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Abstract
A woman in her 20s with no medical history was diagnosed with bulky stage II classic Hodgkin’s lymphoma after an 8-week history of shortness of breath, cough and lethargy. A regimen of doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) was commenced with six cycles planned. During the first cycle, the patient was profoundly hypertensive. She then suffered two self-terminating tonic-clonic seizures.
Examination and investigations diagnosed posterior reversible encephalopathy syndrome (PRES), which resolved completely in 11 days with strict blood pressure control and withholding chemotherapy. Treatment was further complicated by anthracycline-induced cardiomyopathy, requiring a switch in regimen to gemcitabine BVD.
The patient made a full recovery from neurology and cardiology perspectives and completed six cycles of chemotherapy, achieving a complete metabolic response by the tumour. We illustrate the case, describe differential diagnoses and management of PRES, its association with chemotherapy and the successful chemotherapy rechallenge.
- Epilepsy and seizures
- Drugs: CNS (not psychiatric)
- Haematology (incl blood transfusion)
- Cancer intervention
- Oncology
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- Epilepsy and seizures
- Drugs: CNS (not psychiatric)
- Haematology (incl blood transfusion)
- Cancer intervention
- Oncology
Background
Posterior reversible encephalopathy syndrome (PRES) is a diagnosis clinically characterised by encephalopathy with subcortical vasogenic oedema, manifesting neuroradiologically as lesions with posterior and white matter predominance.1–3 The name PRES is a misnomer due to these radiology findings not solely involving the posterior circulation and in 15% of cases the pathology is irreversible, leaving patients with long-term neurological deficit.4
The classical presentation of PRES is a combination of neurological symptoms including seizures, altered cognition and focal deficits. Medical conditions associated with the aetiology of PRES include eclampsia, sepsis and autoimmune disorders.5 Anticancer treatment is recognised as a very rare cause of PRES.1 The incidence is rare, but it is likely this will increase as the number of patients receiving chemotherapy rises.
The pathophysiology of PRES is postulated to be related to dysfunctional endothelial and cerebral autoregulation causing blood–brain barrier (BBB) damage, breakthrough hyperaemia and vasogenic oedema.1 6 Acute uncontrolled hypertension, renal dysfunction and electrolyte imbalance are risk factors7 8 as well as chemotherapy,9 due to the cytotoxic effects of treatment causing direct vascular damage to the BBB. Prompt recognition is vital, as PRES often resolves with blood pressure (BP) control and withdrawal of the offending agents.10
We report a case of a young female with classic Hodgkin’s lymphoma who presented with PRES following one cycle of standard first-line regimen doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD). We describe her clinical course and outcome following ABVD rechallenge, which was complicated by anthracycline-induced cardiomyopathy, requiring a regimen change.
Case presentation
A woman in her early 20s with no medical history presented with an 8-week history of shortness of breath, cough and lethargy. Positive emission tomography CT (PET-CT) scan demonstrated a large mediastinal mass with associated significant attenuation of the superior vena cava and compression of the trachea (figure 1). Lymphoma was suspected and prednisolone 100 mg was started as she was symptomatic with dyspnoea and cough, with allopurinol cover to prevent tumour lysis syndrome. Mediastinal mass biopsy confirmed Hodgkin’s lymphoma and six cycles of chemotherapy with ABVD were commenced.
Coronal PET/CT (colour fused) demonstrating early-stage II bulky classic Hodgkin’s lymphoma.
Cycle 1 went well until day 21, when she experienced persistent hypertension and tachycardia with systolic BP (SBP) 148–158 mm Hg and heart rate (HR) 108 bpm. Baseline BP pretreatment was normal. ECG was normal and she denied chest pain or palpitations. CT pulmonary angiogram (CTPA) ruled out pulmonary embolism.
On day 23 of cycle 1, she presented with fever (38.5°C), fatigue, vomiting and sore throat. She was neutropenic and had an elevated C reactive Protein (CRP) of 133. Her SBP was elevated at 153 mm Hg. While being assessed, she sustained a witnessed, self-terminating tonic-clonic seizure lasting 30 s, after which her SBP was 174 mm Hg. Five hours later, she sustained a second seizure that self-resolved after 30 s.
She has commenced on levetiracetam 500 mg two times per day as well as ampicillin, cefotaxime and acyclovir intravenous to cover for central nervous system (CNS) infection. Clinical examination demonstrated minor weakness in the left upper and lower limbs with an associated pronator drift. Repeated urine, blood and stool cultures were negative for growth. Her lumbar puncture (LP) was normal. Brain MRI demonstrated bilateral hypoattenuation involving the cortex, in keeping with PRES (figures 2 and 3). A diagnosis of PRES was suspected due to the presence of typical radiographic presentation and risk factors (hypertension, chemotherapy and sepsis). Chemotherapy was held and BP controlled with ACE inhibitors. Renal MRI ruled out renal-related causes of hypertension. Repeat MRI 11 days post initial showed almost complete resolution of brain changes (figure 4). An electroencephalogram (EEG) was not performed due to her rapid improvement. ABVD was subsequently recommenced with vigilant monitoring of BP.
Axial MRI FLAIR sequence demonstrating multiple areas of oedema in a ‘near-symmetrical parasagittal distribution’, locations indicated by yellow arrows. FLAIR, fluid attenuated inversion recovery sequence.
Axial MRI T1-weighted postcontrast. Ill defined and ‘spotty’ enhancement at locations indicated by yellow arrows, the distribution raising the possibility of a PRES-type process. PRES, posterior reversible encephalopathy syndrome.
Axial MRI T1-weighted postcontrast at 11 days post the initial. Demonstrating marked radiological improvement, very little enhancement remaining, supporting a clinical diagnosis of PRES. PRES, posterior reversible encephalopathy syndrome.
Further complications occurred when transthoracic echocardiogram (TTE) performed prior to commencing cycle 2 showed a left ventricular ejection fraction (LVEF) of 55%, reduced from 67% prior to treatment. Cardiology suspected this was secondary to tachycardia so ABVD cycle 2 was given. TTE after cycle 2 showed a further reduction in LVEF to 45%—diagnosed as cardiomyopathy with reduced LVEF secondary to PRES and anthracycline (after only two cycles with 75 mg per m2 of doxorubicin). ABVD was switched to gemcitabine BVD, which was commenced when SBP was under 120 mm Hg using ramipril and bisoprolol.
Subsequent cycles occurred as an inpatient to monitor BP, with regular brain natriuretic peptide (BNP) monitoring and troponin I levels before and after each cycle of gemcitabine BVD. Between cycles 2 and 6, troponin I remained <12 and BNP ranged between 53 and 114. After completing six cycles of chemotherapy, cardiac function recovered with LVEF at pretreatment baseline and she achieved complete metabolic remission of the Hodgkin’s lymphoma.
Investigations
Baseline imaging
PET CT at time of diagnosis showed a large bulky stage II disease within the mediastinum with an associated pericardial effusion (figure 1). TTE showed LVEF of 67%. Observations were normal, BP 127/82 and HR 86 bpm.
Neurological investigations
Brain CT showed a small area of hypoattenuation in the right superior frontal lobe, with preserved grey-white matter differentiation. There was no intracranial haemorrhage, major territory infarct or enhancing mass, no intra or extra-axial collection and no hydrocephalus. The ventricles and basal cisterns were normal.
Brain MRI showed bilateral abnormality primarily involving the cortex, representing infection, inflammation or PRES (figures 2 and 3). There was no evidence of significant intracranial mass effect and appearances were not typical for secondary CNS lymphoma. Repeat brain MRI with contrast 11 days later showed a marked radiological improvement, supporting a clinical diagnosis of PRES (figure 4).
LP showed normal appearance and sterilecerebral spinal fluid (CSF) (white blood cells (WBCs) 0 cells/µL) with normal levels of protein (0.28 g/L) and glucose (3.3 mmol/L). No growth on culture, normal cytology and PCR (testing for herpes simplex virus, varicella zoster virus and Epstein-Barr virus). Opening pressure was normal. There were no malignant cells on microscopy and no oligoclonal bands. The CSF also tested negative for the following antibodies; anti-NMDA receptor, anti-AMPA-1/2, anti-GABA B, anti-Caspr-2 and anti-LGI-1.
Investigations for hypertension
Renal MRI ruled out renal artery stenosis or parenchymal abnormality as a cause of the hypertension. Renal function and electrolytes remained at baseline. Glomerulonephritides, nephrotic syndrome and paraneoplastic renal syndromes were ruled out by normal urine sodium, potassium and creatinine levels. The patient was vitamin D deficient.
Primary hyperaldosteronism was excluded by a normal aldosterone to renin ratio. Catecholamine-producing tumours were ruled out by normal serum and urine metanephrine levels. Morning cortisol levels remained normal making Cushing’s or a cortisol-producing tumour unlikely.
Subsequent cycles of gemcitabine BVD were preceded and followed by troponin I and BNP levels—troponin I remained <12 and BNP ranged between 53 and 114.
TTEs performed after cycle 2 showed a declining LVEF to 45%, which improved to 58% after cycle 4.
A cardiac MRI was performed after cycle 3 which showed no structural pathology or tissue ischaemia.
General investigations
CT of neck, thorax, abdomen and pelvis throughout the following cycles of chemotherapy showed favourable response of the mediastinal mass. PET CT after the six cycles showed a complete metabolic response.
Differential diagnosis
Investigations and clinical examinations found the differential diagnoses to be cerebritis, encephalitis or PRES. CNS vasculitis could have been considered, although MRI findings are generally diffuse and irreversible.11 Metabolic encephalopathies can have similar presentations11—but serum glucose, urea and electrolytes were normal. An EEG was not performed. If she had experienced persistent seizures or encephalopathy, then an EEG would have been indicated to exclude mimics or complications.
Cerebritis
In most cases, cerebritis progresses to a cerebral abscess by the time diagnosis is made, due to cerebral tissue necrosis.12 This is not in keeping with a radiological resolution of findings after 11 days. Autoimmune cerebritis is unlikely without encephalopathy and autoimmune diagnoses (eg, systemic lupus erythematosus).
CNS infection
The patient had been neutropenic (secondary to myelosuppressive effects of chemotherapy) and febrile with elevated CRP 133 at the time of the seizures occurring. The following laboratory investigations to locate a source of infection were normal and negative for pathogens; CSF culture and cytology, blood, urine and stool cultures, CSF viral PCR and serum beta-D-glucan. CTPA showed no evidence of respiratory tract infection and there were no skin lesions or rashes.
The CSF sample was obtained 2 days after the onset of seizures, showing normal cell counts and protein. In herpes simplex encephalitis (HSE), 10% of CSF cell counts and 50% of CSF protein are normal within a week of illness.13 CSF PCR has high specificity (99%) and sensitivity (96%) in HSE when sampled at 48 hours and 10 days after symptom onset.13 The LP was not repeated at 10 days due to neurology and pathology having resolved and results would not change management. Furthermore, the patient and her family were keen to avoid unessential invasive procedures.
It is worth noting that intravenous antibiotics and antivirals were started 2 days prior to the LP and continued until after the symptoms and radiological findings had resolved. We cannot completely rule out CNS infection, but it would be less typical to see quick radiographic and clinical resolution.
Autoimmune encephalitis
Association of autoimmune encephalitis in Hodgkin’s lymphoma is very rare but has been noted.14 Autoimmune encephalitis cases are mostly paraneoplastic, with 60% of cases showing antineuronal antibodies associated with specific cancers.15 In this case, the patient tested negative for serum Yo, Hu and Ri antibodies which are associated with paraneoplastic cerebellar syndromes and neuropathies.16
Limbic encephalitis associated with Hodgkin’s lymphoma is known as Ophelia syndrome, with most cases in young people associated with anti-mGLuR5 antibody.16 Unlike PRES, this has a subacute onset with a 12-week history of seizures, confusion and personality change. Neuroradiology typically reveals involvement of the medial temporal lobes and amygdala.17
Anti-NMDA antibody-associated paraneoplastic encephalitis has been described in Hodgkin’s lymphoma.17 This most commonly causes neuropsychiatric symptoms rather than seizures and the patient’s CSF tested negative for antibodies.
The above examples of autoimmune encephalitis associated with Hodgkin’s lymphoma are treated by immunosuppression and high dose steroids—typically symptoms do not resolve without treatment.15 Autoimmune encephalitis is less likely as a differential, due to our patient showing clinical improvement while already established on steroids pre-PRES and without immunosuppressive treatment post-PRES.
Treatment
Hypertensive control and withholding the precipitating agents until symptoms have resolved is the mainstay of treatment for PRES.1 Chemotherapy was stopped until brain MRI showed radiological resolution of PRES and SBP was less than 120 mm Hg. The latter was achieved initially with amlodipine and then with ramipril. The ACE inhibitor was continued throughout the six cycles of chemotherapy as cardioprotective against further cardiomyopathy.
Following the seizures, she was established on levetiracetam 500 mg two times per day which was weaned slowly after a repeat brain MRI showed complete resolution of changes. Subsequently, ABVD was reintroduced at full dose. Routine TTE post cycle 2 showed deterioration of LVEF, and therefore, the regimen was switched to gemcitabine-BVD.
Outcome and follow-up
The patient has complete resolution of neurological function. She completed six cycles of chemotherapy with a complete metabolic response of the Hodgkin’s lymphoma. She has been weaned off antihypertensives and levetiracetam. She will be followed up with regular imaging and has returned to university to complete her degree.
Discussion
Although chemotherapy-induced PRES is rare and unpredictable, it has been increasingly recognised within the cancer population. PRES should be included in differentials when any cancer patient presents with acute neurological symptoms.
There is a lack of formal guidance for chemotherapy rechallenge post-PRES, given its rarity. A study by Singer et al, looking into 31 cases of PRES in cancer patients of various primary sites over a 6-year period, found 55% of the cohort had received chemotherapy within the last month, 35% of which with bevacizumab mostly in combination with other cytotoxic agents.9 Seven (41%) out of 17 patients who received any chemotherapy, hormonal or targeted agent within 1 month of PRES, were offered treatment rechallenge with suspected agents and none suffered PRES recurrence with rechallenge.9 Two patients (12%) experienced PRES again—either secondary to hypertension without concurrent chemotherapy, or secondary to different chemotherapy 2 years later.9
Another literature review examining chemotherapy-induced PRES in 70 patients with cancer showed that CHOP/R-CHOP (which like ABVD, also contains doxorubicin and vincristine) was the combination most frequently associated with PRES.9 Bleomycin monotherapy was also linked to PRES.18
To our knowledge, there is only one previous case report detailing successful ABVD rechallenge for Hodgkin’s lymphoma following PRES.19 The patient was admitted with a non-convulsive status epilepticus and brain MRI demonstrated bilateral lesions, predominantly in the parietal-occipital area, which were hyperintense on T2 with vasogenic oedema. Following treatment with antiepileptic drugs, BP control and nimodipine to complete recovery, rechallenge ABVD was given without recurrence of PRES.19
Some clinical characteristics of chemotherapy-associated PRES have been postulated. PRES often occurred following cycle 2 or 3, with a median onset 8 days after chemotherapy.20 Hypertension is a well-recognised concurrent factor with PRES with a median SBP of 170 mm Hg.20 This correlates with our case, where SBP fluctuated between 150 and 174 mm Hg periseizure. It has been hypothesised that hypertension is why bevacizumab is commonly associated with PRES.9 In studies detailing rechallenge with chemotherapy, strict BP control is always observed.18 21 22 In one rechallenge example, PRES recurred after 2 years which was triggered by hypertension alone.9 It could be argued that all patients receiving chemotherapy should have their BP regularly monitored and tightly controlled. With appropriate management, chemotherapy-associated PRES was largely reversible, and in all non-lethal cases, patients showed symptom resolution within 2 weeks, as observed in our case.20
Learning points
Posterior reversible encephalopathy syndrome (PRES) is a rare life-threatening syndrome, presenting with new-onset seizures and hypertension with typical features on MRI, and may occur in patients receiving systemic anticancer treatment. It is potentially reversible if diagnosed early.
A multidisciplinary team approach is required for suspected PRES, involving neurology, radiology and oncology. Neurological and laboratory investigations (brain MRI, lumbar puncture, biochemistry and microbiology sampling of CSF and blood) must rule out other causes of this clinical presentation such as infection, stroke or tumour.
Management of PRES consists of withholding the offending agent and treating predisposing factors (hypertension, infection or electrolyte imbalance).
Chemotherapy rechallenge following resolution of PRES should be considered with strict control of the exacerbating factors.
In our case, intensive treatment of hypertension and the associated cardiomyopathy led to recovery of PRES and enabled the patient to successfully complete six cycles of chemotherapy to achieve remission of Hodgkin’s lymphoma.
Ethics statements
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Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: RH, BA, BS and DC were all directly involved in the care of this patient. RH is the main author and submitting author for the piece, with BA as coauthor of the drafts. The radiological images used as figures with corresponding captions were chosen by BS. DC was the lead consultant and reviewed the final draft prior to submission.The following authors gave final approval of the manuscript: RH, BA and DC.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.