Case presentation during grand rounds. Discussion about possible differential diagnosis and management

1. Grand rounds
Neurology Dept.
Daniel Vela-Duarte, MD
PGY-2. Department of Neurology
Loyola University Medical Center
March 8, 2013

2. Chief Complaint
Transient speech difficulties and confusion

3. History of Present Illness
 65 years-old left handed man presented to the ED with:
 Transient speech difficulties and confusion
 Symptoms lasted for 15 minutes.
 Right sided headaches associated with bilateral tinnitus
for three months
 Followed an episode of acute sinusitis
 Tylenol and Ibruprofen provided minor relief
 No photophobia or sonophobia
 No jaw claudication, paresthesias or visual disturbances
 ESR was 88
 Unilateral temporal artery biopsy done April 2012 for
presumed GCA:
 Negative biopsy
 Prednisone 60mg daily

4. History of Present Illness cont’d
 Headaches continued
 Decreased energy
 Increased appetite
 Mood changes
 Memory difficulties
 Hoarseness
 Persistent elevation of inflammatory markers (ESR and CRP)
 Treatment
 Prednisone 40mg BID
 Methotrexate 4 tabs weekly
 Alendronic acid 35mg weekly

5. Past Medical History
 Hypothyroidism
 Right Rotator cuff tear
 Left knee osteoarthritis
 No history of hypertension, diabetes, coronary artery
disease, hyperlipidemia, strokes, TIAs
 No history of migraines
 No history of autoimmune disease

6. Social History
 Former smoker
 Used to drink wine
 Frequent trips to Guatemala and New Mexico
Family History
 Brother had history of hairy cell leukemia
 Father with history of lymphoma

7. Physical Examination
 Vitals
 BP 128/61 | Pulse 72 | Temp 98.5 °F (36.9 °C) | Resp 18 | SpO2 98%
 General exam:
 Redness, flushed faced.
 No tenderness to palpation of Sup. Tem Art.
 Neurological exam
 Higher functions intact
 Visual acuity stable since 2008.
 Fundoscopic examination:
 Mild hemorrhagic retinopathy
 Increased cup/disc ratio
 Normal intraocular pressure
 Inability to fully abduct right eye
 Remainder of the neurologic examination was normal

8. Ancillary Data
134 96 10 14
191 15.1 269
3.3 25 1.08 97.3
 EEG normal
 CT chest/abd/pelvis:
 Low density area along the posterior wall of the right atrium,
suspicious for thrombus.
 TEE: No evidence of mass or thrombus in the right atrium
 Galium Scan: Negative for malignancy or sarcoidosis

9. MRI Brain T1 Post

10. MRI Brain T1 Post

12. Differential diagnosis ?

13. Ancillary tests.
 SPEP: Hypogammaglobulinemia
 UPEP: Unable to quantitate globulins
 Quantiferon gold test for TB: Negative
 ACE level: Normal
 ANCA, ANA, ENA, pANCA: Negative
 Cultures:
 Bacterial cultures negative
 Fungal cultures negative
 HSV negative
 HIV negative
 RPR negative
 CRP: 3.8

14. CSF Studies. 9/26/2012 9/26/2012
RBC 0 /UL 214 (H) 1360 (H)
Lumbar puncture
 Opening pressure WBC 0 - 8 /UL 2 1
 26 cm H20
 CSF Flow cytometry SEG % 45 53
 Limited by small number of
cells LYMPH % 41 30
 CSF culture
MONO % 14 17
 Negative
 Cryptococcal antigen GLUCOSE, CSF 62
 Negative
PROTEIN 114 (H)
APPEARANCE CLEAR

15. 8
CRP7 6.9
7.3
6.6
100 6
Sed rate (mm/hr) 5
5.5
4.6
90 4 3.8
88 2.5
3
2.5
2
80 1.6 1.8
1 0.7
0
70
66
60
50
40 39
29 28 28
30 28
20 22
16
10 11
2
0
4/4/2012 5/4/2012 6/4/2012 7/4/2012 8/4/2012 9/4/2012 10/4/2012 11/4/2012 12/4/2012

16. Management
 Increased intracranial pressure
 Acetazolamide 250 mg twice daily
 Prednisone 50mg daily
 Methotrexate 20mg once a week
 Pachymeningeal biopsy

17. Pachymeningeal Biopsy
 Right temporal biopsy
 Multinucleated giant cells
 Chronic inflammatory changes
 Increased kappa and lambda plasma cells
 Focal acute necrotizing areas containing neutrophils
 CD20, CD3, CD5 lymphocytes
 Negative for pankeratin, CK20 and PSA
 Focal CK7 positive staining of myofibroblasts
 Microscopically negative for microorganisms
 PAS, Gram, FITE, AFB
 Mycobacteria DNA negative.

18. Differential Diagnosis
 Idiopathic hypertrophic pachymeningitis
 IgG4-related disease
IgG4-sclerosing pachymeningitis
 ? Rheumatoid pachymeningitis
 ? Neurosarcoidosis

19. Idiopathic hypertrophic pachymeningitis
 First description in 1869 by Charcot and JoVroy
 Association with neurosyhpillis or tuberculosis
 NaVziger in 1949 described first case of idiopathic
hypertrophic cranial pachymeningitis (IHCP)
 Clinical symptoms results with compression of
anatomical structures by thickened meninges *
 Headache ~ 88%
 Cranial nerve palsy ~ 62 %
 Ataxia ~ 32 %
 Ancillary Investigations:
 ESR elevated in up to 41 % patients **
 CSF with increased proteins in up to 51% patients **
* Parney et al. Neurosurgery (1997) 41:965–971
** Kupersmith et al. Neurology (2004) 62:686–694

20. Clinical Findings in Patients with
IHCP *
* Goyal et al. Neuroradiology (1997) 39: 619–623

21. Imaging in Patients with IHCP *
* Yu Chan Lee et al. AJNR (2003) 24:119–123

22. Clinical Outcomes in Patients with IHCP *
* Kupersmith et al. Neurology (2004) ;62:686–694

23. Pachymengitis - Etiology
 Infective
 Neurosyphilis
 CNS tuberculosis : tuberculous pachymeningitis
 CNS cryptococcosis
 Chronic bacterial meningitis
 Inflammatory
 Wegener's granulomatosis
 Polyarteritis nodosa
 Rheumatoid pachymeningitis
 Neurosarcoidosis
 Haemodialysis
 Mucopolysaccharidoses
 Meningeal metastases, including CNS lymphoma
 Multiple meningiomas
 Intracranial involment with Erdheim-Chester disease
 HTLV-1 Infection

24. Leptomeningeal Enhancement
Diffuse Focal
 Leptomeningeal carcinomatosis
 Leptomeningeal
carcinomatosis  Hyperaemia : post-ictal
 Ependymoma  Infarction :
 Intracranial Haemorrhage  Leptomeningeal collaterals
(SAH)  Lymphoma
 Intracranial hypotension  Meningitis (localized)
 Meningitis  Tuberculous
 Encephalitis  Encephalitis
 Granulomatous conditions  Neurosarcoidosis
 Neurosarcoidosis  Postoperative
 Post-operative (late finding)  Vasculitis
 Post-traumatic (late finding)  Neurosyphilis

25. Leptomeningeal carcinomatosis
 Primary intracerebral malignancies
 Glioblastoma multiforme (GBM) and anaplastic astrocytoma
 Medulloblastoma
 sPNET
 Ependymoma
 Germinoma
 Choroid plexus carcinoma
 Widespread metastatic disease (more common)
 Breast cancer : most common
 Lung cancer : most common
 Melanoma
 Lymphoma and leukemia

26. IgG4-related disease
 Mass-forming disorder with frequent systemic involvement
 commonly in the pancreas, salivary glands and lacrimal glands.
 Recently defined disease entity, characterized by a high
serum IgG4 concentration and various
complications, including:
 Mikulicz’s disease
 Autoimmune pancreatitis (AIP)
 Riedel’sthyroiditis
 Sclerosing cholangitis
 Retroperitoneal fibrosis
 Tubulointerstital nephritis
 Hilar lymphadenopathy,
 Pseudotumour
 Interstitial pneumonia

27. IgG4-related
Disease

28. Five Cases of IgG4-related Disease with
Hypertrophic Pachymeningitis

29. Radiological differential diagnosis
Images provided by: Bruno Di Muzio, MD and Frank Gaillard et al.

30. Radiological differential diagnosis

31. Back to our patient ...

32.  Memmory difficulties
 Short-term memory
 Incoordination
 Left upper extremity ataxia
 Intermittent binocular horizontal diplopia
 Episodic confusion and combativeness
 EEG: slowing of the normal basic frequency
 Excess bilateral 4-7 Hz > 1-3 Hz slowing
 Depression
 Sertraline 50mg /daily
 Poor response to Medical management of depression
 ECT

33.  Tocilizumab. (IL-6 receptor blocker - Actemra)
 4mg/kg per infusion intravenously once every 4 weeks
at least 1 year.
 First dose: Feb 04
 Second dose Feb 26 with continuation of prednisone
10mg for a month
 Treatment interrupted due to increase LFTs
 Other option considered
 Rituxan
 Azathoprine (Imuran)
 Equivalent to Methrotexate
 Loger time to achieve immunosupresion

34. Response to treatment ?

36. Response to treatment ?
T1, sagital coronal, pre

37. Idiopathic hypertrophic
pachymeningitis.
 50% to 66% of patients do no respond to
therapy with steroids
 Other immunosuppressive agent to be
considered
 No clear guidelines for treatment
 No literature on infliximab and hypertrophic
pachymeningitis

38. Questions ?