Expansion of pulmonary arteriovenous malformations after grand mal seizures and other circumstances of PAVM growth

Abstract

A woman with asymptomatic pulmonary arteriovenous malformation (PAVM) discovered incidentally on admission developed recurrent generalised seizures. Immediately after, the PAVM demonstrated marked expansion, and was safely resected. Congenital PAVMs (associated with hereditary haemorrhagic telangiectasia or sporadic) are considered stable lesions that exhibit very slow growth if at all. A review of the literature reveals all circumstances of accelerated growth of PAVM (puberty, pregnancy, postpartum, pulmonary hypertension) and suggests a novel mechanism of seizure-associated expansion. This is important because the size and rapid growth of PAVMs correlate with the potential for rupture and other ominous complications such as right to left shunt and paradoxical emboli. The new seizures–PAVM progression association mandates recognition since the risk of seizures in patients with PAVM is substantial. Our observations strongly suggest the need to monitor PAVM in patients with or without haemorrhagic telangiectasis by repeated imaging after generalised seizures to evaluate potential expansion and risk.

Background

Pulmonary arteriovenous malformation (PAVM) is considered a rare, orphan disorder,¹ although active screening by CT demonstrated a considerably higher prevalence than previously suspected.² The size of the lesion is an important predictor of its myriad symptoms and consequences, some of them ominous such as rupture with brisk bleeding and paradoxical emboli.³ PAVMs are traditionally considered stable or very slowly growing lesions. Circumstances that are associated with rapid growth and expansion are hazardous and deserve wider recognition as our literature review and first report of accelerated PAVM progression subsequent to recurrent grand mal seizures reveal.

Case presentation

A 54-year-old woman was admitted having 2 days of high-grade fever, headache, neck pain and left flank/low back pain without dysuria. She had been previously healthy except for obesity and diabetes mellitus with no target organ damage treated with metformin, sitagliptin, aspirin and simvastatin.

On admission, she was febrile (39°C) but her other vital signs were normal and a complete examination was non-contributory. All laboratory tests were normal: Haemoglobin 132 g/L (Mean Corpuscular Volume 88), white cell count (WCC) 9.2×10⁹/L, platelets 248×10⁹/L, Erythrocyte Sedimentation Rate (ESR) 30 mm/hour, serum albumin 4.2 g/L, sodium 144 mEq/L and the liver enzymes, kidney function tests and urinalysis were normal. Blood and urine cultures remained negative. CT (without contrast injection) ruled out urolithiasis but demonstrated an unexpected finding in the apical segment of the left lower lobe (LLL) which was not seen on her normal admission chest X-rays (CXRs) (figure 1).

Figure 1.

Normal posteroanterior and lateral chest radiographs obtained on admission.

Twelve hours later, still febrile and having severe neck pain, she became agitated and confused with recurrent vomiting, photophobia and episodes of altered level of consciousness. Examination now revealed meningeal irritation signs: nuchal rigidity with positive Kernig and Brudzinski signs. She also developed grand mal seizures that were followed by left hemiparesis with extensor plantar response.

Investigations

Neuroimaging studies were normal. They included an immediate brain CT and later an MRI that failed to demonstrate any intracranial abnormality. The cerebrospinal fluid (CSF) showed normal pressure, protein 143 mg/dL (N up to 40 mg/dL), WCC 0.002X10⁹/L and red cell count 0.00014X10¹²/L, with normal glucose levels and negative Gram’s stains. The EEG was abnormal but non-specific (low amplitude, 10 Hz alpha activity over right hemisphere with non-synchronous theta activity over left hemisphere and occasional sharp activity over left temporal region). PCRs for enteroviruses and herpes viruses and serology tests for West Nile virus, rickettsia and Coxiella burnetii were negative. Autoantibodies were not found and thyroid function tests were normal.

Diagnosed as acute meningoencephalitis, the patient was treated with intravenous anticonvulsants (phenytoin) and fluids, while empiric acyclovir, antibiotics (ceftriaxone, then ampicillin) and dexamethasone that were administered initially were stopped. The patient gradually stabilised and attained marked neurological improvement.

Plain CXRs were repeated and a new oval lesion in the LLL was clearly demonstrated (figure 2).

Figure 2.

Radiographs obtained 3 days later show a large oval lesion (demarcated by arrowheads) not seen on the recent previous radiographs.

CTA revealed a large lesion in the apical segment of the LLL consistent with PAVM (figure 3) that increased significantly in size within 72 hours as compared with the initial CT scan, a dramatic change supported by comparing the first and second sets of CXRs.

Figure 3.

Sagittal 10 mm maximum intensity projection image from a chest CT angiogram performed 2 days later depicting a saccular pulmonary arteriovenous malformation between a segmental pulmonary artery (thin arrow) to the left lower lobe and a segmental tributary (short fat arrow) to the left lower pulmonary vein. The rest of the aneurysmal sac is taken up by a thrombus (curved black arrow).

Differential diagnosis

We diagnosed an acute infectious meningoencephalitis of uncertain causative agent, probably viral, as the cause of her presentation which included fever, pain, disturbed consciousness, photophobia, meningeal irritation signs, abnormal CSF and seizures. The self-limited course supported the diagnosis.

However, once we demonstrated the PAVM in its typical location (LLL) and its rapid growth, the differential diagnoses included PAVM-associated cerebral complications. It is well known that PAVM may not uncommonly present with cerebral complications, at any age. Many cerebral consequences may occur prior to PAVM diagnosis.⁴ We, therefore, considered paradoxical emboli with cerebral ischaemia or abscess, as well as intracerebral haemorrhage of a concurrent cerebral AVM but all were excluded by the normal MRI and accumulating clinical data strongly supporting an alternative diagnosis: acute ‘aseptic’ meningoencephalitis with secondary seizures and transient Todd’s paralysis.

In addition, we had to determine if the patient’s PAVM was ‘sporadic’ or part of haemorrhagic telangiectasis (HHT) and this was done according to the current guidelines.⁵ She had no history of epistaxis or haemoptysis. Neither telangiectasia nor clubbing was found and her oxygen saturation was normal (98%) at rest. The family history was unremarkable and their clinical workup for HHT was negative. The patient had no symptoms such as platypnoea (dyspnoea induced by assuming the upright position rare in PAVM patients) or signs such as orthodeoxia (≥2% decrease in saturation on rising). She had neither elevated jugular venous pressure nor right ventricular uplift, and no ECG or CXR signs of pulmonary hypertension. On echocardiography, pulmonary artery pressure was estimated to be normal (<25 mm Hg), but the study was done near her admission.

Treatment, outcome and follow-up

The patient was transferred to the department of chest surgery and because embolotherapy was not immediately available and the the recent rapid growth of the PAVM was endangering the patient surgery was recommended and she agreed and underwent successful resection of the LLL. Her postoperative course was uncomplicated. She was discharged home 1 week later and remains well over a follow-up of 5 years.

Histology of the resected lung tissue showed a large nodule with abnormally dilated vessels around a bronchovascular bundle, compatible with diagnosis of PAVM (figure 4).

Figure 4.

Section of lung parenchyma obtained at surgery (H&E staining) showing a well-circumscribed proliferation of small capillary-sized blood vessel lined by attenuated endothelium with no evidence of cellular pleomorphism or increased mitosis. Occasional admixed large thick walled blood vessels are also seen.

Discussion

PAVMs, also termed pulmonary arteriovenous fistulas are abnormal direct communications between branches of the pulmonary artery and pulmonary veins without an intervening capillary bed.¹ Population-wide, CT-based cancer screening programmes have revealed that PAVMs are considerably more prevalent than previously thought, occurring in 1:2600 individuals.² Over 80% of PAVM are congenital, and of these, 70%–80% are associated with the autosomal dominant disease hereditary HHT, Osler-Weber-Rendu syndrome.^{1 3 6}

In HHT, telangiectasia may be identified on examination in the nasal mucosa (>90%, often with recurrent epistaxis since childhood), mucocutaneous junction (>50%) and conjunctivae (up to 45%), as well as in the mucosa of the gastrointestinal tract (up to 40%, often bleeding and causing iron deficiency anaemia).³ They are derived from postcapillary venules which become dilated, increasing with age. In addition to PAVM, cerebral AVMs of potentially ominous complications and hepatic AVMs may also occur in patients with the Osler-Weber-Rendu syndrome.

PAVMs are nearly always fed by an artery from the pulmonary rather than the systemic circulation (afferent supply) while the efferent limb drains into one or more branches of the pulmonary vein and hence the systemic circulation.⁷ This anatomic right to left shunt impairs both gas exchange (reducing the oxygen content of the blood returning to the left heart) and mechanical filtration (of thrombi, bacteria) to a variable degree. These PAVMs are designated ‘simple’ (80%), while those receiving multiple afferents from several segmental pulmonary arteries are termed ‘complex’ (15%) and hundreds of simple and complex AVMs diffusely involving at least one lung segment are the unusual ‘diffuse’ type (5%).^{1 7} PAVM may be either solitary (usually), or multiple (roughly one-third of the patients) and bilateral and are mostly located in the lung periphery close to the visceral pleura, with the lower lobes as their most common site (left>right), so-called ‘basal prominence’.⁴ Many patients today are asymptomatic, diagnosed by screening or incidentally.⁶ However, the consequences of PAVM might be classified as haemorrhagic, functional, embolic (ischaemic or infectious) and other cerebral consequences, as summarised in box 1 (classification conceived by AS).^{1 4}

Box 1. Potential bleeding, functional and embolic consequences of pulmonary arteriovenous malformations (PAVM).

1. Bleeding consequences

   1. Bleeding into the bronchi (presenting as haemoptysis, mild to severe with danger of suffocation).

   2. Bleeding into the pleural space (presenting as acute dyspnoea and haemothorax).

   3. Bleeding consequences.

2. Functional consequences

   Cardiac haemodynamics are not affected (as opposed to systemic AVM/fistula) but right to left shunt (pulmonary arteries to pulmonary veins) with a large shunt fraction (large, multiple, bilateral or diffuse PAVM) often causes asymptomatic hypoxaemia and sometimes dyspnoea (worse on exertion and on assuming the upright position—orthodeoxia).

3. Embolic consequences (may be either ischaemic or infectious).

   Paradoxical embolisation across a PAVM can cause cerebral ischaemia (stroke, Transient Ischaemic Attack) or infection (brain abscess). Other manifestations in the systemic circulation such as limb ischaemia or infective endocarditis are considerably more unusual.

4. Other cerebral consequences

   PAVM can be associated with migraine or seizures. The mechanism is unclear. In addition, concurrent cerebral AVM can bleed causing intracerebral haemorrhage.

The screening test of choice is transthoracic contrast echocardiography with a sensitivity of up to 97% and a negative predictive value of 99%.⁸ CT is the test of choice for the diagnosis and characterisation of PAVMs. Percutaneous image-guided embolisation has become the preferred treatment and is currently recommended for all PAVMs with feeding arteries >3 mm in diameter, although some patients may require surgery.^{9 10}

Our patient had a solitary, sporadic, congenital PAVM with no evidence of HHT. It was entirely asymptomatic and discovered incidentally in an imaging study that was not even meant to include the chest. Its unique feature was rapid growth: the second set of imaging indicated a considerably larger LLL lesion (ie, PAVM) than the first, and the 5.5 cm nodule on the plain CXR was not even visible on her admission (figures 2 vs 1) The size and rate of PAVM are of special importance since the presence of symptoms and danger of rupture correlated best with lesion size.¹¹

We conducted a literature search to identify factors associated with increasing size or rupture of PAVM (PubMed in English, since inception, searching for PAVM and ‘natural history’ or’ growth’, or ‘rupture’, or ‘complications’). All relevant articles were retrieved. We then used the reference lists of pertinent articles to identify additional relevant reports.

We found that the natural history of PAVM has not been properly studied. Current knowledge must be cautiously interpreted because of bias due to the very large number of case reports; differences between older studies and more recent, CT-based series characterised by earlier presymptomatic detection; as well as the potentially inherent differences between HHT-associated and sporadic (congenital ‘non-HHT’) PAVMs.

Having said that, the expected natural history of PAVM is either that of stability or low growth rate over the years. Thus, manifestations of the disease become more prominent with age.⁶ For example, in a follow-up study of 20 patients over 11–13 years, nine patients showed slow radiographic progression (estimated at 0.3–2 mm/year) while 11 remained unchanged.^11–13 If an increased right-to-left shunt can be taken as indicative of growth of PAVM, it was observed in 18% of 200 patients with HHT followed over 5 years.¹⁴ It appears that PAVMs as part of HHT are more prone to enlargement than ‘sporadic’ PAVMs that often remain stable.^{3 11} This may be related to the increased prevalence of complex, multiple and bilateral PAVMs in HHT.⁶ Regression of PAVM almost never occurs spontaneously, and when it does, thromboembolic occlusion of the PAVM vessels is the likely mechanism.¹⁵ The circumstances that we found to be associated with PAVMs growth, progression and expansion are presented in box 2.

Box 2. Circumstances associated with progression and increase in size of pulmonary arteriovenous malformations (PAVMs)*.

1. Natural history: In some of the patients (possibly more in HHT), size increases over the years and clinical manifestations become more prominent with age.⁶

2. HHT associated (vs sporadic): More likely to be complex, multiple and bilateral.⁶

3. Anatomical considerations: Initially large size; complex lesions; multiple lesions.¹⁵

4. Puberty†.¹⁶

5. Pregnancy†.19 20 22 23

6. Labour†.^{22 24}

7. Pulmonary hypertension: Identified in 0/82 in one series,⁶ but may occur in a predominantly HHT-associated PAVM population (6% had a pressure>25 mm Hg) either in the context of high cardiac output failure secondary to hepatic AVMs or as a true phenotype³¹; also, it may have myriad additional non-HHT aetiologies.

8. Grand mal seizures (present report).

Except for ‘natural history’ or ‘idiopathic’ growth which is usually slow (if it occurs), anatomical factors seem important so that initially larger, multiple, complex or diffuse malformations are more susceptible to enlargement and complications.^{1 3} Except for anatomical factors, 4"P"s have been associated with more rapid progression/expansion and higher risk of complications in patients with PAVM. They include puberty, pregnancy, postpartum and pulmonary hypertension. There is paucity of data on the mechanisms. However, it was repeatedly observed that the vast majority of children with ruptured cerebral AVMs presented around or after the onset of puberty,¹⁶ suggesting instability and possibly hormonal factors. Immunohistochemical and molecular analysis of AVM tissue in vitro support this hypothesis by demonstrating neovascularisation contributing to AVM progression and identifying its controlling factors, which include hormones. Both oestrogen and testosterone stimulate vascular endothelial growth factor, and growth hormone is proangiogenic,¹⁷ and was overexpressed in AVMs.¹⁸ Pregnancy-associated expansion and/or rupture of PAVMs is well described,¹⁹ especially in the third trimester.²⁰ This can probably be ascribed to both haemodynamic factors (increased blood volume and cardiac output accelerate blood flow through the PAVM) and hormonal effects (since progesterone receptors were identified in AVMs and increased progesterone levels during pregnancy dilate arteriolar smooth muscle increasing AVM blood flow.²¹ Indeed, HHT-associated pregnancies carry a significant risk of PAVMs major bleeding (1% of 487 pregnancies reported and 1% maternal death rate).²² In another similar series of 244 pregnancies, four developed haemothorax (2.1%), two had minor haemoptysis (1.1%) and no mortality occurred.²³ The immediate postpartum period may also pose a special risk to patients with PAVMs, even without concurrent HHT.²⁴ Interestingly, patients with the vasculopathy of another inherited disease—neurofibromatosis type 1, exhibit similarly increased risk due to combined hormonally exacerbated vascular pathology during pregnancy and increased heart rate and systolic blood pressure during labour.^{25 26}

Our patient’s PAVM expanded substantially within hours with recurrent grand mal seizures as the only factor developing in between the imaging studies (figure 1 vs 2 and 3). The postulated explanation probably lies in the sudden seizure-associated increases in pulmonary artery pressure. Animal models of sudden unexplained death in epilepsy have repeatedly demonstrated hypoxia-induced marked pulmonary hypertension,^{27 28} and these data are supported by demonstration of significant oxygen desaturation in human epilepsy,²⁹ and documented pulmonary hypertension.³⁰ Nearly all patients with PAVM have normal (or even low) pulmonary artery pressures.^{1 6} If PAVMs are perfused at systemic pressure due to marked pulmonary hypertension of any cause, their expansion as in our patient is likely and the risk of imminent major haemorrhage is substantial. In our patient, it was averted by the successful lobectomy of the lower lobe with the PAVM, considered more prudent here than embolectomy by the chest surgeons.

In conclusion, grand mal seizures in a patient with PAVM can be added to the shortlist of causes (HHT association, anatomical considerations, puberty, pregnancy, postpartum and pulmonary hypertension) that increase the patient’s risk of rupture or other adverse event by facilitating or causing more rapid progression and expansion of the PAVM.

Since the risk of seizures in patients with PAVM is substantial (box 1, C. and D. as well as acquired non-PAVM aetiologies), our observations strongly suggest the need to monitor PAVM in patients with or without HHT in addition to current guidelines⁵ by repeated imaging after sustaining generalised seizures to evaluate potential expansion, future risk and need of treatment.

Patient’s perspective.

When I was hospitalized I thought I had the Flu, but soon I lost control and became confused and everybody was so worried. Then, Thank G-d it was over, but I was told they found another problem in my lung. They were afraid it was going to burst, as it seemed to be growing fast… They explained it and suggested an operation. My family and I agreed at once. I am so glad all this is over now.

Learning points.

• Pulmonary arteriovenous malformations (PAVMs) are usually stable lesions or slowly growing.

• Our case demonstrates rapid expansion of PAVM after recurrent grand mal seizures, a first report.

• Acute pulmonary hypertension, which occurs in generalised seizures, may underlie the change.

• Additional causes of accelerated growth of PAVMs include underlying hereditary haemorrhagic telangiectasia (HHT), anatomical factors, puberty, pregnancy and post partum were identified in a comprehensive literature review.

• Grand mal seizures in a patient with PAVM or HHT may mandate imaging to evaluate possible PAVM enlargement and subsequent ominous complications.