History of Present Illness
Patient is a 14-year-old female.  It is difficult to say exactly when in the spring of 2007 she began to weaken. The clearest early sign of weakening was her inability in May 2007 to jump over a mini-hurdle that virtually all other members of her eighth-grade gym class could quite easily jump.  As a result of this hurdle accident, Patient sustained a painful injury to her left knee that caused her to limp for several days.  This injury occurred roughly 2 months after she received her third vaccination of Gardasil (March, 2007) and roughly 1 month before her first menstrual period (June, 2007).  She received no other vaccinations at the time of her Gardasil vaccination.

The lot numbers for the three Gardasil vaccinations are:
Sept 1, 2006 – 0688F
Nov 1, 2006 – 0637F
March 1, 2007 – 0187U

After the hurdle-jumping injury, Patient's symptoms improved for about a month, and she appeared to be back to her normal state, without pain or weakness. However, between July and August 2007, she developed a strange gait resulting in proximal weakness of her left hip and leg.  She went to Physical Therapy at Oakland Children's Hospital.  Nevertheless, her left leg continued to weaken, followed by weakness in her right arm.  She started using crutches in the fall of 2007, a few months into her illness.  Not long thereafter, both legs became so weak that she had to use a walker, and she had so much difficulty using the walker by the end of 2007 that she began using an electric scooter.  By March, 2008 she was wheelchair-bound.
She has very minimal use of her left arm, but she is unable to walk, write, hold herself up, or even eat by herself. This deterioration has unfolded since July, 2007. She has some minor difficulties with her speech and swallowing, and respiratory tests show she is losing muscle strength in her diaphragm as well. Her latest FVC was about 20%, and she is using BiPaP part of the day and as much as she can while sleeping.  She has never had any upper motor neuron signs.
In addition, Patient had two seizures in March, 2008, both of which occurred during her sleep, a few hours after medication (Solumedrol with one and IVIG with the other). She had a third seizure in April, 2008 during a sleep test, with no medication involved.

Patient’s past medical history is notable for a rare skin disease that she developed at 10 years of age, known as pityriasis lichenoides, which is felt to be autoimmune in nature.

Developmental history reveals that as an infant, she had postural hypotonia.  She also had delayed walking, and she began walking somewhere between 16 and 18 months.  She also had a speech delay, requiring an IEP, and she had an academic IEP for a learning disability.  She was diagnosed with attention deficit disorder, but has not been on any medications for this.  Early in life, she required occupational therapy to help her with her midline issues.  Later, occupational therapy was needed for her writing.  Formal neuropsychiatric evaluation as a child concluded that she had a nonverbal learning disability.  Her skills were weaker in math than in reading.  Another Neuropsychiatric evaluation revealed that she has weakness in attention, auditory sequencing, and auditory discrimination.  Patient (and her mother) has also suffered from migraine headaches for several years.

Family history is notable for a maternal cousin has with autism and seizures born to a maternal aunt with Raynaud syndrome.  Another maternal cousin has a pain syndrome/reflex sympathetic dystrophy of the right leg which developed at age 15.  The maternal grandmother had progressive supranuclear palsy, confirmed at autopsy.  The mother reports that she is healthy, but she does have dry eyes.  There are no family members with Sjogren syndrome, lupus, arthritis, or other known autoimmune diseases.  There are no neurologic diseases in the family.  On the father's side, there are family members with liver cirrhosis, heart attacks, and senility which developed in their 80s.

Patient has been seen by neurologists and rheumatologists in 4 medical centers: Dr. ******** at UCSF, November 2007-January 2008; most recently, March 2008 in rheumatology; Dr. ********** (Neurology) at Children's Hospital of Pennsylvania, December 2007; Drs. **********, **********, ********** (Neurology) and ********** (Rheumatology) at Stanford Children's Hospital, February 2008 - present; and Dr. ********** (Neurology) at California Pacific Medical Center. 

Patient's initial diagnosis was demyelinating polyneuropathy, based on two EMG studies done in 2007 at UCSF and CHOP, each of which showed possible signs of demyelination (prolonged dispersed F wave latencies; slightly prolonged distal motor latencies, but no definite evidence of conduction block).  The EMG also showed some active and chronic denervation.  She was also found to have a slightly elevated spinal fluid protein, with no cells.  One MRI of her lumbosacral spine showed possible enhancement of some of the nerve roots.  At CHOP, Dr. ********** diagnosed her with multifocal motor neuropathy (MMN), and Patient received two courses of IVIG (one at CHOP and one at UCSF), and as well as oral prednisone (60 mg per day).  She then went to Stanford, where Dr. ********** continued her immunomodulation therapy with two courses of high-dose Solumedrol and two courses of plasmapheresis.  She did not respond to any of these medications, and might have even worsened more quickly on the high-dose Solumedrol.  Dr. ********** then started her on IV Cytoxan, and she completed 3 of 6 planned courses of IV Cytoxan before it was decided to discontinue that treatment.  She continues to deteriorate.  Patient has suffered a recurrence of at least one skin lesion while under immunosuppressive therapy at Stanford (but pre-Cytoxan).

Dr. ********** has also considered some form of motor neuron disease. Her DNA tests for spinal muscular atrophy have shown no deletions, but mutational analysis was not done.  Dr. ********** referred Patient to Dr. ********** at CPMC.  After another EMG, Dr. ********** found no evidence of demyelination, and the EMG showed active and chronic denervation throughout.  He diagnosed Patient with Progressive Muscular Atrophy.  He started her on a combination of lithium and Riluzol.  At one point she was noted to have lithium toxicity, and the dose was lowered.  She has recently started IGF1 subcutaneously, and ceftriaxone intravenously.  Because of problems with nausea and vomiting, however, we have had to hold some of these medications for a while, to see if we can get her nausea and vomiting under better control. 
After Patient’s flurry of seizures, the possibility of a metabolic disorder was considered, especially a mitochondrial disorder.  Blood tests have shown no evidence of a known mitochondrial mutation.  However, her urine organic acids have shown moderate elevations of lactic acid, with minimal elevations of fumaric, 2-hydroxyglutaric and 2-ketoglutaric acids, suggesting the possibility of mitochondrial dysfunction (primary vs. secondary). Patient is currently taking a mitochondrial cocktail, since mid-April, 2008, in case the mitochondrial hypothesis is correct.  Muscle biopsy was sent for mitochondrial enzyme analysis, and was normal, with no abnormalities.

Muscle/Nerve biopsy: Muscle/Nerve biopsy (after high-dose steroids) showed the following:  Skeletal muscle, right quadriceps, biopsy: Neuropathic process with denervation atrophy.  Peripheral nerve, right sural, biopsy: Mild axonal neuropathy with wallerian degeneration and regeneration. Nerve: Occasional fibers with watery dissolution of cytoplasm indicative of Wallerian degeneration are seen. Occasional regenerative clusters are identified.  No significant loss of large myeinated axons is detected.  No vasculitis or endoneurial inflammation is identified.  Muscle: Histochemistry. H&E stained slides show skeletal muscle in cross-sectional array.  Marked variation in fiber size is seen.  Group fiber atrophy with compensatory hypertrophy of adjacent fibers is identified.  Frequent nuclear bag fibers indicative of severe fiber atrophy are present.  No regenerative, degenerative, or split fibers are seen.  Rare large ring fibers are identified.  Fibers with centrally positioned nuclei are not increased in number.  There is no evidence of inflammation or vasculitis.  The trichrome stained sections reveal no increase in endomysial connective tissue, ragged red fibers, or abnormal cytologic inclusions.  ATPase preparations at pH 9.4, 4.6., and 4.3 demonstrate type II fiber hypertrophy without fiber type grouping, fiber type predominance, or selective atrophy. The NADH and estrerase preparations stain frequent acutely angulated fibers overly dark.  No moth-eaten fibers, target fibers, or fibers with increased accumulations of mitochondria are seen on the NADH preparation.  Myophosphorylase activity is present.  The combined succinic dehyrogenase and cytochrome oxidase (COX) preparation shows no COX negative fibers.

Other Laboratory studies/diagnostic tests.
Other laboratory studies of interest have included a slightly positive ANA (1:40, speckled pattern), a slightly elevated von Willebrand antigen, and moderately positive IgG anti-cardiolipin antibodies (with IgM normal).  Testing for HNPP, CMT, anti-GM1, anti-GD1b, and SMA at Athena have been normal.  DNA testing for SMA was negative, but Patient only has one copy of the SMN2 gene. DNA testing for an SOD mutation associated with ALS was also negative. Other ALS associated gene testing is pending. Lysosomal panel done on leukocytes have been negative for multiple lysosomal disorders including GM1 gangliosidosis, galactoside galactosidase, alpha and beta-mannosidosis, fucosidosis, tay sachs and its variants, arylsufatase A, metachromatic leukodystrophy, krabbe disease, Fabry disease, mucolipidoses II and III.

Medications as of Aug 9, 2008
(1) 3 mg of prednisone (left over from days of steroid treatment for hypothesized autoimmmune disease process);
(2) sodium phenylbutyrate, in IV form, dosage of 2 grans, accompanied by Lipostabil to facilitate absorption;
(3) hydroxyurea (just started--at introductory dosage of 500 mg).
(4) catapres –TTS -2 patch for high blood pressure
(5) Isradipine 2.5 mg capsule as needed if systolic blood pressure greater than 145