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Case presentation GVHD PNS

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Junaid Tonse

on 18 June 2016

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Transcript of Case presentation GVHD PNS

64 male
MDS diagnosed in 2013
Transformed to AML Oct 2014
Induction chemotherapy with Fludarabine, Busulfan, Antithymocyte globulin prior to Allogenic Haematopoitic Stem cell transplant (HSCT) in September 2014.

Paraesthesia started to progress slowly in October but in a disabling manner since November 2014 which led to his admission mid-November.
Still he was able to walk but slightly unsteady.
Severe tingling, hyperesthesia in both lower limbs.
No weakness.
Initial review by Neurology registrar in November
Above history was confirmed.

He had mild rash day 2 post transplant.
Had raised ALT (max 457) in the first week after transplant. US liver- Normal.
? drug induced hepatitis related to busulfan
?sepsis (Hickman line infection Rx teicoplanin)
He had a rash in the R wrist, forearm- Rx as cellulitis due to subclavian DVT on US doppler.
He also c/o Pins and Needles in the toes.
Case presentation
ST5 Neurology LGI
Bindu Yoga
Differential is LEMS,
Presynaptic Neuromuscular junction disorder
Proximal weakness with autonomic features
Voltage gated calcium channel antibody  
Neurophysiology showing increamental response after 10hz, >10s primarily voluntary contraction.

Avoid precipitating drugs
beta blockers
neuromuscular blocking agents
Myasthenic crisis:
IV immunoglobulins or plasmapheresis

The diagnosis of myasthenia gravis is supported by electrophysiological tests.
In myasthenia gravis, repetitive nerve stimulation with low frequency (2–5 Hz) produces a progressive decrease in the amplitude or the area under the curve of the compound muscle action potential.

It not usually associated with antecedent infections.
Sural nerve biopsy may be helpful to r/o amyloidosis, vaculitis, toxic neuropathy
CIDP associated with malignancies like Hodgkin’s lymphoma can lead to quadriplegia and fatal outcome after HSCT.
Severe symmetrical weakness of proximal muscles, neck flexors, limb girdle.
Muscle pain not always a feature
Rarely respiratory muscle involvement
Can involve heart muscle resulting in myocarditis especially after donor lymphocyte infusion or discontinuation of immunosuppressive drugs

Auto --> ‘self’
Autoimmunity is immune response to own proteins.
Allo --> ‘other’
Alloimmunity is immune response to foreign antigens.
Pt developed C-diff diarrhoea.
Pregabalin was helping his symptoms but discontinued as he had liver impairment.
ALT was raised ( max value190) but gradually improved.
Hepatology review:
? autoimmune hepatitis
? Drug induced hepatitis.
2.12 The Neurological Complications of Immunosuppression
2.19 Disorders of Peripheral Nerve

Curriculum topics

Cholinestarase inhibitors such as pyridostigmine used. if fails, steroids used.
Long term treatment with cyclosporin (C-2 IIb) and cyclophosphamide (C-2 IIb) should be given.
Other immunosuppressants such as mycophenolate mofetil (C-2 III-1b) and tacrolimus (C-2 III-1b). Refractory cases, rituximab.
no evidence for steroid combination with immunosuppressants in long term therapy.

Patients with aplastic anaemia prior to allogeneic HSCT seem to have an increased risk for developing myasthenia gravis after transplantation
Patients at high risk for developing myasthenia gravis after allogeneic HSCT have been shown to express specific HLAs, particularly HLA-Cw1, HLA-Cw7 and HLA-DR2, whereas idiopathic myasthenia gravis is associated with HLA-DR3, HLA-DQ2 and HLA-B8 
High titres AchR antibodies are present but around 40% of transplant patients have raised Abs without myasthenia.
In few MUSK or titin antibodies are present. 

1% after GVHD
22-60 months post transplant
usually associated with other manifestations of Chronic GVHD, it is considered as an associated feature of GVHD
often present with myasthenic symptoms after discontinuation or tapering of their immunosuppressive drugs
associated with other autoimmune complications after allogeneic HSCT such as glomerulonephritis and polymyositis

Myasthenia gravis
In addition to immune mediated neuropathies, Toxic peripheral nerve damage can be present
Cyclophosphamide , tacrolimus, thalidomide
Normally has axonal motor sensory neuropathy with typical dying back pattern
It is dose dependent phenomenon
Rx: Consider changing to different immunosuppressant

Treatment of CIDP associated with GVHD is similar to idiopathic forms
IV Immunoglobulin/Plasmapheresis
Immunosuppression with cyclosporine, mycophenolate, methotrexate, pulsed cyclophosphamide.
Interferon beta 1a is used in idiopathic CIDP with some success. It has to be used with great caution in allogenic HSCT related CIDP.

CIDP associated with Chronic GVHD
Similar to GBS, rarely autonomic, respiratory involvement, urinary incontinence
Neurophysiology same as CIDP but chronic axonal polyneuropathy can occur as a variant.
CSF analysis shows raised protein
Exact pathology behind CIDP not clear but seems to be predominantly T cell mediated.

Strong evidence implicates Antibodies against gangliosides as a cause of the axonal subgroups of GBS
Antibodies against GM1 are usually associated with Campylobacter and against GM2 can be present in CMV associated GBS
In axonal variants of GBS, T cell mediated immunity against myelin antigens is the major cause (resembles features of experimental autoimmune neuritis)

Rare but an important complication
First 3 months post HSCT
Can be acute or chronic GVHD or non GVHD
Most of them are associated with antecedent infections like coxsackie, CMV, Chlamydia, Mycoplasma, Campylobacter jejuni, EBV, Hep C, Varicella

Immune mediated neuropathies

Needle EMG findings
Typical myopathic pattern with fibrillation potentials, positive sharp waves, short duration and small amplitude motor unit APs, full interference patterns in weak muscles.
Segmental muscle fibre necrosis
Muscle fibre regeneration, mononuclear cell infiltration
Lymphocytic infiltration composed of donor cells

Rarely present like dermatomyositis with heliotrope rash on the eyelids, edema and erythema of the knuckles
CK increased by 5-50 fold
Others like LDH, transaminases, highly sensitive aldolase
Myositis specific antibodies are not yet found
HLA association- HLA DR52, HLA B8, HLA DR3 (DRb*0301), HLA DQA1*0501

PNS involvement

Neurological manifestation is mainly a feature of chronic GVHD.
Peripheral nervous system
Muscle cramps
Immune mediated neuropathies
Myasthenia gravis
Central nervous system
Cerebrovascular disease
Demyelinating disease
Immune mediated encephalitis

Neurological manifestation of GVHD

Acute GVHD
Gastrointestinal system

Organ involvement
Graft contains immunologically competent cells
Host appears foreign to graft; it has alloantigens that are capable of antigenically stimulating the graft.
Host is unable to mount an effective immunological reaction against graft.
Graft versus host disease
Factors supporting diagnosis:
? Hepatic failure secondary to GVHD
Mismatched unrelated donor aged 40
Peripheral Blood Stem Cell transplant
No other cause was found for the neuropathy!
Sensation to touch and pin prick was reduced in both lower limbs up to chest.
Vibration sense absent upto Hips.
Joint position absent up to knees.
Power in LLs 3/5 at hips, 4/5 at knees and ankles, ULs 4/5.
Upper limbs reduced reflexes, Lower limbs absent reflexes.
Unable to stand without trained staff.
Q: Patient getting worse. Should he have a scan again? and advise regarding neuropathic symptom control.
Unable to walk independently, needed A2 to transfer.
No bladder or bowel involvement
Tingling with altered sensation both lower limbs up to chest and upper limbs.
Referred to neurology for review 6/1/15

Add pregabalin for symptom control.
Investigations with blood tests and neurophysiology
Follow up in neurology clinic.

Peripheral neuropathy secondary to chemotherapy
Peripheral neuropathy secondary to cyclosporin
Team to rule out Graft versus host disease which is less likely.

Initial differential diagnosis

Review article- Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease; Oliver Grauer, Daniel Wolff, et al.; Brain 2010: 133; 2852–2865
Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria; Mary E. D. Flowers, Yoshihiro Inamoto, et al.; Blood, 17 march 2011: Volume 117, Number 11
Diagnosis and management of chronic graft-versus-host disease; Fiona L. Dignan, Persis Amrolia et al; British Journal of Haematology; 1365-2141.2012.09128.

Neurological symptoms post HSCT
Understanding of alloimmunity versus autoimmunity
Assess the risk factors
Think of GVHD even if no other cause is found
Team discussion between haematology and neurology regarding further treatment is vital!

Take home messages

Risk factors

CIDP associated with
Graft Versus Host Disease
in combination with possible cyclosporin induced polyneuropathy.
B12, folate, TFT, HbA1c normal.
Viral screen negative for HIV, CMV, EBV, Adeno, varicella, Hepatitis B, C.
VZV antibody positive.
IgA anti thymocyte globulin Antibody- negative
Autoimmune screen including ANA, ANCA negative
Ceruloplasmin negative
IgG, IgM normal. IgA-4.46. No paraproteinamia.
Cerebellar antibodies screen , Anti GM1,GM2 negative.
Cyclosporin level normal.
MRI spine normal.
Ultrasound abdomen- normal
NCS- mixed axonal and demyelinating motor sensory polyneuropathy.
Cranial nerves intact.
All four Limbs- normal power.
Reflexes intact & symmetrical, plantars-flexors.
Hyperesthesia up to mid thigh on the right, up to hip on the left.
Sensory ataxia with positive Romberg’s.
Joint position absent up to knee bilaterally. Vibration reduced up to knees bilaterally.
In between Neurology reviews
On examination
Usually not found in acute GVHD
Common feature of Chronic GVHD
Presents 3-69 months post transplant
Myositis alone cannot be diagnostic for Chronic GVHD
It requires involvement of other organs
Chronic GVHD:
oral mucosa, GI, Liver
Immune diseases

acute > chronic
Mismatched unrelated donor
Matched unrelated donor
Mismatched related donor
Total body irradiation prior to transplant (acute)
chronic > acute
Female donor to male recipient
Mobilized blood cell graft or PBSC
Older donor age
Older recipient age (chronic)

Protective factors:
Gene profiling
HLA matching
Antithymocyte antibody treatment
Classification of GVHD as per NIH Consensus criteria
Classic acute GVHD
within 100 days of hematopoietic cell transplant (HCT) and display features of acute GVHD.
Diagnostic and distinctive features of chronic GVHD are absent.
Persistent, recurrent, late onset acute GVHD 
greater than 100 days post-HCT with features of acute GVHD.
Diagnostic and distinctive features of chronic GVHD are absent.
Classic chronic GVHD
present at any time post-HCT.
Diagnostic and distinctive features of chronic GVHD are present.
No features of acute GVHD.
Overlap syndrome 
presents any time post-HCT
features of both chronic GVHD and acute GVHD.
Sometimes referred to as "acute on chronic" GVHD.
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