Approach to neurological symptoms

Bruce J. Brew : Immunology/HIV/Infectious Diseases Clinical Services Unit and Department of Neurology, St Vincent’s Hospital, Sydney NSW
Edwina J. Wright : Department of Infectious Diseases, Alfred Health and Monash University, Burnet Institute, Melbourne VIC
Phillip Chan : Department of Neurology Queen Elizabeth Hospital, Hong Kong
Jeffrey J. Post : Department of Infectious Diseases and Albion Street Centre, Prince of Wales Hospital and School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney NSW

In human immunodeficiency virus (HIV)-related neurological disease, the differential diagnosis of the pathology is largely determined by the stage of HIV disease. The best measure of HIV disease stage is the CD4 T-lymphocyte (CD4) cell count, particularly the nadir CD4 cell count. In HIV-related central nervous system (CNS) disease, it is useful to consider whether the clinical presentation is predominantly focal or non-focal (Table 1), as well as the likelihood of several co-existent neuropathologies in the same or different parts of the nervous system.

The Case study illustrates several diagnostic and management issues in approaching neurological symptoms in the patient with HIV infection and Table 2 outlines an approach to a patient with neurological symptoms in the context of HIV-associated immunodeficiency.

Case study. Neurological symptoms in an immunodeficient patient with HIV infection

Joe is a 48-year-old married man with HIV infection. He has partially adhered to antiretroviral therapy (ART) and has had multiple antiretroviral drug regimens, including nucleoside analogues, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. He has not tolerated some agents and experienced virological failure with others. Joe is currently taking an antiretroviral drug regimen of tenofovir, emtricitabine, ritonavir and darunavir. His most recent CD4 cell count is 80 cells/μL and HIV viral load is 79,432 (4.9 log10) HIV RNA copies/mL. It is unclear whether Joe has adhered to cotrimoxazole prophylaxis, as he has not required repeat prescriptions as regularly as predicted.

He is referred to a specialist HIV physician after his wife reported that he has had difficulty walking and 'isn’t quite himself' lately. On review, he reports slowness and difficulty walking at times. He and his wife confirm poor adherence to ART, as he has experienced significant nausea with the prescribed regimen. On specific questioning, he agrees that he has experienced intermittent headaches and possibly fevers, although no rigors. He does not drink alcohol and does not take illicit drugs or non-prescribed medications. Examination reveals peripheral neuropathy, with reduced pinprick and light touch sensation to the ankles bilaterally, but preservation of the ankle jerks. Heel-toe gait is impaired, with the patient predominantly falling to the left. He is afebrile.

The serum Toxoplasma gondii immunoglobin G antibody assay was positive and syphilis serology was non-reactive when last performed 2 years ago. Biochemical tests reveal normal serum electrolytes and renal function. Serum B12, folate and thyroid-stimulating-hormone levels are also normal. Repeat syphilis serology is non-reactive.

A computed tomography (CT) scan of the brain with intravenous contrast is undertaken, looking for space-occupying lesions, ring-enhancing lesions, evidence of raised intracranial pressure and cerebral atrophy (Figure 1). A magnetic resonance imaging scan does not reveal any focal pathology. As there are no stigmata of raised intracranial pressure or focal neurological signs, a lumbar puncture (LP) is performed.

The LP opening pressure is 16 cm of water and the cerebrospinal fluid (CSF) appears clear and colourless. CSF biochemistry reveals a normal glucose concentration and a raised protein concentration of 0.56 g/L (normal range 0.15-0.45 g/L). Microscopy of CSF reveals a mononuclear cell pleocytosis of 10/mm3, and no organisms are seen on Gram stain or India ink stain. Tests for CSF and serum cryptococcal antigen reveal titres of less than 1:4. CSF mycobacterial culture is pending.

Further investigation of the CSF is undertaken including measurement of CSF HIV viral load, beta 2-microglobulin and neopterin. The CSF HIV viral load is 11,000 (4.04 log10) HIV RNA copies/mL and the CSF beta 2-microglobulin concentration is 4 mg/L. Neuropsychometric testing reveals some deficits in attention and motor functions.

Given the absence of an alternative cause for the neurological manifestations and the consistent clinical and laboratory findings, the physician makes a diagnosis of HIV-1-associated dementia (HAD). Genotypic HIV drug resistance assays are pending. The physician reviews the antiretroviral history, identifies an appropriate regimen for the management of advanced HIV infection and selects agents with high CNS penetration in HAD.

 

Table 1 Differential diagnosis of causes of central nervous system symptoms in patients with HIV infection
Focal deficits Absence of focal neurological signs

Cerebral toxoplasmosis

Primary cerebral lymphoma

Progressive multifocal leukoencephalopathy

Meningovascular syphilis

Cryptococcoma

Varicella-zoster virus

Tuberculoma

Aspergilloma

Stroke

HIV-1-associated dementia (HAD)

Cryptococcal meningitis

Aseptic (HIV) meningitis

Cytomegalovirus encephalitis

HIV headache

Tuberculous meningitis

 

Table 2 Approach to the diagnosis of persistent headache, seizures, altered level of consciousness or focal neurological symptoms or signs in the immunodeficient patient with HIV infection

Initial assessment

History

  • Degree of blood CD4+ T cell depletion – informs on differential diagnosis
  • Headache – persistent headache should be investigated, as even mild headache may be indicative of significant neurological pathology
  • Recent commencement of antiretroviral therapy – an immune reconstitution inflammatory syndrome should be considered
  • Adherence to cotrimoxazole prophylaxis – reduces likelihood of cerebral toxoplasmosis
  • Focal neurological symptoms
  • Systemic symptoms – sinusitis and other infections (e.g. pneumococcal pneumonia with bacteraemia) may cause headache and fever, with or without altered neurological status)
  • Seizures
  • Prior neurological disease
  • A history of exposure to tuberculosis

Examination

  • Focal neurological signs
  • Seizures
  • Signs of raised intracranial pressure
  • Clinical evidence of immunodeficiency when CD4+ T cell count unknown (e.g. oral candidiasis)
  • Evidence of disseminated disease processes (e.g. pulmonary tuberculosis, cytomegalovirus retinitis)

Blood testing

  • Serum Toxoplasma gondii IgG antibody status – most cases of cerebral toxoplasmosis are IgG antibody positive
  • Serum syphilis serology – interpreted in conjunction with treatment history and consideration of possible re-infection
  • Serum cryptococcal antigen titre
  • Serum cytomegalovirus IgG antibody status
  • Blood CD4+ T cell count

neuro

CSF: cerebrospinal fluid; CT: computed tomography; HSV: herpes simplex virus; IgG: immunoglobulin; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; PML: progressive multifocal leukoencephalopathy; PMN: polymorphonuclear; VZV: varicella-zoster virus; JC = John Cunningham; CMV: cytomegalovirus. 2;[1] 3;[2]4.[3].
  • Potential pointers to incomplete treatment adherence may be readily identified. For example, the patient who does not request or require a repeat prescription when the medication should have run out may not be taking medication as prescribed.
  • Although the signs are not completely consistent with a focal neurological deficit, the suggestion of possible focal pathology warrants cerebral imaging. Magnetic resonance image (MRI) scanning is more sensitive than a CT scan for focal neurological lesions.[4] The differential diagnosis is broad (Table 1).
  • An examination of CSF is warranted in immunodeficient patients with HIV infection who have headache and fever as cryptococcal meningitis may not present with meningism. The symptoms attributable to the CNS may be mild and non-specific. If the LP opening pressure is raised and a diagnosis of cryptococcal meningitis is made, repeat LPs and possibly CSF shunting are important aspects of management.
  • CSF findings of a mild mononuclear pleocytosis and slightly raised protein are consistent with HIV infection, although, in the context of positive CSF syphilis serology or the possibility of past untreated syphilis, these findings are also consistent with neurosyphilis.
  • Non-infective causes must be excluded as the origin of neurological symptoms.
  • HIV-1-associated dementia (HAD) is a diagnosis of exclusion, as other pathology may present similarly and other opportunistic processes may unmask HAD. There is no single diagnostic test for HAD. Elevation of CSF beta 2-microglobulin and HIV viral load are correlated with the degree of severity of HAD in patients not taking combination antiretroviral therapy (cART), but are not diagnostic per se.
  • Multiple coexisting pathological processes can occur in the neuraxis (termed parallel tracking). In the case study, HAD and peripheral neuropathy are present concurrently.
  • The serum cryptococcal antigen titre is elevated in 94 - 100% of cases of cryptococcal meningitis. A titre below 1:4 is within the normal range for the assay. 

Figure 1 Cerebral computerised axial tomograph scan reveals cerebral atrophy with no evidence of space-occupying lesions

brain
Source: Jeffrey J. Post, University of NSW, Sydney NSW. Used with permission.

 

1.
Mathews C, Barba D, Fullerton SC. Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis. AIDS 1995;9:1243-50 
2.
Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med 1993;329:995-1000 
3.
4. Holland NR, Power C, Mathews VP, et al. Cytomegalovirus encephalitis in acquired immunodeficiency syndrome (AIDS). Neurology 1994;44:507-14 
4.
Levy RM, Mills CM, Posin JP, et al. The efficacy and clinical impact of brain imaging in neurologically symptomatic AIDS patients: a prospective CT/MRI study. J Acquir Immune Defic Syndr 1990;3:461-71. 

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