Residency Training: Progressive gait difficulty and incontinence in a 40-year-old man with HIV

Section 1

A 40-year-old South African man presented with progressive difficulty walking, bilateral leg weakness, and balance problems. He described vague cognitive symptoms and new-onset urinary incontinence. Notwithstanding a 2008 HIV diagnosis (infection date unknown), due to social issues he did not obtain medical care. There was no medical history of opportunistic infections (OIs) or other problems associated with HIV. Three months before presentation, however, he had stopped working as a home care assistant due to unsteady gait. In addition, he described a recent 30-pound weight loss. He denied headaches or neck pain. There was no relevant family history, and he took no medication.

The patient had normal vital signs and was well-appearing, alert, and oriented to person, date, and setting. On initial examination, he was considered to have normal mental status. However, on further evaluation, his speech was noted to be quiet and slow, and there was a question between examiners whether his flattened affect was culturally determined. When asked to name words beginning with the letter F, he was able to name 6 in 1 minute (normal >14). His upper extremity strength was 5/5 bilaterally, and 4/5 strength was noted in both hip flexors. He displayed small, slow, and clumsy finger and foot taps, and snout and jaw jerk reflexes were present. Furthermore, he was incontinent of urine multiple times throughout the examination. Hoffmann sign and hyperreflexia were not present. There was no neck stiffness, papilledema, or skin findings. Visual field and cranial nerve testing was normal, and the remainder of the neurologic and general examinations was unremarkable.

Section 2

The onset of symptoms over several months implicates various possible etiologies including neoplastic, metabolic, inflammatory, and neurodegenerative processes. In considering a supratentorial vs spinal process, the differential diagnosis remains broad: inflammatory and neurodegenerative diseases of the CNS (e.g., myelitis related to autoimmune or paraneoplastic processes), metabolic disorders (e.g., vitamin B₁₂ or folate deficiency), and infectious diseases (e.g., human T-lymphotropic virus, syphilis, Lyme). The combination of urinary incontinence and gait instability could be attributed to a spinal cord defect; however, the presence of primitive reflexes (snout and jaw jerk), in combination with bradyphrenia, suggests that diffuse or frontally predominant subcortical dysfunction must also be involved. Vacuolar myelopathy must be considered in a patient with advanced HIV and gait disturbance, though the lack of hyperreflexia and sensory loss renders localization to the posterolateral spinal columns unlikely. The absence of lateralizing signs points away from focal lesions such as CNS lymphoma or progressive multifocal leukoencephalopathy (PML), though if extensive and bilateral, these could produce a consistent clinical picture.

In this case, the constellation of urinary incontinence, cognitive impairment, and gait instability strongly implies a subcortical frontal lobe condition, with or without additional cord involvement. While normal pressure hydrocephalus (NPH) is on the differential, conditions more common in a potentially immunocompromised patient should be considered. Given the setting of treatment-naive HIV infection, PML and cerebral toxoplasmosis should be ruled out. Causes of more generalized encephalopathy associated with immunosuppression and infection, including cryptococcal meningitis and HIV-associated dementia, should also be considered.

Section 3

Given the reported HIV diagnosis, a blood CD4 count and quantitative plasma HIV RNA level in addition to an infectious disease panel should be ordered. To further localize the pathology, MRI examinations of the spinal cord and brain along with blood and CSF examinations should be performed.

Laboratory testing revealed a CD4 count of 31 cells/μL (normal 500–1,500) and plasma HIV viral load 1.7 million copies/mL. The patient’s complete blood count revealed leukopenia, thrombocytopenia, and mild anemia (white blood cells 2,100 cells/μL, hemoglobin 12.5 g/dL, hematocrit 38.9%, platelets 100,000 cells/μL). Serum chemistries, liver profile, lipid panel, vitamin B₁₂, and folate levels were normal. Plasma infectious and sexually transmitted disease screening tests were negative with the exception of positive cytomegalovirus (CMV) immunoglobulin G, weakly positive CMV DNA PCR (<137 IU/mL), and reactive hepatitis A and hepatitis B total core antibodies. A lumbar puncture yielded CSF with glucose 39 mg/dL, protein 134 mg/dL, and 9 white blood cells/μL (93% lymphocytes). The CSF microbiology panel was negative except for CSF HIV RNA count >10 million copies/mL.

On brain MRI, prominence of the ventricles and sulci was visualized with diffusely symmetric, periventricular T2 hyperintensity on fluid-attenuation inversion recovery (FLAIR) signal within the supratentorial white matter, extending into the corona radiata (figure 1). The spine MRI was normal, with no abnormal enhancement on postcontrast imaging.

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Figure 1 Fluid-attenuated inversion recovery MRI

Section 4

The patient's clinical picture and laboratory findings point strongly towards a diagnosis of HIV-associated dementia (HAD). Laboratory tests and neuroimaging effectively ruled out other metabolic and infectious etiologies, including toxoplasmosis and CNS lymphoma, which would appear as multiple or isolated ring-enhancing lesions, respectively, with positive CSF findings. Instead, the patient's diffuse subcortical T2 hyperintensity on FLAIR MRI is more characteristic of HIV encephalitis. In addition, while the patient's clinical picture may be similar to one of NPH, NPH is a disease of the elderly (>65). This patient instead represents a case of advanced AIDS and HAD.

To further characterize the patient's disease, comprehensive neuropsychological testing was performed. Neuropsychological evaluations help determine the degree of neurocognitive impairment and monitor its resolution or persistence on therapy.¹ The raw neuropsychological scores were standardized using data from HIV-uninfected, age- and education-matched controls. Our patient's sum neuropsychological score was roughly 3 SD below the neurotypical mean. In particular, major domains of impairment included gross and fine motor skills, processing speed, attention, executive function, as well as verbal learning (figure 2).

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Figure 2 Longitudinal neuropsychological testing

Neurocognitive improvement in performance in HIV-associated dementia (HAD) with treatment after presentation. Gross and fine motor functioning were the most affected areas at baseline, a classic presentation underlying the damage to myelinated tracts in white matter, as commonly seen in HAD. Other domains, listed from most to least impaired, were attention, speed of processing, executive function, and learning. These domains are also affected by demyelination/damage in white matter, often periventricular, and by tracts leading from there to prefrontal and frontal cortex (executive, learning). Relatively preserved domains that remained normal throughout were language skills and verbal memory.

Section 5

Under close inpatient monitoring, combination antiretroviral therapy (cART) was initiated in the form of Triumeq, a single daily tablet comprising abacavir (600 mg), dolutegravir (50 mg), and lamivudine (300 mg). The patient received prophylactic azithromycin (1200 mg once/wk) and sulfamethoxazole/trimethoprim (800/160 mg qd) to prevent OIs.

Two weeks following initiation of treatment, measures of viral load and lymphocyte counts dramatically improved in proportion with the patient’s clinical examination. At 24 weeks after cART initiation, repeat neuropsychological testing demonstrated substantial improvement across motor and verbal domains with pronounced improvement in gait.