Clinical Pathological Conference multifocal numbness and weakness - - PowerPoint PPT Presentation

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Clinical Pathological Conference

Cheryl Jay, MD, Professor of Neurology, UCSF Director of Neurology Clinics, San Francisco General Hospital Andrew W. Bollen, MD, DVM Professor of Pathology, UCSF Mark Burish MD, PhD Neurology Resident, UCSF

• 55yo male with a history of cryptogenic

strokes at age 45

• Chief complaint: left leg swelling, progressive

multifocal numbness and weakness

• Jan 2012: progressive left leg swelling and erythema starting

in the calf and extending to the foot, initially intermittent then became constant and slightly painful

• March 2012: admitted to an outside hospital for leg swelling

and pain.

– Lower extremity Doppler U/S negative – Noted to have leukopenia with ANC of 1000 – Muscle biopsy with “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes” – Treated for possible vasculitis with prednisone, mild improvement in symptoms

• May 15 2012: Feeling of being off balance, needing to hold
• n to objects while walking progressing over 1 week to left

foot drop

• May 29 2012: Numbness on right medial palm and ring and

pinky fingers

• June 5 2012: softening of his voice
• June 8 2012: Admitted to UCSF
• Jan 2012: progressive left leg swelling and erythema starting

in the calf and extending to the foot, initially intermittent then became constant and slightly painful

• March 2012: admitted to an outside hospital for leg swelling

and pain.

– Lower extremity Doppler U/S negative – Noted to have leukopenia with ANC of 1000 – Muscle biopsy with “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes” – Treated for possible vasculitis with prednisone, mild improvement in symptoms

• May 15 2012: Feeling of being off balance, needing to hold
• n to objects while walking progressing over 1 week to left

foot drop

• May 29 2012: Numbness on right medial palm and ring and

pinky fingers

• June 5 2012: softening of his voice
• June 8 2012: Admitted to UCSF

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• Jan 2012: progressive left leg swelling and erythema starting

in the calf and extending to the foot, initially intermittent then became constant and slightly painful

• March 2012: admitted to an outside hospital for leg swelling

and pain.

– Lower extremity Doppler U/S negative – Noted to have leukopenia with ANC of 1000 – Muscle biopsy with “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes” – Treated for possible vasculitis with prednisone, mild improvement in symptoms

• May 15 2012: Feeling of being off balance, needing to hold
• n to objects while walking progressing over 1 week to left

foot drop

• May 29 2012: Numbness on right medial palm and ring and

pinky fingers

• June 5 2012: softening of his voice
• June 8 2012: Admitted to UCSF
• Jan 2012: progressive left leg swelling and erythema starting

in the calf and extending to the foot, initially intermittent then became constant and slightly painful

• March 2012: admitted to an outside hospital for leg swelling

and pain.

– Lower extremity Doppler U/S negative – Noted to have leukopenia with ANC of 1000 – Muscle biopsy with “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes” – Treated for possible vasculitis with prednisone, mild improvement in symptoms

• May 15 2012: Feeling of being off balance, needing to hold
• n to objects while walking progressing over 1 week to left

foot drop

• May 29 2012: Numbness on right medial palm and ring and

pinky fingers

• June 5 2012: softening of his voice
• June 8 2012: Admitted to UCSF
• Jan 2012: progressive left leg swelling and erythema starting

in the calf and extending to the foot, initially intermittent then became constant and slightly painful

• March 2012: admitted to an outside hospital for leg swelling

and pain.

– Lower extremity Doppler U/S negative – Noted to have leukopenia with ANC of 1000 – Muscle biopsy with “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes” – Treated for possible vasculitis with prednisone, mild improvement in symptoms

• May 15 2012: Feeling of being off balance, needing to hold
• n to objects while walking progressing over 1 week to left

foot drop

• May 29 2012: Numbness on right medial palm and ring and

pinky fingers

• June 5 2012: softening of his voice
• June 8 2012: Admitted to UCSF
• Past medical history: cryptogenic strokes at age 45 (frontal and cerebellar)

– Normal transthoracic and transesophageal echocardiograms – Holter negative – Normal cerebral angiogram – CSF: 7 WBC (94%L), 8 RBC, glucose 57, and total protein 81, normal IgG index

• Allergies: None
• Medications: Ibuprofen prn
• Family history

– Daughter with AML at age 16 – Maternal grandmother with first stroke at age 45, additional strokes in the following years, died in 50s – Father with prostate cancer – No family history of clotting disorders (DVT, miscarriage, etc)

• Social history

– Never smoker, occasional EtOH, no illicits – Operates motorcycle shop. Prior to this illness physically active, running marathons, gardening – Travel: Originally born in the San Francisco Bay Area. Has traveled extensively in US. Last trip

• utside US in 2006 (Spain), has also been to Italy, Japan, China and New Zealand but last was

to Spain in 2006. – Exposures: Has 2 healthy adult dogs. Pricked by rose thorns in November 2011. Swims in fresh water lakes but not since last summer. Does not eat raw meat or unpasteurized cheese. No known TB contacts, has never been incarcerated or spent time in homeless shelters.

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May 6, 2003 June 5, 2003 May 6, 2003 June 5, 2003

• Past medical history: cryptogenic strokes at age 45 (frontal and cerebellar)

– Normal transthoracic and transesophageal echocardiograms – Holter negative – Normal cerebral angiogram – CSF: 7 WBC (94%L), 8 RBC, glucose 57, and total protein 81, normal IgG index

• Allergies: None
• Medications: Ibuprofen prn
• Family history

– Daughter with AML at age 16 – Maternal grandmother with first stroke at age 45, additional strokes in the following years, died in 50s – Father with prostate cancer – No family history of clotting disorders (DVT, miscarriage, etc)

• Social history

– Never smoker, occasional EtOH, no illicits – Operates motorcycle shop. Prior to this illness physically active, running marathons, gardening – Travel: Originally born in the San Francisco Bay Area. Has traveled extensively in US. Last trip

• utside US in 2006 (Spain), has also been to Italy, Japan, China and New Zealand but last was

to Spain in 2006. – Exposures: Has 2 adult dogs, both healthy. Pricked by rose thorns at some point in November

• 2011. Swims in fresh water lakes but not since last summer. Does not eat raw meat or

unpasteurized cheese. No known TB contacts, has never been incarcerated or spent time in homeless shelters.

• Initial general exam

– HEENT: normal. Neck supple – CV: normal – Pulm: normal – Abdominal: normal – Skin: Left lower extremity below knee with decreased hair, erythematous – Musculoskeletal: left calf with 1+ nonpitting edema, tender to palpation

• Initial neurologic exam

– MS: AOx3, 6 digits forwards, intact naming and repetition, 0/3 recall at 5 minutes – CN: Visual fields full, PERRL, EOMI, facial sensation intact. R lower facial

• droop. Palate midline. Shoulder shrug full. Tongue midline

– Str: No pronator drift, slow right finger taps. Unable to tap with left foot

• Bilateral upper extremities and right lower extremity: full strength
• Left lower extremity: Ililopsoas 4+, Quad 4, Hams 4, AnkleFlex 1, AnkleExt 1,

AnkleEvert 1, Ankle Inv 1, Toe flex 1, Toe ext 1

– Sens: Decreased sensation to pin in the hand (right 5th digit), otherwise intact to light touch, pin, temperature, vibration, and proprioception – Reflexes (R/L): 2+ on right, 3+ on left throughout. Plantar flexor on right, extensor on left – Coord: Normal finger-to-nose bilaterally – Gait: Steppage gait on left. Romberg positive.

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FLAIR FLAIR T1 POST-GAD T1 POST-GAD

• Vascular work-up

– Normal intracranial MRA and MRV – Normal Transthoracic and Transesophageal Echos with no shunt – Transcranial dopplers: no emboli detected of the B/L MCAs over 30 minutes

• EEG (20 hours)

– diffuse slowing and disorganization, worse over the right hemisphere – No epileptiform activity or electrographic seizures

• EMG

– Normal Motor Nerve Conduction Studies (R ulnar, R median nerves) – Normal Sensory Nerve Conduction Studies (R ulnar, R median, B/L superficial peroneal, B/L sural nerves) – Normal EMG of RUE

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MRI leg

• Enhancement

– left soleus – Left tibialis posterior (post. aspect) – Left gastroc. (medial&lateral heads)

• Atrophy and fatty infiltration

– left soleus (medial aspect)

• Fluid collection

– fascial plane b/w soleus & gastroc.

• Initial biopsy March 2012

– “focal mild endomysial inflammation in 1 muscle fascicle with histiocytes”

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Progression of disease

– Hospital day 2: New onset seizure

• head twitching to the right for 10-15 seconds followed by tonic clonic

movements with loss of consciousness

• started on Dilantin

– Hospital days 7-9: Fever and rash

• Fever to 39.9
• Maculopapular rash on back, derm biopsy consistent with drug rash
• Dilantin changed to keppra
• Exam unchanged

– Hospital day 11

• Repeat MRI shows enlarging lesions

– Hospital day 13

• Empiric ceftriaxone started (T. Whipplei)

– Hospital day 18: exam worsens

• Worsening word-finding difficulty and LUE weakness.
• New RLE weakness 1/5 proximally and distally
• Empiric Doxycycline started (C. Psittaci, Brucella)
• IV solumedrol started (1g daily x5 days)

HD4 HD4 HD16 HD16

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Faculty Discussants

• Dr. Cheryl Jay, MD

Professor of Neurology, UCSF Director of Neurology Clinics, San Francisco General Hospital

• Dr. Andrew W. Bollen, MD, DVM

Professor of Pathology, UCSF

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Hemophagocytic Lymphohistiocytosis (HLH)

Source: Jordan et al, 2011

Hemophagocytic Lymphohistiocytosis (HLH)

Source: Jordan et al, 2011

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Causes of HLH

Primary HLH

• PRF1 gene / Perforin
• UNC13D gene / Munc13-4
• STZ11 gene / Syntaxin 11
• STXBP2 gene / Munc18-2
• Other genetic diseases associated

with HLH

– X-linked lymphoproliferative syndrome (SH2D1A or BIRC4) – Chediak-Higashi syndrome (LYST) – Wiskott-Aldrich syndrome (WAS) – Hermansky-Pudlak type 2 (AP3B1) – Griscelli syndrome type 2 (Rab27a) – DiGeorge syndr (22q11.2 deletion) – Severe combined immunodeficiency (multiple genes identified)

Secondary HLH

• Infection

– EBV – CMV, Parvovirus B19, TB, salmonella, leishmaniasis

• Malignancy

– T and NK cell leukemia/lymphoma

• Immunosuppression

– HIV/AIDS – Post-transplant

• Autoimmune diseases

– Lupus – Rheumatoid arthritis – Sjogren’s – Systemic scleroderma – Polymyositis/Dermatomyositis – Still’s disease – Sarcoid Fisman 2000, Fukaya et al., 2008, Henter et al., 2007, Johnson et al., 2011, Jordan et al., 2007 Source: Jordan et al., 2007

Pathophysiology of HLH

Diagnosis

• f HLH
• Genetic testing
• Flow cytometry

– Perforin – Granzyme B

• NKC and Cytotoxic T-

cell assays

• HLH activity

biomarkers

– Soluble IL-2R levels – Soluble CD163 levels

• Bone marrow

biopsies are unreliable (Ho et al, 2014)

Jordan et al., 2007; Johnson et al., 2011

Treatment of HLH

Source: Henter et al., 2007

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References

• Cea1.com (human body picture)
• Chiapparini L et al., 2011. Neurol Sci 32:473-477.
• Fisman DN, 2000. Hemophagocytic syndromes and infection. Emerging Infectious Diseases

6(6):601-608

• Fukaya S et al., 2008. Clinical features of haemophagocytic syndrome in patients with systemic

autoimmune diseases: analysis of 30 cases. Rheumatology 17:1686-1691.

• Henter J-I et al., 2007. HLH-2004: Diagnostic and Therapeutic Guidelines for Hemophagocytic
• Lymphohistiocytosis. Pediatr Blood Cancer 48:124-131.
• Ho et al., 2014. Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor

correlation with disease probability. Am J Clin Pathol 141(1):62-71

• Johnson TS et al., 2011. Contemporary diagnostic methods for hemophagocytic lymphohistiocytic
• disorders. J Immunol Methods 364:1-13.
• Jordan MB et al., 2011How I treat hemophagocytic lymphohistiocytosis. Blood 118:4041-4052.
• Park et al., 2012. Clinical features of adult patients with secondary hemophagocytic

lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors. Ann Hematol 91:897-904.

• Course after discharge

– Remained on solumedrol – Readmitted for seizure 2 months later, keppra dose increased – Received repeat solumedrol dose and PLEX with no response – Brain MRI unchanged at months 2, 3, & 4 after discharge – Progressive functional decline with aspiration pneumonias – Deceased 11 months after admission

Source: Park et al., 2012