningeal signs. Toxoplasma antibody levels – although inadequate – were not routinely done at the study center. Primary CNS lymphoma has a similar presentation except that there is absence of Toxoplasma antibody and lack of response to empiric toxoplasmosis treatment.
Cryptococcal meningitis: Features of subacute meningitis without laboratory / radiological evidence of TB and a positive response to anti-fungals (Diflucan / Amphotericin B). Cryptococcal antigen detection and or Indian – ink staining were not available.

Peripheral neuropathy – Six patterns are recognised :a) Distal symmetrical polyneuropathy (DSP); b) Inflammatory Demyelinating Poly neuropathy (IDP) ; c) Progressive polyradiculopathy (PP) ; d) Mononeuropathy multiplex (MM); e) Autonomic neuropathy (AN) ; f) Diffuse infiltrative lymphocytosis syndrome (DILS – presenting as Sjogren’s syndrome). Nerve Conduction Studies, EMG and Nerve biopsy were not done.

DSP: glove and stocking dysaesthesia (burning distal acral dysaesthesia) with nocturnal exacerbations, hypoesthesia, absent ankle jerks, contact allodynia and absence of any other obvious cause of peripheral neuropathy (diabetes, alcoholism, exposure to toxins or drugs including ARV, or excessive cassava consumption) and poor response to carbamazepine and gabapentin (neurontin).
IDP: diffuse weakness including facial musculatures, asymmetric in early cases; global areflexia and minor sensory signs. Typically occurs during seroconversion with resolution on neurovitamins + physiotherapy.

PP: flaccid paraparesis; saddle anaesthesia and sphincteric dysfunction

MM: multiple sensory / motor abnormalities.

AN: Sympathetic -: postural hypotension; syncope, diarrhea; anihydrosis;

Parasympathetic: resting tachycardia; impotence; urinary dysfunction.

DILS: conjuctivitis sicca -like presentation
Aseptic meningitis: Presence of meningeal signs with normal CSF.

AIDS dementia complex (ADC): Triad of cognitive, motor and behavioural dysfunction usually evolving within weeks to months. In early phase, concentraton and memory deficit, inattention, motor-incoordination and ataxia are common while in the late phase, global dementia with spastic paraplegia and mutism set in. Frontal release signs such as glabella tap and snout reflex may be present. The Mini-Mental Scale is usually insensitive, and Neuropsychological test such as HIV Dementia Scale (HDS) suggests subcortical dementia. The Memorial Sloan Kettering (MSK) scale was not available at the time of study.
Progressive Multifocal Leukoencephalopathy (PML): Progressive focal and cranial nerve deficits with cortical blindness. Patients are usually alert with no headaches, and cognitive dysfunction sets in very late. PCR of the CSF or brain biopsy was not done.

Statistics: Analyses of the patients’ characteristics, clinical features and results of investigations were done by standard statistical methods and use of Epi-Info 6.04.

RESULTS

A total of 5,035 patients were reviewed, of which, 156 patients were seen at the HIV out-patient clinic and 4,879 were in-patients on the medical wards. Of the medical admissions, 206 (4.2%) were patients with AIDS, of which 93 (45 %) presented with neurological manifestations. Sixty-one out of the 156 (39.1%) out- patient attendees had neurological manifestations. Thus, a total of 362 patients with HIV / AIDS were reviewed, of which 154 (42%) had neurological manifestations and this formed the basis for this study. There were 86 males and 68 females giving a male : female ratio of 1.3 :1 (Table 1). One hundred and eleven (72%) were HIV I positive, 36 (23%) were HIV I and II, and 7 (5%) were HIV II positive. The age range was between 21 to 43 years with a mean of 32 + 3.6 years.
Of the 61 patients with neurological manifestations attending the HIV out-patient clinic, 45 (73%) had Herpes zoster, 10 (16.4%) had distal sensory polyneuropathy, 4 (6.5%) had inflammatory demyelinating polyneuropathy and 2 had subacute combined degeneration of the cord (Table 2). Of the 93 medical in-patients with neurological indicator diseases, 40 (43%) had Tuberculous meningitis, 19 (20.4%) had Vacuolar myelopathy, another 19 (20.4%) AIDS dementia Complex and 15 (16.1%) had Cerebral toxoplasmosis. (Table 3).

Of the overall 154 patients that presented with neurological manifestations, forty-five (29%) patients had Herpes zoster, 40 (26%) had TB meningitis, 19 (12%) had vacuolar myelopathy, another 19 had AIDS dementia complex, 15 (9.7%) had toxoplasma encephalitis, 10 (6.5%) had distal sensory polyneuropathy, 4 (2.6%) had inflammatory demyelinating polyneuropathy, and 2 (1.3%) had subacute combined degeneration of the spinal cord (Table 4).
Forty-four of the 45 patients (98%) with Herpes zoster presented with affectation of the thoracic dermatomes while only 1 had ophthalmic herpes. Forty had the T6 dermatome affected while two each had affectation at T8 and T8/9. All the patients had carbamazepine and amitryptilline with minimal relieve, and developed post herpetic neuralgia, skin depigmentation or hypertrophic scars.

Of the 40 patients with TBM, 32 (80%) had antecedent pulmonary disease, five (12.5%) had abdominal TB, and in three (7.5%), no focal TB lesion was identified (? cryptogenic). The CSF was xanthochromic in thirty-seven (92.5%) of them and normal in three (7.5%). They all had significant mantoux reaction above 15 mm. Thirty-one (77.5%) patients died before completion of anti-tuberculous medications and the remaining nine were stable albeit with neurologic sequelae (Table 5).

Two of the patients with AIDS Dementia Complex had serial seizures requiring anti-convulsants but all the patients died within 12 weeks of hospitalisation.
Of the 19 patients with vacuolar myelopathy, the blood film showed a megalocytic picture in 2 (10.5%) cases. One hundred percent mortality was recorded within 6 months of diagnosis.

All the patients with toxoplasma encephalitis remained alive and well.

All the patients with distal sensory polyneuropathy had poor response to carbamazepine and amitryptilline..All the patients with inflammatory demyelinating polyneuropathy had 7th cranial nerve palsies: three were unilateral while one was bilateral. They made full neurological recovery within 7 weeks of the onset of symptoms. The 2 patients with subacute combined degeneration of the spinal cord improved and remained alive.

DISCUSSION

About 42% of patients with HIV / AIDS presented with neurological manifestations in this study and this is comparable with reports that up to 30 -40% of PLWHA present with neurological manifestations ante-mortem ( 6,10). The neurological complications of HIV infection are highly stage-specific, and disease incidence rates depend on where the individual is on the course of the systemic HIV infection ( 2,3,8). Herpes zoster was the commonest neurological manifestations in those without indicator disease, followed by Distal sensory polyneuropathy and Inflammatory demyelinating Polyneuropathy. TBM was the commonest indicator disease in those with AIDS, followed by AIDS dementia complex, vacuolar myelopathy, and toxoplasma encephalitis.

In this study, herpes zoster ganglionitis was found in about 74% of out-patient attendees living with HIV and this is comparable with its predictive value of 71-98% for HIV sero-positivity (4). It tends to occur early in the course of the illness with good neurological recovery especially in young patients. The findings of post-herpetic neuralgia, skin depigmentation and hypertrophic scar in all the patients is therefore extremely unusual. It is plausible that the immunosuppressive state is contributory and the hypertrophic scars could be related to the high prevalence of Keloid in the black skin. The thoracic dermatome – T6 – was the predilection site in 98 % of the patients and only one case of ophthalmic herpes was found. No obvious explanation could be adduced for this observation in this study. HIV screening of all patients with herpes zoster is advised.

TBM was the commonest indicator disease in those with AIDS and a high index of clinical suspicion is needed for early institution of treatment and favourable outcome
No focal TB lesion was identified in 7.5% of the study subjects, and in another three (7.5%), the cerebro spinal fluid (CSF) was normal. The predisposing focus of infection in TBM could be cryptogenic in 15% of cases and normal CSF does not negate or exclude the diagnosis of TBM (6).
All the patients with TBM had significant mantoux reaction despite the expected anergy or immunosuppression. Although, the CD4 count was not done, no reason could be adduced for this observation in this report. It was however possible that some of the patients had an earlier mantoux test done before presentation.

All the patients with AIDS dementia complex and vacuolar myelopathy died within 6 months of onset of symptoms. This is consistent with mortality of 80% reported in such patients within 6 months of diagnosis (1,5). The overall fatality of 45% reported in this study portends neurological complications such as ADC, VM and TBM as high predictors of fatality. The distinction between VM and sub-acute combined degeneration of the spinal cord is of clinical relevance. The two patients with subacute combined degeneration of the spinal cord improved upon administration of hydrocobalamine. A very high index of clinical suspicion in PLWHA is necessary to ensure that such patients are identified and treated promptly.
As TB is endemic in our environment and BCG vaccination protects strongly against TBM (9), BCG vaccination of infants and unexposed individuals should continue to be a must in our environment. Furthermore, INH prophylaxis should routinely be used in our HIV population without overt evidence of TB.

Some neurological manifestations were not reported in the study. It is possible that this could reflect inadequate screening techniques or lack of necessary investigative tools such as Neuro-imaging techniques and PCR among others to corroborate the diagnosis. The shortcomings of a retrospective study and the highly selected group of patients could also be contributory.

In conclusion, our experience indicates that unusual neurological manifestations could be the first manifestation of HIV/AIDS. There is need for awareness of these entities by practising doctors for prompt diagnosis and treatment to reduce misdiagnosis and delayed reporting in our environment. Screening of patients with Herpes zoster for HIV as well as prophylactic use of INH in our HIV population without overt clinical / radiological TB is advised.

TABLE 1. HIV positive patients with Neurological manifestations

TABLE 2. Neurological manifestations in HIV positive patients

TABLE 3. Neurological manifestations in Patients with AIDS defining illness

TABLE 4. Neurological manifestations in patients with HIV / AIDS

TABLE 5. Relationship between fatality and Neurological diseases