Transcript

PLEASE NOTE: While an effort has been made to correct errors in this AI-generated transcript, some mistakes may have been missed by the non-clinician moderator. This transcript should be taken merely as supporting material to the podcast discussion and neither is as an authoritative last word on the subject matter.

MIC CAVAZZINI:          Welcome to Pomegranate Case Reports, a series of learning podcasts developed by Trainees of the Royal Australasian College of Physicians. Associate Professor Stephen Bacchi from Adelaide will be hosting this chat with a neurologist who conducted a complex workup following a referral for diplopia. The 58 year old patient had actually started out in the haematology department, where he was diagnosed with acute myeloid leukaemia and initiated on chaemotherapy. No spoilers just yet, but I’ll provide a link to the report published in the Journal of Neuroimmunology in April 2023.

STEPHEN BACCHI:      Hi everyone, I'm Stephen. I'm a neurology registrar at the Lyell McEwin Hospital and today I've got with me. Doctor James Triplett, who's a neurology consultant and neurophysiologist at Flinders Medical Centre. He completed fellowships at Concord Repatriation Hospital in NSW and Mayo Clinic, Rochester, Minnesota. Thanks for joining us, Doctor Triplett.

JAMES TRIPLETT:          Thank you, Stephen. Thanks for the opportunity.

STEPHEN BACCHI:      So, today we'll be going through a case in a question and answer manner, aiming for a generalist audience and trainee relevant content. So, to start off with, we have a 58-year-old male. They've presented with features of disseminated intravascular coagulation or DIC and leukocytosis. And they then are diagnosed with an acute myeloid leukaemia or AML. And this has a monoblastic morphology and high-risk cytogenetics.

Now at this stage they've got no symptoms of central nervous system involvement and they’re not going to have a lumbar puncture because of their DIC. And they go on and have induction chaemotherapy with cytarabine and daunorubicin and they can proceed to have consolidation with high dose cytarabine. So, now we have a fair likelihood of having neurological features arise in this case, since we've got a neurologist with us, although they haven't yet developed. So, thinking ahead Dr Triplett, are neurological side effects common with chaemotherapy and which agents are classically associated with neurological side effects.

JAMES TRIPLETT:          Unfortunately, some of the more commonly used chemotherapeutic agents are associated with neurological side effects. Now these can range from mild sensory disturbance to more profound sensorimotor peripheral neuropathies. And this whole category of side effects is termed chaemotherapy-induced peripheral neuropathy and it often occurs in the hours to days after drug infusion and in some studies is reported in up to 70 percent of patients within one month of completing chaemotherapy with 30 percent of patients having on ongoing symptoms thereafter.

Some of the therapies associated with chaemotherapy induced peripheral neuropathy include some of the platinum-based agents, taxanes as well as vinca alkaloids and thalidomide analogues. In more recent times, the use of immune checkpoint inhibitors has also, led to widespread autoimmune symptoms and including those is peripheral nerve symptoms, and they can either be sensory or motor predominant and even mimic Guillain-Barré syndrome.

STEPHEN BACCHI:      Thank you. So, now the case is progressing. So, we're nine days down the track now, nine days after the first cycle, rather. And the patient has developed new symptoms and they've developed painless diplopia and ptosis. And the physical exam findings are indicative of a right third nerve palsy, So, Dr Triplett, in general, what's your approach to a patient with a new third nerve palsy? And how does your approach differ if, say, the pupils is involved or spared?

JAMES TRIPLETT:          So, the first part of the approach is to determine from clinical history is it painful or painless? How that can give some clues as to what a possible aetiology is. And then actually, obviously assessing the patient clinically and determining what the position of the eye is. It should typically be in a down and out position with impairment of adduction elevation and depression of the eye. And then there should also, be a degree of ptosis involved.

The next part is—and what you were asking about—the pupillary involvement. Is there, is there an enlarged, unreactive pupil? If the pupil is enlarged and unreactive pupil it suggests that there's been injury to the parasympathetic pupillary fibres. Now the parasympathetic pupillary fibres are located peripherally in the nerve, and they're generally more likely affected by external compression as opposed to injury to the third nerve itself. There's actually a secondary blood supply, as such, that supplies those fibres, So, if we see an enlarge on an unreactive pupil concern is for a compressive lesion.

The causes and initial work up of these from this point of view again, it painful or painless? If it's painful, may be suggestive of a vasculitic phenomena or if there's severe headaches, may need to think of other causes. And then the next steps can include MRI of the brain stem as such, and also, looking at the cavernous sinus, making sure with the imaging that we do an angiogram to assess for any aneurysm, particularly posterior communicating artery aneurysm, which can compress the nerve as well.

STEPHEN BACCHI:      Great, thanks. So, third cranial nerve palsy, the key things for a trainee to think about is whether the pupils involved or not and whether there's pain or not, with differentials including intracranial cerebral aneurysms and vasculitis, including giant cell arteritis can present at typically. So, now we're going further down the track. So, now we're getting to the realm of something that you might get in a short case for your physician training exams. So, we're now up to day 12 and they’ve now got a painless right 5th, right 7th and left third nerve palsies. So, I'll just say that again so, everyone can think about it. So, up to day 12 now and they've got a right 5th, a right 7th and the left third nerve palsies. So, this changes our formulation significantly. Would it be fair to call this a multiple cranial neuropathy? I imagine this is going to invoke a slightly different set of differential diagnosis/

JAMES TRIPLETT:          I yeah, I would agree that this is  certainly multiple cranial neuropathies, or you know another way of terming it would be mononeuritis multiplex. Where we have nerves both left and right sided nerves involved and painless. The differential for mononeuritis multiplex or multiple mononeuropathies is relatively broad and again has to be taken in the in the clinical context. Okay, so, in this in this circumstance, you would be wondering about whether there was a leukaemic involvement. There can be direct tumour involvement as well. So, lymphoma or another metastatic malignancy.

These have also, been reported in systemic autoimmune conditions likely associated with vasculitic phenomena, including lupus, and also the paraneoplastic syndromes. Other causes can include sarcoidosis. Sarcoidosis, though typically when affecting cranial nerves f or some reason, has a predilection for bifacial palsies as opposed to this patchy process we've seen thus far in this case.

STEPHEN BACCHI:      Alright, so, that's brought a number of other considerations into the front of our mind. So, now we're going down the track again slightly further. So, we're up to day 17 now and they've developed further neurological features. So, now they've developed left, radial ulnar and perineal neuropathies. So, at this point they receive nerve conduction studies and these demonstrate a conduction block on the left on the nerve. And it's at a non-compressible site in the forearm, and then the perineal neuropathy is also demonstrated on nerve conduction studies. So, now we have non-cranial nerve involvement as well. And in this case there's conduction block and it's at a non-compressible site. So, could you please explain to us what conduction block is and what's the significance of that occurring at a non-compressible site?

JAMES TRIPLETT:          So, conduction block is one of many pieces of information we can gather from nerve conduction studies. The basic principles of nerve conduction studies is giving an electrical impulse over a nerve, either sensory or motor. Now, in this case, we're talking about a motor nerve, the ulnar motor responses, and we're trying to generate a motor response or. Compound motor action and potential or CMAP. We stimulate this initially distally at the ulnar nerve at the wrist, then below the elbow and more proximately above the elbow and first site can include the axilla and Erb’s point.

Conduction block is defined as a drop in that CMAP amplitude between two points. Now in this circumstance. The patient had a normal response at the wrist and a significant reduction in amplitude at the elbow, below the elbow and similar response above the elbow. And this drop in amplitude suggested that a side of injury or impairment of the nerve's ability to propagate this electrical stimuli occurred over the forearm.

Conduction block sometimes is accompanied by slowing and is thought to represent focal demyelination at that area. Which is why often we  talk about compressible sites. Because of this compression at the elbow there will be a reduction in the amplitude because some fibres are not firing at all, or they're firing asynchronously. And so, the importance in this case of it being located in the forearm was suggesting that it hadn't occurred at the elbow, that there was an alternate pathology occurring in that segment across the forearm.

STEPHEN BACCHI:      I think that probably most people have encountered an ulnar neuropathy even if they invoked themselves accidentally. But could you please just remind us what the most common sites of compression are for the on the nerve, although it's not relevant in this particular case?

JAMES TRIPLETT:          So with regards to compressible sites of the ulnar nerve at the elbow the most common site is in the cubital tunnel as the ulnar nerve runs through the cubital tunnel. Other areas of entrapment can include in the arcada Struthers which is a little further proximally up the arm. And rarely in the forearm at the exit of the cubital tunnel. So, in some cases in neurophysiologically this is confirmed by inching studies where the probe is moved two centimetres approximately or distally to determine the site at where that drop off occurred. And then can be confirmed using imaging studies either ultrasound or MRI.

STEPHEN BACCHI:      Well, thank you for that perfect segue. So, we're now going tp proceed with some investigations. So, ultrasonography of the on the nerve was unrevealing as was MRI and FDG PET. And they've had multiple cerebrospinal fluid, or CSF, examinations. On Day 10 and 15 after chaemotherapy and this has been largely unrevealing with a normal protein negative flow cytometry, normal cell count and their serological tests have been unrevealing g, including an antineuronal antibody panel. So, how does this information help your diagnostic formulation. Are there particular diagnosis that you think you can now almost exclude? I know that you know there's going to be options left, though, and we'll arrive at one of those shortly.

JAMES TRIPLETT:          Yeah, Stephen. So, the testing thus far or at this point time as you've mentioned, have been relatively unenlightening as to what the underlying aetiology of these neuropathies were. Importantly, though there was concern this was a man who had received new, or induction chaemotherapy, regarding infection, whether it be bacterial or fungal. The fact that repeated CSFs were normal made that less likely, and we were able to take that off the table as one of the differentials. Similarly,  repeated negative anti neuronal antibodies and serum antineuronal antibodies made a paraneoplastic phenomena less likely. Though the first of these initial CSFs were negative, the potential still for CNS and PNS involvement of the underlying leukaemia was still a possibility. And they can, as the literature has suggested, they can be notoriously difficult to identify on CSF, both lymphoma and leukaemia. And sometimes up to three large volume taps are required to identify blasts or abnormal cells.

STEPHEN BACCHI:      In that context, just as you've suggested, a third  cerebrospinal fluid sample was obtained. This was obtained on day 24, and this did confirm the presence of myeloblasts, and this is consistent with central nervous system infiltration with leukaemia. And this led to a presumptive diagnosis of neuroleukaemiosis. Now Dr Triplett, I think one of the first times I ever encountered this diagnosis was when you told me about it on the ward. Neuroleukaemiosis may be a new diagnosis to some of our listeners. Could you please just tell us a bit more about the diagnosis?

JAMES TRIPLETT:          Yep, certainly. So, neuroleukaemiosis is the infiltration of leukemic cells into peripheral nerve sites. It's a rare condition with probably around 45 to 50 cases described in the literature. The condition is thought to occur due to infiltration [unclear] of these leukaemic cells that then interact and alter the blood nerve barrier allowing them to enter the peripheral nervous system itself and this basically becomes a sanctuary for leukemic cells. And they allow they thus replicate cause for the damage to the peripheral nerves. Cases that have occurred in the past have been either multifocal in nature with a large or a significant painful component to them, suggesting a vasculitic component. Where other cases have been almost a fulminant presentation mimicking Guillain-Barré syndrome syndrome or inflammatory polyreticular neuropathies. Though it's rare, it generally portends a poor prognosis for patients because the cases reported thus far have either occurred in the setting of relapse or in the setting of poor cytogenetics.

And diagnosis for this condition can be difficult, and often CSF on its own is insufficient to make a diagnosis and in some cases, a nerve biopsy is required. Obviously, in this circumstance, there was no easily biopsible site, and eventually a CSF did return positive. But to put that in perspective here, you know literature review of the previous cases, the initial CSF was only diagnostic a third of cases and became positive on serial testing in around a total of 50 percent of cases. So, the remaining cases were diagnosed either from nerve biopsy or were presumptive based on other conditions being excluded.

Once diagnosed, though, it is important that it often leads to escalation of treatment or the commencement of intrathecal chaemotherapy. And in some cases where there's a single lesion or a single nerve involved, there may be focal radiation or surgery considered. In this case, obviously the changes in treatment, et cetera, were managed by the haematology team with the neurologists taking a back seat.

STEPHEN BACCHI:      Right, so, in this case, as you've described, treatment was escalated with intrathecal cytarabine and methotrexate in addition to the intravenous escalation of therapy. And this did lead to clearance of the central nervous system blasts and this is within a week. And then subsequently there was resolution within two months of the neuropathies. Unfortunately, later in the patient’s course, they did relapse and subsequently died as a result of their leukaemia now. Now, this is a sad outcome and was a very serious illness. However, the case does provide us with an opportunity to learn about a neurological manifestation of a systemic illness which has treatments. The treatments enabled this patient to have resolution of their neuropathies for a period of time, So, it's a very valuable case for all of us to learn from and we're thankful to the patient and their family for sharing it. So, Dr Triplett, what do you think are the key take home points from this case.

JAMES TRIPLETT:          So, Stephen, I think there's numerous points from this case. The first and foremost is that patients with haematological malignancy, malignancy of any kind, can develop neuropathies and neurological sequelae from a multitude of reasons. The first being, as in this case it's direct malignancy; the second that it's treatment associated; or third that it's a paraneoplastic phenomena. So, I think we have to keep an open mind, when a patient, is either being worked up for an initial malignancy or is thought to be in remission from their condition starts to develop new neurological symptoms.

This case of neuroleukaemiosis is obviously a rare condition, and I would assume that it's been underreported over the years. But again, the presence of a in a patient with leukaemia at the time, efforts should be made to confirm the diagnosis in as timely manner as possible, and as mentioned that may require multiple high volume CSF analyses,  the CSF being normal doesn’t exclude malignancy [unclear]. It often requires the input of multiple specialties; obviously the haematology team and neurologist, but also input from radiology colleagues in regards to the optimal ways of trying to assess for metastatic spread either via PET scan or in this circumstance trying to identify areas of nerve infiltration using ultrasound or MRI.

And finally, the presence of neuroleukaemiosis should lead to consideration for escalation of therapy.  In a more broader aspect, as opposed to this case itself, I think it is important,  and it is a good teaching case to discuss the potential causes of third nerve palsies and also of mononeuritis ,ultiplex or multi multifocal motor neuropathies. Which do again have a relatively broad differential, though all of which often require acute treatment.

STEPHEN BACCHI:      Tthank you very much for joining us, Doctor Triplett, this has been a very educational case for me and I hope for our listeners. So, if they'd like to learn more, the original article was titled “Painless progressive mononeuritis multiplex secondary to AML associated neuroleukemiosisis” published in the Journal of Neuroimmunology in 2023. And the senior author was Doctor James Triplett, who has joined us today. Thanks again, Doctor Triplett.

JAMES TRIPLETT:          Thanks very much, Stephen. Thank you for the opportunity.

MIC CAVAZZINI: Thanks again to Stephen Bacchi for coordinating this case report. He’s done this on top of a whole host of other responsibilities so please don’t hold this podcast up as the authoritative clinical text book. These case reports are mostly intended to demonstrate a structured approach to diagnostic reasoning and case presentation.

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