Clinical Reasoning: A case of Wegener granulomatosis complicated by seizures and headaches
Curiouser and curiouser
G. Gorman, MRCP,
M. Hutchinson, MD and
N. Tubridy, MD
From the Department of Neurology, St Vincent’s University Hospital, Elm Park, Dublin, Ireland.
Address correspondence and reprint requests to Dr. Niall Tubridy, Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland n.tubridy{at}st-vincents.ie
A 19-year-old man presented with a 5-day history of vomitingand passing dark urine. He gave a 6-month history of arthralgiasand joint swelling, particularly affecting larger joints. Hehad recurrent epistaxis and recent episcleritis. He was notedto be thin and pale, with conjunctival suffusion and deformityof his nasal bridge. He was normotensive (115/60 mm Hg) andapyrexic (35.5°C). Blood parameters revealed normocyticnormochromic anemia and acute renal failure. Renal biopsy showedextensive crescent formation with segmental necrotizing inflammationand fibrin deposition of the glomeruli. cANCA was strongly positive(titer 1280; ELISA PR3+) and he was diagnosed with Wegener granulomatosis.He commenced hemodialysis, steroids, and oral cyclophosphamide,and he was discharged home.
One month later, he presented with acute onset of throbbingheadaches associated with nausea and photophobia, as well asrecurrent generalized seizures necessitating sedation and intensivecare unit admission. He was pyrexic (38°C) and hypertensive(165/95 mm Hg). Renal indices were abnormal (urea 29.1mmol/L;creatinine 755 µmol/L; potassium 5.4 mmol/L). Clinicalexamination revealed no focal neurologic deficits.
Initial noncontrast brain CT was normal. Brain MRI with gadoliniumshowed small, ill-defined, nonenhancing high signal areas measuring5–20 mm in several locations (figure, A).
(A) Axial fluid-attenuated inversion recovery (FLAIR) brain MRI showing small, ill-defined, nonenhancing high signal areas measuring 5–20 mm in several locations. (B) Axial FLAIR brain MRI showing progression in radiologic changes over a further 1-month interval. Bright confluent lesions are seen in both parieto-occipital regions. (C) Axial FLAIR brain MRI showing marked progression in radiologic changes over a further 2-month interval. Bright confluent areas are seen extensively involving the occipital and parietal lobes, and including the frontal lobes. (D) Axial FLAIR brain MRI showing full resolution of radiologic changes 6 months after commencement of IV cyclophosphamide.
Questions for consideration:
What are the possible etiologies of the changes on brain MRI?
What additional diagnostic testing would you consider at thispoint?
Full septic screen including midstream urine, chest x-ray, echocardiogram,and blood cultures were negative for active infection. MR angiographyand formal four-vessel angiography were normal and revealedno beading. Postictal EEG was normal. A lumbar puncture wasdeclined by the patient. He was commenced on oral phenytoinwith titration of his immunosuppression and discharged home.
He was readmitted 1 month later with further seizures and neutropenicsepsis. He was normotensive (120/60 mm Hg) and pyrexic (38.6°C).Neurologic examination was within normal limits. Focal areasof abnormal high signal were again noted on brain MRI and wereidentical to those previously reported (figure, A). ANCA levelswere low (1:80). Cyclophosphamide was discontinued and mycophenolatewas commenced. He was again admitted 1 month later with pyrexia(38.5°C) and diarrhea. He described brief episodes of visualblurring and central loss of vision. No evidence of centralscotoma was detected clinically. Brain MRI now showed more extensiveareas of high signal in both parieto-occipital regions (figure, B).CSF analysis showed normal protein and glucose parameters andwas acellular. Testing for JC Virus was negative. He commencedantimicrobial therapy and his immunosuppressive therapy wasincreased.
He presented again 2 months later with recurrent partial seizuresand severe throbbing headaches characteristic of migraine withaura. He described episodes of body image distortion (macrosomatognosia)with his hand "ballooning," colored visual spectra phenomenacharacterized as a "kaleidoscope" effect or a light moving diagonallyacross his visual field from left to right, and an impairedsense of passage of time (a perceived increased speech velocity).These episodes heralded the onset of headache, seizures, ora combination of both. He had intractable hiccups and episodesof vertigo, ataxia, slurred speech, and nystagmus. He was normotensive(100/60 mm Hg), pyrexic (38.6°C), and neutropenic. Serumantiepileptic drug levels were within normal limits and cANCAwas negative.
Questions for consideration:
What is the term coined for the symptoms he is describing?
Whatis the postulated anatomic basis of his symptoms?
The clinical picture at this stage was thought consistent withthe Alice in Wonderland syndrome (AIW). The features of AIWwere first reported by Coleman in 1932,1 but it was Todd2 whocoined the term in 1955 to describe the phenomena of distortedspace, time, and body image. Lewis Carroll made this phenomenonfamous in "Alice’s Adventures in Wonderland" (1865) andit has been suggested that Alice’s transformations werebased on Carroll’s own migrainous symptomatology; however,this remains controversial.3,4 AIW has been associated withmigraine, epilepsy, drug intoxication, cerebral mass lesions(particularly involving the occipital and temporoparietal lobes),psychiatric disease, viral infections, pyrexia, and vasculitis.5,6Perceptual errors of body schema and objects (kinesthetic illusionsor metamorphopsia), of people appearing smaller (micropsia)or bigger (macropsia) than normal, visual hallucinations (Lilliputianhallucinations), and acceleration or deceleration of the passageof time have been attributed to AIW. It may also be associatedwith vertigo.7 The etiology and anatomic basis are not fullyunderstood. Body image distortion, vertigo, and metamorphopsiahave been described from posterior parietal stimulation.8 Positivevisual phenomena of flashing lights and colored visual spectraequated to a kaleidoscope and negative visual phenomena (scotoma)are both established occipital lobe phenomena. In addition,headache and vomiting may have an occipital origin.9
These symptoms prompted more brain imaging. Brain MRI showeddiffuse white matter high signal abnormalities demonstratingdramatic interval progression involving the occipital, parietal,and temporal lobes in addition to bilateral cerebellar lesionswith no enhancement with gadolinium (figure, C).
The differential diagnosis of the underlying pathologic etiologywas reversible leukoencephalopathy syndrome (RPLS) vs activecerebral vasculitis.
Questions for consideration:
How would you manage a patient with Wegener granulomatosis,cerebral complications, and recurrent neutropenic sepsis?
He was commenced on a modified dose of IV cyclophosphamide withclose monitoring of bone marrow suppression. Sepsis and fluctuationsin blood pressure were aggressively treated. Seizure controlrequired quadruple antiepileptic drug therapy. Response to treatmentwas monitored by clinical status and serial C-reactive proteinand c-ANCA measurements. Six months later he is well with fullresolution of the radiologic changes (figure, D), seizures,and headaches. He remains dependent on dialysis.
We present a patient with cANCA-positive renal failure associatedwith progressive but reversible symmetric FLAIR-bright brainMRI lesions who developed features of AIW syndrome. The differentialdiagnosis initially included an infectious etiology, progressivemultifocal leukoencephalopathy, Neuro-Behçet disease,acute disseminated encephalomyelitis, multiple sclerosis, cerebralvasculitis, and RPLS. CSF analysis showed no abnormalities suggestinginflammation, infection, or malignancy. MR and catheterizationangiography revealed no evidence of vasculitis, although thiswould not completely exclude CNS vasculitis as Wegener diseasetypically affects small and medium vessels, which are not formallyassessed by these methods. Serial brain MRI with gadoliniumrevealed no enhancement, however, also favoring a diagnosisof prolonged RPLS precipitated by renal failure, sepsis, andpossible transient changes in blood pressure, not captured clinically.
RPLS is caused by subcortical white matter edema predominantlyinvolving the posterior regions of the brain, but gray matterand other regions including the brainstem and cerebellum maybe involved. Although this is usually recognized as a singleevent, recurrent episodes have been reported.10 The durationand recurrence of symptoms over a 4-month period despite changesin immunosuppression is atypical, and, despite instigation ofthese measures, there was clinical and radiologic progression.Aggressive immunosuppression was recommenced, albeit at modifieddoses, resulting in full resolution of symptoms and radiologicchanges. We propose that the amended dosage of cyclophosphamideimmunotherapy induced disease remission salvaging residual intrinsicrenal function, reducing subclinical systemic blood pressurealterations, while reducing the risk of sepsis and direct chemotoxiceffects of this therapy and thus improving cerebral autoregulation.
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