A 57 Year-Old Man With HIV Presenting With Severe Headache and Progressive Weakness

Case Presentation

A 57 year-old man with HIV with undetectable viral load and CD4 count of 600, managed with antiretroviral therapy, presented to the hospital with severe neck pain, progressively worsening headache, and general malaise.

In the emergency department (ED), his examination was non-focal with a normal mental status. Non-contrast head computed tomography (CT) was unrevealing. He was admitted for cardiac and neurologic evaluation. Neurology was consulted and found his examination to be unremarkable. They recommended MRI of his brain to evaluate his headaches; this revealed punctate foci of left hemispheric ischemia, primarily at the gray-white junction, leading to a stroke workup. Carotid duplex ultrasound revealed severe (70-90%) left carotid stenosis. Intracranial vessel imaging was not performed. On hospital day (HD) 1, he developed a fever to 39.2C and photophobia. This prompted concern for endocarditis, so TEE was performed and was unremarkable. On HD 2, he abruptly became unresponsive. Repeat head CT was unchanged. Routine EEG demonstrated diffuse slowing without focal or epileptiform activity. His mentation spontaneously recovered. Levetiracetam was empirically started. Three days later, a lumbar puncture was performed. CSF analysis demonstrated a lymphocytic pleocytosis (WBC 1435, 83% lymphocytes; RBC 147), elevated protein (641), normal glucose (50), and varicella zoster virus (VZV) polymerase chain reaction (PCR) positivity. Intravenous (IV) acyclovir and IV methylprednisolone were initiated. On HD 6, he developed respiratory distress and was intubated for hypoxic respiratory failure and transferred to the ICU.

Several days after arrival to the ICU, he developed progressive weakness and areflexia. Weakness was initially present in his left lower extremity, then evolved to affect his left upper extremity and then right lower and upper extremity, respectively. On HD 13 and ICU day 7, he remained febrile, which prompted a chest CT to be obtained to evaluate for pulmonary embolism (PE). A small, bilateral proximal PE was discovered. He was heparinized and then transferred to our institution at the family’s request.

Initial Evaluation

Upon transfer to our NeuroICU, his examination demonstrated normal mental status while intubated, with alertness and ability to follow commands and appropriately answer questions with head nods. No volitional movement aside from slight motions of his bilateral fingers was appreciated, and there was no withdrawal from noxious stimuli. He was diffusely areflexic. Platelet count was 184, INR 0.9, and anti-Xa level was 1.22 (therapeutic heparin range for PE 0.3-0.7). Head CT revealed a new subarachnoid hemorrhage (SAH) in the bilateral sylvian fissures, premesencephalic and suprasellar cisterns, and overlying the right and left frontoparietal lobes (Figure 1). Heparin was stopped and further work-up was initiated.

Figure 1.

Diffusion-weighted images (DWI) from the first MRI brain. Initial MRI brain showing left frontal gray-white junction infarcts as well as corona radiata infarcts. All areas of brightness showed corresponding hypointensity on Apparent Diffusion Coefficient Images.

Clinical Discussion: Differential Diagnosis

Discussant: Craig A. Williamson, MD, MS

This patient presented with multiple, severe neurological symptoms which may or may not be due to a single underlying disease process. I was involved in his management and am aware of the final diagnoses, so will present the differential diagnosis that was formulated in real time. Given the complexity of his presentation, a differential diagnosis of his multiple intracranial and neuromuscular abnormalities will be presented separately.

Cerebral areas of restricted diffusion and diffuse subarachnoid hemorrhage

The patient’s initial neuroimaging demonstrated several pathologies that most likely reflect underlying cerebrovascular disease. The pattern of restricted diffusion can suggest a causative etiology, most commonly ischemia due to thromboembolism, but sometimes prolonged seizures, abscess, or malignancy such as lymphoma. ¹ Multifocal restricted diffusion generally raises concern for cardiac or other central embolic source, such as aortic atherosclerosis. When unilateral, artery-to-artery emboli from carotid atherosclerosis should be strongly considered. The presence of ipsilateral severe (70-99%) carotid stenosis is typically sufficient to identify artery-to-artery emboli as the presumed etiology. ² However, given the known VZV encephalitis, a VZV vasculopathy is the single most unifying diagnosis for this particular presentation. Small, well-defined infarcts located at the gray-white junction is characteristic of VZV vasculopathy. Lesions in the deep white matter may also occur with VZV, and are more common than cortical infarcts. ³ Both types of lesions were present in this patient (Figures 2 and 3). In this context, his subsequent SAH is also parsimoniously attributed to a VZV vasculopathy, which has myriad cerebrovascular manifestations including large-vessel occlusions, small-vessel infarcts, and intraparenchymal and subarachnoid hemorrhage. ⁴ SAH can occur in the absence of intracranial aneurysm, but VZV has also been associated with new aneurysm formation, so it is crucial to rule out an underlying aneurysm to avoid a potentially devastating aneurysmal rebleed. ⁵ Angiography is abnormal in a majority of patients (up to 70%, with large and small arteries abnormal in 50% of cases). ⁴ Less likely causes of diffuse SAH include reversible cerebral vasoconstriction syndrome (RCVS), arteriovenous malformation (AVM) or dural-arteriovenous (AV) fistula, sympathomimetic use, and severe coagulopathy.

Figure 2.

Non-contrast head computed tomography (CT) scan. Scattered areas of subarachnoid hemorrhage are seen in the bilateral sylvian fissures and adjacent sulci, as well as anterior to the inferior medulla.

Figure 3.

MRI images of the cervical spine. Sagittal and axial views demonstrating a T2-hyperintense lesion at the C5-C6 level.

Progressive weakness

Subacute progressive bilateral weakness leading to near quadriplegia can involve localizations of the peripheral nerves, nerve roots, and spinal cord. Brainstem (e.g. bilateral corticospinal tracts) remains possible, though is much less likely here given the absence of cranial neuropathies and preserved mental status. Rarely, VZV can cause a rhombencephalitis, ⁶ but this is more commonly associated with autoimmune and other infectious etiologies such as Listeria and Human Herpes Virus 6 (HHV-6). Critical illness polyneuropathy/myopathy (CIP/CIM) are extremely common complications of critical illness, and are of concern for patients with multiorgan dysfunction who are treated with steroids, as was the case with this patient. Guillain-Barre syndrome (GBS) must also be considered in light of ascending, although initially asymmetric, weakness, especially with a recent antecedent viral infection. VZV-associated GBS is typically associated with demyelination without axonal involvement. ⁷ Additionally, VZV polyradiculitis may cause weakness; the pleocytosis for an isolated polyradiculitis is typically much more modest (up to 20 cells/uL). This patient’s CSF protein was severely elevated, but in the context of VZV encephalitis, his WBCs were also elevated.^4,8 Of note, thesensitivity of VZV PCR is only 30%, but improves improves to 93% with VZV IgG. ⁹ In this patient’s clinical setting, cervical cord involvement should also be strongly considered as VZV can cause both myelitis and cord infarction. The presence of diffuse areflexia suggests that a peripheral localization is more likely. However, the acute phase of a myelopathy can present with areflexia. Myelitis due to opportunistic infections such as CMV are of substantially less concern here based on his adequate CD4 count.

Clinical Discussion: Imaging Evaluation

Discussants: Craig Williamson, MD, MS, and Venkatakrishna Rajajee, MBBS

Advanced neuroimaging can assist in assessing the extent of disease and related sequelae for patients with meningoencephalitis. In this patient’s case, initial brain MRI (Figure 2) demonstrated multiple left hemispheric punctate foci of ischemia and no brainstem lesions. Brain MRI was repeated upon transfer to our institution to further assess the extent of his strokes, and his cervicothoracic cord were also imaged to evaluate for myelitis. The repeat MRI revealed multiple new bilateral areas of diffusion restriction, primarily in the corona radiata and centrum semiovale, but also in the dorsal medulla, right insula, and anterior temporal lobe (Figure 3). Cervicothoracic cord MRI revealed a non-enhancing T2/STIR lesion within the left lateral hemicord at C5-C6 (Figure 4). There was no nerve root enhancement. Conventional angiography, obtained to evaluate for cerebral aneurysm and other manifestations of VZV vasculopathy, did not show any evidence of aneurysm, vasculitic changes, nor large-vessel occlusions. His left ICA had a focal stenosis of 55%.

Figure 4.

Diffusion-weighted images (DWI) from the second MRI brain. Subsequently obtained MRI brain showing interim development of multiple infarcts within the deep white matter. All areas of brightness showed corresponding hypointensity on Apparent Diffusion Coefficient (ADC) images.

Electrodiagnostic Testing

Discussants: Janae Dupuis, MD, and Ann Little, MD

Electrodiagnostic testing (EDx) may yield both diagnostic and prognostic information, thereby guiding therapy. There were several possible localizations/etiologies here. While a myelitis was demonstrated radiographically, this unilateral lesion could not explain his entire presentation with progressive bilateral weakness. EDx was pursued to help confirm localization and thus etiology. The yield of testing varies based on time course, with a lower sensitivity earlier in the disease course for GBS. The earliest findings of acquired demyelination may include prolonged distal and F-wave latencies, prolonged distal compound muscle action potential (CMAP) latencies, and temporal dispersion. In a small case series of 31 patients, only 5 had reduced nerve conduction velocities in at least 1 nerve, though temporal dispersion was seen in at least 1 nerve in more than 50%. By 1 week, 67% of patients had significantly prolonged distal CMAP latencies. ¹⁰ Several electrodiagnostic criteria for GBS exist, with varying sensitivities. ¹¹ The Brighton criteria are often used in the research setting and involve key clinical criteria, including bilateral and flaccid weakness of limbs, hypo- or areflexia in weak limbs, monophasic course and time between onset-nadir of 12 hours to 28 days, CSF cell count < 50/uL, elevated CSF protein, nerve conduction studies (NCS) findings consistent with a GBS subtype, and absence of alternative diagnosis for weakness. ¹²

EDx was performed 20 days after the onset of weakness while the patient remained in the NeuroICU. NCS of the right upper and lower extremity revealed diffusely prolonged latencies with reduced amplitudes of motor responses and absent sensory responses. There was temporal dispersion between the ankle and below knee sites for the right peroneal nerve. Needle electromyography was performed on proximal and distal muscles in the right upper and lower extremities (Table 1). Every muscle sampled demonstrated increased insertional activity and diffuse spontaneous activity with P-waves and fibrillations. Recruitment was markedly decreased in all muscles with neurogenic motor units observed primarily in distal muscles. This patient met electrodiagnostic criteria for acquired demyelination, and level 2 of diagnostic certainty of the Brighton criteria. The clinical picture was supportive of a diagnosis of AIDP.

Table 1.

Electromyography Results.

	INSERTIONAL/SPONTANEOUS					VOLUN MOTOR UNIT POTENIALS
Muscle	ins	other	p-wave	fib	fasc	eff	recrt	amp	dur	poly
Anterior tibialis	I	0	sust	3+	0	N	D3+	I1+	I1+	I1+
Medial gastrocnemius	I	0	sust	2+	0	N	D3+	I1+	N	N
Vastus medialis	I	0	sust	1+	0	N	D2+	N	N	N
Deltoid	I	0	sust	2+	0	N	D2+	N	N	N
FDI (hand)	I	0	sust	3+	0	N	D3+	I1+	I1+	I2+
Triceps	I	0	unsust	1+	0	N	D2+	N	N	I+/-

All results are from right-sided muscle groups.

Abbreviations: ins – insertional, fib – fibrillation, fasc – fasciculation, eff – effort, recrt – recruitment, amp – amplitude, dur – duration, poly – polyphasia, I – increasing, sust – sustained, unsust – unsustained, N – normal, D – decreasing, I – increasing, volun – voluntary.

Management

Discussants: Craig Williamson, MD, MS and Venkatakrishna Rajajee, MBBS

Antiviral therapy with IV acyclovir had been started prior to his transfer. Randomized controlled trials pertaining to the duration of therapy for VZV vasculopathy and myelitis are lacking. Expert guidelines recommend treatment with 14 days of IV acyclovir in immunocompetent patients with a concomitant 5-7 day course of oral steroids, acknowledging that immunocompromised patients may require a longer course. ¹³ Due to his clear radiographic progression, with input from infectious disease colleagues, we opted to extend his course of IV acyclovir to 28 days. Maintenance valacyclovir was not pursued. A 5-day course of IV methylprednisolone was administered. Therapeutic anticoagulation had been stopped due to the discovery of his SAH, and an IVC filter was placed.

In terms of his progressive weakness, given the EDx findings consistent with demyelination, GBS was felt to be the most prominent etiology, though some degree of polyradiculitis and critical illness neuropathy may also have contributed. His medullary infarct appeared to be dorsal to corticospinal tracts, and the small lateral hemicord lesion could not explain his severe bilateral weakness. His underlying VZV was treated with IV acyclovir as noted above, and care for critical illness neuropathy was supportive. IVIg for treatment of presumed GBS was empirically started prior to his transfer to our institution, and a total 2g/kg load was completed prior to EDx. Of note, GBS remains a clinical diagnosis, and prompt initiation of treatment should not be delayed while awaiting EDx results, particularly in the early phase of illness when their sensitivity is low.

Patient Outcome

This single case exhibited many of the protean neurologic manifestations of VZV, including ischemic strokes, subarachnoid hemorrhage, myelitis, and AIDP. These occur primarily due to the virus’ ability to infect multiple cell types in the central and peripheral nervous system including the cerebral vasculature, as well as triggering autoantibody formation. ¹⁴ He underwent tracheostomy at the beginning of his NeuroICU stay. His overall hospital course was complicated by dysautonomia secondary to AIDP and pneumonia with parapneumonic effusion. He had gradual improvement in extremity strength after IVIg therapy, and respiratory muscle use improved so that he was liberated from mechanical ventilation 4 weeks after initial intubation. He was discharged to an acute inpatient rehabilitation unit (IPR). In IPR, he had ongoing improvement in his strength and ability to manage activities of daily living (ADLs), culminating in a discharge home, 3 months after his initial presentation. At that time, he was nearly full strength in his upper extremities, though he continued to have left lower extremity weakness worse than right. He was seen in clinic 2 months post-discharge. He continued to require a wheelchair for ambulation, but was living independently and could manage his ADLs.

ORCID iD

Venkatakrishna Rajajee, MBBS https://orcid.org/0000-0002-7183-8324

Craig A. Williamson, MD, MS https://orcid.org/0000-0002-9336-3913