Neurological Manifestations of Rheumatic Diseases - Disclosure
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6/18/2021
Neurological
Manifestations of
Rheumatic Diseases
AMER AL-KHOUDARI, MD, FACR
ARIZONA ARTHRITIS CLINIC, PLLC
1
Disclosure
Pharmaceutical company speaker
Novartis, Medexus, Horizona, Amgen
2
16/18/2021
Introduction
Rheumatic diseases are a collection of chronic inflammatory conditions stemming
from autoimmune attack on connective tissue.
The systemic nature of these diseases can result in secondary neurologic
symptoms.
- direct result of immunologic attack
- indirect degradation of supporting structures.
- Neurotoxic effects of treatment can also cause complex neurologic symptoms.
3
EPIDEMIOLOGY OF NEUROLOGIC
COMPLICATIONS
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Rheumatoid Arthritis
-Spinal cord involvement > cerebral complications
-Usually appear late in the course of the disease
-Usually involve the peripheral nervous system.
-Caused by- vasculopathy secondary to systemic inflammation or by
-nerve entrapment secondary to musculoskeletal degradation
characteristic
-Many RA patients experience subclinical neuropathies.
-The true incidence and emergence patterns of RA-associated neurologic
complications may be unknown.
5
Systemic Lupus Erythematosus
-SLE is associated with the highest incidence of neurologic sequelae among all
rheumatic diseases.
-25% and 70% of SLE patients will experience neurologic or psychological symptoms.
-12% of sequelae established before a diagnosis of SLE and another
-12% presenting with neuropsychiatric symptoms at the time of diagnosis.
-Up to 50% of SLE patients will experience CNS complications.
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Systemic Lupus Erythematosus
-A significant percentage of SLE patients develop distinct neuropsychiatric
symptoms during the course of the disease.
-17% to 30% will be diagnosed with neuropsychiatric SLE (NPSLE).
-NPSLE patients generally do better than SLE patients with psychiatric symptoms
not related to the disease,
7
Systemic Lupus Erythematosus
-NPSLE patients have worse outcomes than SLE patients without NPSLE.
-Recognition and treatment of this subset may be critical for disease prognosis.
- Antiphospholipid syndrome and cerebrovascular disease in SLE patients
contributes to morbidity and mortality in SLE.
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Sjogren Syndrome
-Neurologic involvement in Sjogren syndrome range from 0% to 70%,
-Prevalence is probably closer to 20%.
-Peripheral nervous system (PNS) dysfunction in Sjogren syndrome includes
Symmetric sensorimotor polyneuropathy
Cranial neuropathy as common findings;
-PNS involvement in primary Sjogren syndrome has an estimated prevalence of
20%.
-CNS involvement in primary Sjogren syndrome is less frequent;
9
Sjogren Syndrome
-1% to 8% of Sjogren syndrome patients show CNS dysfunction including mild
cognitive deficits, headache, and spinal cord involvement in
-The majority (63%) of Sjogren syndrome patients with CNS involvement will also
have PNS abnormalities.
-Central deficits precede the diagnosis of primary Sjogren syndrome in many
cases.
-Patients who have primary Sjogren syndrome with neurologic involvement are
generally older than those without neurologic symptoms.
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NEUROLOGIC COMPLICATION
CATEGORIES
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Vasculitis
-Vasculopathy is common in systemic autoimmune disease and contributes to
many of the neurologic presentations in rheumatic disease.
-Direct autoimmune-mediated destruction and chronic systemic inflammation
contribute to vascular degradation.
-Homogenous noninflammatory fibrointimal hyperplasia results in progressive
vascuar occlusion collateral vessel formation and digital vessel infarction.
-Polyarteritic lesions result in intravascular occlusion and thrombosis and carry a
worse prognosis than noninflammatory lesions.
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Vasculitis
-Histologically, polyarteritic lesions affect small- to medium-sized arteries, with all
vascular layers undergoing mononuclear infiltration, nondestructive fibrinoid
necrosis of the internal elastic lamina, and intimal proliferation.
-Micro-vessel vasculitis in the vasa nervorum contributes to the peripheral
neuropathies associated with rheumatic disease.
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Vasculitis -RA
-Systemic rheumatoid vasculitis is associated with an increased risk of
cardiovascular morbidity and mortality. Cerebral vasculitis may occur with or
without systemic vasculitis and may be fatal unless promptly diagnosed and
managed.
-The major peripheral neurologic complications in RA (distal sensory neuropathy
and mononeuritis multiplex) are directly caused by vascular degradation, and this
implied vascular involvement carries great prognostic weight.
-RA patients with vascular involvement have early-onset cardiovascular disease
and are twice as likely to experience myocardial infarction
-Vascular disease may account for one-third of all mortality in RA patients.
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Vasculitis- SLE
-Vascular complications are observed in 10% to 40% of patients with SLE and can
cause multiorgan pathology.
-The immune complexes observed in SLE are known to activate endothelial cells
and elicit a proinflammatory and proliferative response, contributing to the
pathologic development of vasculitis.
-Concurrent antiphospholipid syndrome in SLE patients may play a role in vascular
complications as a result of the antiphospholipid syndrome prothrombotic effect,
but this is difficult to discern from small vessel vasculopathy.
15
Vasculitis- SLE
SLE patients have an increased risk of stroke, but increasing evidence suggests
that CNS complications and myelopathies in lupus are rarely caused by vasculitis.
Vasculopathy plays a larger role than simple vessel occlusion in the pathogenesis
of peripheral neuropathies in SLE.
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Vasculitis- Sjogren syndrome
-Primary Sjogren syndrome is rarely associated with vascular disease as an early
manifestation
-The true incidence is difficult to characterize as vasculopathy occurs in late-stage
disease in the presence of multiple confounding risk factors.
-Small vessel vasculitis and ischemia is implicated in small fiber neuropathy,
multiple mononeuropathies, and autonomic neuropathy described in primary
Sjogren syndrome.
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Vasculitis- Sjogren syndrome
-Subtle peripheral neuropathy may be present in 20% to 50% of Sjogren syndrome
patients.
-Axonal polyneuropathies are the most common and clinically present as distal ad
symmetric.
-Although rare, cerebral vasculitis is implicated in some of the diffuse encephalitic
complications of Sjogren syndrome.
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Vasculitis- Behcets syndrome
-Neurological involvement is classified into:
-inflammation of CNS tissue or
- vasculitis with a stroke-like presentation and sinus venous thrombosis which is
less frequent.
--The wide variety of neurological findings that occur are headaches, ocular and
other cranial nerve palsies, seizures, cerebrovascular insufficiency, brainstem
syndrome leading to cerebellar ataxia and pseudobulbar palsy.
-Spinal cord disease, hemisphere lesions and meningoencephalitis also occur.
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Stroke
-Systemic inflammation increases atherogenesis and thrombotic risk through
suppression of anticoagulation and fibrinolysis and increased procoagulant
production.
-Sjogren syndrome is associated with enhanced atherogenesis and carries an
increased risk of ischemic stroke early in the disease course
-RA and SLE have a much more defined role in risk of atherosclerosis, thrombosis,
and subsequent stroke.
-Both RA and SLE show a small but significantly increased risk of ischemic and
hemorrhagic stroke within a year of a hospitalization for rheumatic disease, and
RA carries this elevated risk for up to 10 years.
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Stroke-RA
-The moderate stroke risk in RA has a late evolution in the course of the disease
compared with other cardiovascular complications that are early onset in these
patients.
-RA does not cause large-artery cerebrovascular disease, but systemic
inflammation is well established as an accelerant of atherosclerosis in the RA
population and probably plays a role in the increased risk of stroke over time;
procoagulable factors may be upregulated in established RA,
-possibly this late-stage increase in hypercoagulability may account for the slow
evolution of increased stroke risk in RA patients.
21
Stroke-RA
-posterior embolic stroke may result from direct occlusion of the vertebrobasilar
circulation secondary to rheumatic degradation of the transverse ligament and
subsequent atlantoaxial subluxation.
-Vertebral artery compression due to cervical subluxation occurs in 5% of RA
patients; the insidious destruction of the atlantoaxial joint over time also
contributes to the late onset of RA stroke risk.
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Stroke-SLE
-Cerebrovascular disease is one of the neuropsychiatric manifestations of SLE.
-All neuropsychiatric syndromes in SLE patients have a strong negative impact on
morbidity.
-cerebrovascular disease and myelopathy are associated with increased risk of
mortality.
-3% to 15% of SLE patients will experience stroke at some point in the disease
course.
-Studies suggested increased risk of all types of stroke except subarachnoid
hemorrhage.
-the youngest SLE patients have the highest stroke risk
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Encephalitis
-The brain is protected from potentially destructive autoantibodies by the blood-
brain barrier (BBB),
-some patients with rheumatic diseases can develop significant breaches.
-CNS injury in rheumatic disease is multifactorial and poorly understood at a
pathophysiologic level,
-serum and CSF antineuronal antibodies, prothrombotic factors, and chronic
systemic inflammation are contributory.
-TNF and IL1B increase cerebral inflammation and have receptors on the BBB, in
conjunction with prostaglandins, may also play a role in increasing BBB
permeability and leukocyte migrations through Rho-dependent pathways.
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Encephalitis-RA
-Cerebral manifestations of RA are infrequent complications.
-include rheumatoid nodulosis and vasculitis.
-Nodules typically develop in the dura, meninges, or choroid plexus but have been
reported in the brain parenchyma;
-rheumatic nodules are often asymptomatic,
-the true incidence and pattern of these lesions remains unknown.
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Encephalitis-RA
-Cerebral vasculitis in RA is rare and develops in the meninges, choroid plexus, and
parenchyma.
-Patients with established, seropositive, active RA and other extraarticular
manifestations of the disease appear to be at higher risk of developing CNS
complications.
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Encephalitis-SLE
-CNS involvement is seen in about 50% of SLE cases and carries a worse prognosis
than PNS disease.
-The 5-year survival figure of patients with encephalitic SLE is 55%, compared with
75% to 90% of those with nonencephalitic SLE.
-Neuropsychiatric complications are so pervasive in SLE that the American College
of Rheumatology has developed definitions, reporting standards, and diagnostic
recommendations for 19 neuropsychiatric syndromes associated with SLE.
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Neuropsychiatric Syndromes in Systemic Lupus
Erythematosus as Defined by the ACR
Central Manifestations
Acute confusional state Anxiety disorder
Aseptic meningitis Cerebrovascular disease
Cognitive disorder Demyelinating syndrome
Headache
Mood disorder Movement disorder
Myelopathy Psychosis Seizure disorder
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Neuropsychiatric Syndromes in Systemic Lupus
Erythematosus as Defined by the ACR
Peripheral Manifestations
Autonomic neuropathy
Cranial neuropathy
Guillain-Barre´ syndrome
Mononeuropathy
Myasthenia gravis
Plexopathy
Polyneuropathy
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Encephalitis-SLE
-mild cognitive deficits and headache 50% of SLE patients.
-psychosis, seizure, and stroke (reported in approximately 10% of SLE patients.
-Memory disturbance is the most common cognitive deficit and may herald the
diagnosis of the disease
-symptoms of NPSLE will develop within the first 6 to 12 months after initial SLE
diagnosis, but onset may occur at any time,
-It is important to rule out non-SLE-attributable causes of neuropsychiatric events
and monitor for antiphospholipid syndrome comorbidity in order to properly
diagnose and treat the patient with NPSLE.
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Encephalitis-SLE
-Animal experiments have shown that the immune complexes characteristic of SLE
increase the permeability of the BBB, creating antineuronal antibody access to the
cerebral circulation.
-Antiphospholipid antibodies, present in 2% to 5% of healthy individuals, but in
50% to 60% of SLE patients with CNS complications, and in 20% of SLE patients
without central neurologic symptoms.
-antiphospholipid antibodies are recognized for their contributions to a
prothrombotic state,
-they also have cross-reactivity with myelin and brain phospholipids, creating
complex pathophysiologic mechanisms for neurologic injury beyond thrombotic
infarction.
31
Encephalitis- Sjogren
-most recent estimates put CNS involvement in primary Sjogren syndrome
between 1% and 8%, although this may not capture mild or minor complications.
-Sjogren syndrome-related CNS manifestations can occur very early in the disease
course.
-Focal encephalopathic manifestations such as seizure, aphasia, and movement
disorders are more common than diffuse patterns of involvement such as
subacute encephalopathy, aseptic meningitis, and psychiatric abnormalities.
-Onset may be recurrent and must be distinguished from multiple sclerosis (MS).
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Myelopathy- RA
-Myelopathies secondary to atlantoaxial subluxation are common in RA patients.
-The extent of damage observed on imaging does not always correlate with the
presence of clinical signs of spinal cord compression.
-approximately 15% of RA patients with radiographic lesions are asymptomatic.
-Atlantoaxial subluxation in RA patients may occur in isolation or in combination
with cranial settling (vertical translocation of the dens).
33
Myelopathy- RA
-Lower cervical spine involvement, including multilevel anterior dislocation, occurs
in up to 29% of RA patients later in the disease course.
-Cervical spine changes start early in the course of RA, and these abnormalities
typically progress from C1-C2 dislocation to cranial settling to lower cervical spine
involvement.
-Severity of RA (indicated by seropositivity, high C-reactive protein at disease
onset, and polyarthritis) is predictive of the extent of progression of cervical spine
involvement.
-Acquired cervical syringomyelia has also been described secondary to atlantoaxial
subluxation in RA.
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Myelopathy- SLE/Sjogren
-Inflammatory myelopathy, sometimes in the form of a catastrophic, longitudinally
extensive transverse myelitis, may occur in patients with rheumatologic disease,
particularly SLE and primary Sjogren syndrome.
-neuromyelitis optica (NMO) is commonly associated with systemic autoimmune
diseases, and this association is increasingly accepted as NMO that is concomitant
with systemic autoimmune disease.
-lymphocytic infiltration of spinal roots and dorsal root ganglion degeneration is
particularly associated with Sjogren syndrome and presents as a progressive
sensory ganglionopathy
35
Other Diseases-Sarcoidosis
-In the CNS sarcoid, granulomas most often involve the meninges.
-The commonest findings are cranial nerve involvement, CNS parenchymal disease and
demyelination.
-Rarely, features such as aseptic meningitis and peripheral neuropathy are found.
- CNS granulomas, symptomatic or asymptomatic, can be seen on T2-weighted MRI or
contrast-enhanced CT.
-MRI and PET are being used to identify otherwise occult sites of inflammation that
may be amenable to biopsy.
-Lumbar puncture is usually performed in cases of suspected neuro-sarcoid, although
CSF findings are non-specific. Angiotensin-converting enzyme (ACE) levels may be
increased, decreased or normal in the CSF.
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Other Diseases-Ankylosing
Spondylitis
-The main neurological complications in ankylosing spondylitis occur due to axial
disease with spinal cord impingement at multiple levels.
-Surgical procedures in patients with atlanto-occipital disease, atlantoaxial
subluxation and spinal stenosis have been performed for pain and neurological
deficit.
-surgery is not without risk of permanent neurological damage. Suitable patients
must therefore be identified and counselled carefully.
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Early manifestations of rheumatic vasculitis may present as scleroderma,
including fibrosis of the skin, sclerodactyly, and Raynaud phenomenon.
-The presence of these symptoms in the context of neurologic abnormalities
increases the likelihood of neurovascular pathology
-Transesophageal echocardiology and carotid ultrasound in combination with
serologic analysis of a prothrombotic state may be indicated, especially in light of
cerebrovascular or vasculopathic history.
-Neither MRI nor CT can distinguish small vessel vasculitis from thrombosis;
-positron emission tomography (PET) imaging can detect these metabolic and
perfusion abnormalities but is still considered investigational.
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-For suspected vasculopathy, conventional arteriograms are superior to magnetic
resonance or CT angiography.
-Isotype (eg, immunoglobulins M, G, and A) and titer of lupus anticoagulant,
anticardiolipin, and anti B2- glycoprotein I are recommended and can be
diagnostic for comorbid antiphospholipid syndrome.
-Peripheral neuropathy is often associated with vasculitis.
-autonomic dysfunction may also involve antiacetylcholine receptor antibodies at
the autonomic ganglia
-Sjogren syndrome was the only connective tissue disorder with detectable
antineuronal antibodies.
39
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-The American College of Rheumatology has outlined basic laboratory matrices
and imaging guidelines to aid in differentiation of neuropsychiatric SLE symptoms
and disease activity from other neurologic diseases.
-CNS-SLE syndrome and CNS-Sjogren syndrome with recurrent symptoms,
antineuronal antibody titers, and small multifocal white matter abnormalities on
MRI can resemble MS, and differentiation remains challenging.
-Stroke, TIA, seizure, headache, and isolated peripheral neuropathy are not
common in MS, as they are in SLE and Sjogren syndrome.
-MS will typically show oligoclonal banding on CSF evaluation, but this can also be
observed in SLE
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-MRI is the preferred imaging modality for investigating encephalopathic
rheumatic involvement,
-CT when MRI contraindications or in cases of suspected acute hemorrhage.
-MRI with gadolinium is the most sensitive method of evaluating CNS lesion
presence, extent, and progression.
-Single-photon emission computed tomography (SPECT), PET, and diffusion and
perfusion MRI are investigational in this context.
-MRI abnormalities in SLE are typically subcortical and static, as opposed to the
dynamic periventricular, cortical, basal ganglia, and corpus callosum lesions in MS
41
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Encephalopathic involvement in primary Sjogren syndrome is associated with MRI
abnormalities approximately 50% .
- lesions described as small, diffuse punctate white matter hyperintensities in
subcortical and periventricular regions on T2-weighted and fluid-attenuated
inversion recovery (FLAIR) sequence.
-diffuse encephalopathic involvement in primary Sjogren syndrome presenting as
memory impairment, cognitive dysfunction, and psychiatric problems is not
associated with MRI changes or CSF abnormalities, but angiographic and
technetium-99m (99mTc)YSPECT changes have been described.
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Inflammatory and possible demyelinating lesions are rare in Sjogren syndrome
and tend to appear in younger patients without hypertension.
-Patients with possible CNS-Sjogren syndrome should also undergo serologic
evaluation for Sjogren antibodies with anti-Ro (Sjogren syndrome A [SSA]) and
anti-La (Sjogren syndrome B [SSB]) titers.
-Evaluation of the CSF is of particular importance in diagnosing primary Sjogren
syndrome neurologic complications and distinguishing between Sjogren syndrome
and MS.
43
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Disease activity in Sjogren syndrome is correlated with increased immunoglobulin
G index in many patients.
-CSF oligoclonal banding may be helpful, as banding occurs at a much lower
frequency in patients with primary Sjogren syndrome (20% to 25% of primary
Sjogren syndrome versus 90% of MS patients.
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-NPSLE remains challenging to diagnose due to the high frequency of many of the
19 defined neuropsychiatric entities within the general population, and the lack of
specific diagnostic criteria for SLE-associated neuropsychiatric events.
-Emergence of neurologic sequelae in SLE may be associated with inflammatory
flare.
-diagnostic workup should begin with detection of serologic and CSF acute-phase
markers of inflammation of disease activity; elevated erythrocyte sedimentation
rate and decreased complement are associated with disease flare
45
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-antiribosomal P protein antibodies is considered investigational but is highly
specific for SLE and is informative in the presence of neuropsychiatric symptoms
without an SLE diagnosis.
-Basic CSF Gram stain and culture can evaluate bacterial cause or comorbidity
with neuropsychiatric symptoms, and neurosyphilis should be excluded.
-EEG changes in NPSLE are nonspecific.
-EEG monitoring is indicated in seizure and encephalopathic presentations.
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DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Myelitis is best diagnosed on MRI,
-MRI helps excluding compressive hematoma, tumors, and spinal deformities.
-Hyperintensity on T2-weighted imaging in combination with elevated CSF protein
and cell count is consistent with myelitis,
-extensive CSF workup is essential to exclude an infectious cause before
therapeutic immunosuppression therapy can safely begin
It is of note that the high concurrence of antiphospholipid antibodies in rheumatic
disease can cause a false positive result for CSF oligoclonal banding.
47
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
-Spinal imaging can direct the differential against MS,
-spinal lesions spanning multiple segments are rare in MS but would be consistent with
the longitudinally extensive myelitis of an NMO-spectrum disorder in patients with
systemic autoimmune disease.
-In patients with rheumatologic disease who have possible NMO, workup should
proceed as in any patient with this neurologic syndrome (eg, assessment for
aquaporin-4 antibodies).
-RA suggests that clinicians order imaging studies early in the course of RA and in
cases of rapid disease progression.
-Radiographs in maximum flexion and extension or dynamic MRI can reveal the extent
of dislocation that neutral films may miss.
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Treatment
-The treatment involves both controlling the underlying immune attack on the
nervous system and the treatment of the specific neurologic symptoms caused by
the immune attack, such as seizures and neuropathic pain.
-Neurologists are often consulted for the treatment of symptoms,
-neurologists may be less comfortable with the use of immunosuppressive
treatment.
-Nontargeted therapy and targeted therapy can sometimes be used together.
-Treating the underlying rheumatic disease is crucial
-Understanding the side effects of both therapy Is important as some may have
neurological complications (TNFi.)
49
Treatment : Nontargeted Immune Therapy
Drug Mechanism Route Use
Glucocorticoid Multiple IV, oral, IM Acute therapy
Methotrexate Folate inhibition Oral, IV, subcutaneous Steroid sparing
Azathioprine Inhibits purine synthesis Oral Steroid sparing
Mycophenolate mofetil nhibits DNA/ribonucleic Oral Steroid sparing
acid synthesis in
leukocytes
Cyclophosphamide Alkylating agent Oral, IV Acute therapy in severe
disease
Cyclosporine T-cell inhibition Oral Short-term treatment
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Treatment: Targeted Immune therapy
Drug Mechanism Route Use
TNFi Tumor necrosis factor-! Subcutaneous except IV Rheumatoid arthritis,
blocker infliximab psoriatic arthritis
Rituximab Anti-CD20 IV Rheumatoid arthritis
Belimumab Antibody to B-cell IV,SC Systemic lupus
stimulator erythematosus
Abatacept T-cell costimulation IV,SC RA, PsA
molecule
Tocilizumab Anti IL6 IV,SC Rheumatoid arthritis,
juvenile rheumatoid
arthritis. GCA
Ustekinumab Anti IL 12/23 SC PsA
51
Anti-rheumatic drugs associated with
neurological side-effects
Drug Side Effects
Allopurinol Paraesthesia, neuropathy
Antimalarials Retinal damage, ototoxicity, psychosis, myopathy
Colchicine Peripheral neuritis, myopathy
Corticosteroids Proximal myopathy, psychosis, euphoria, depression
Cyclosporin Myopathy, myalgia, muscle weakness, leukoencephalopathy
Cytokine inhibitors Demyelinating disorders with etanercept and infliximab; seizures and drowsiness
with infliximab; drowsiness, dizziness, paraesthesia and neuralgia with
adalimumab; persistent multifocal leukoencephalopathy (PML) with nataluzimab
Dapsone Headaches, psychosis
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Anti-rheumatic drugs associated with
neurological side-effects
Drug Side Effects
Gold salts Peripheral neuritis
Leflunomide Headache, dizziness, asthaenia, paraesthesia
Methotrexate Dizziness, drowsiness, malaise, headache, mood changes, abnormal cranial
sensations
MMF Insomnia, headache, tremor
NSAIDs Headache, dizziness, depression, tinnitus, aseptic meningitis
Sulfasalazine Ataxia, aseptic meningitis, vertigo, tinnitus, insomnia, depression, hallucinations
Tacrolimus Headache, insomnia, paraesthesia, confusion, depression, dizziness, convulsions,
incoordination, encephalopathy, psychosis
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Questions?
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