A 66-year-old, left-handed, retired physician was referred to our clinic due to a multiple-year history of behavioral changes. Approximately five years earlier, Dr. A began to have problems with social function. At the time Dr. A, a practicing surgeon, began to have trouble running his medical practice. He started to see fewer patients and his medical practice partners began to pressure him to increase his billing. Dr. A was unresponsive to their requests, and underwent a forced retirement in April 2002.
Behavioral change became evident four years prior to presentation and gradually worsened. Once described as “Mr. Fun” by his grandchildren, Dr. A. became progressively more aloof. On one occasion, he abandoned his two young grandchildren (approximately 3 years-old) suggesting that they return home on their own in the dark. When asked about this incident, Dr. A. seemed unconcerned, and stated that they were familiar with the neighborhood and should have been able to get home by themselves. Around the same time period, he began to exhibit insensitivity to others. After one of his daughters arranged an elaborate birthday celebration for him, Dr. A declined to participate without an explanation. His social withdrawal continued and he left his son’s wedding party abruptly and returned to his hotel room to sit quietly in the dark. He became more aggressive and stubborn and pushed his wife when she attempted to redirect him.
In the years preceding presentation, there were several incidents of sexually inappropriate behavior. At a wedding rehearsal dinner, his sexual advances toward three different women caused considerable embarrassment. This inappropriate behavior continued to the time of referral to our clinic. Additionally, Dr. A’s eating changed over the previous four years. His family noted that he began to eat voraciously and his manners deteriorated. He began to eat out of boxes before food was unpacked, using his hands instead of utensils. He subsisted on junk food, ice cream sundaes and pizza.
Shortly following his retirement in 2002, he began to drink heavily finishing multiple glasses of wine in rapid succession. Dr. A was sent to rehab more than once, but each time left against medical advice after a few days. On several occasions, he entered his neighbor’s garage and stole several bottles of expensive liquor. He later denied this indiscretion, but was cited by the police and instructed to stay away from the neighbor’s property. Shortly afterwards he was arrested for returning. During this time, Valium and Vicodin misuse commenced and he started taking up to 30 mg of Valium per day. When admitted to a detoxification and rehab unit, caregivers noted Dr. A. showed lack of insight as well as his difficulty with understanding the consequences of his actions. He was started on sertraline for anxiety/agitation. Dr. A was treated with Aricept by a local doctor despite the absence of evidence for an Alzheimer-type dementia for approximately two months, but this medication was discontinued in 2003 due to lack of improvement.
In December 2003, the patient was evaluated by UCSF Memory and Aging center. In March 2004, he underwent follow-up examination. In August 2004, the patient was seen by orthopedic oncologist for a chondrosarcoma and elected to enroll in comfort care with transition to hospice. In December 2004, the patient died of sepsis. An autopsy was performed.
Neurocognitive Review of Symptoms
At the time of his initial evaluation Dr. A’s family stated that his memory was “excellent” and he did not lose objects such as his wallet or keys. He read well, although he restricted his reading material to model train magazines. He had no problems with fluency, comprehension or naming. His spontaneous conversational repertoire was restricted to certain topics such as model railroads and the careers of his children. He talked to strangers for extended periods of time about these subjects apparently oblivious to the fact that they were uninterested. In the spatial domain, Dr. A had no difficulties and gave excellent directions to his daughter on how to get about in Central California. He traveled between cities by bus and successfully navigated multiple bus lines and transfers. Shortly prior to his evaluation, Dr. A’s family suggested that his decision-making and problem-solving were poor. He bought many model train components, but was unable to put the tracks or the trains together. When he attempted to help with a family move he spent most of his time shuffling boxes around without purpose. When given money he used it to buy alcohol. Alcohol use seemed unrelated to his pain. There was slightly decreased mobility secondary to hip surgery, but he was able to walk well and rode his bike well up to the time that he was institutionalized. There were no tremors or parkinsonian symptoms.
Past Medical History
Past medical history was significant for multiple osteochondromata with multiple surgeries beginning in 1966 with removal of a sarcomatous osteochondroma from the left scapula. His bone tumors required surgery nearly every five years including left shoulder surgery for removal of a left humerus/axilla osteochondroma (2002) and right hip surgery (1988). He used alcohol, benzodiazepines, and opioids. He had well-controlled hypertension and had a remote history of partial thyroidectomy and appendectomy. Medications at the time of the first evaluation included: quetiapine 25 mg b.i.d. for behavior control; lisinopril 20 mg b.i.d.; atenolol 25 mg b.i.d.; hydrochlorothiazide 25 mg q.d.; (all for hypertension) and sertraline 100 mg q.d. for treatment of mood.
Family history was significant for bone tumors in multiple members of the family (). The patient’s father carried a diagnosis of myasthenia gravis and died at the age of 88 of cardiac failure and pneumonia. His mother is alive, independent and well at age 93. He has two younger brothers and one younger sister with no known neurological history, although his younger sister took citalopram following some difficult life events. His two daughters and one son are neurologically well. He has one grandson with Beckwith-Wiedemann syndrome.
Family history of multiple osteochondromas.
Basic neurological examination included normal cranial nerves and sensation. Strength examination was somewhat limited due to the patient’s multiple orthopedic issues. Some proximal weakness was noted, particularly of the deltoids and the hip flexors and neck flexor and extensors, which had approximately 4/5 strength. The remainder of his strength exam, including distal strength, was 5 and symmetric, although he had to be encouraged to give full effort. He was unable to supinate his left arm completely secondary to his shoulder problems, but he did not have a pronator drift. His finger and foot taps were rapid, rhythmic, and normal amplitude. Tone was normal in the upper and lower extremities. His reflexes were 2+ at biceps, 2+ at patellae, 2+ at Achilles. His Babinski responses were never tested as he consistently declined to remove his shoes for the examination. His gait was notable for a slightly wide base, with moderate bowing of the legs. He held his left shoulder lower than his right but toe and heel walks were normal. He stumbled with tandem walk. He did not have a Romberg sign, and maintained his stance with retropulsion.
Nerve conduction studies were normal and EMG studies revealed: 1) an increased incidence of short-duration, low amplitude motor unit action potentials (MUAPs), 2) rapid recruitment of MUAPs in the left extensor digitorum communis, iliopsoas, and biceps brachii muscles, and 2) decrease peak-to-peaks amplitude of the interference pattern of the left biceps brachiii. These abnormal electrodiagnostic studies provide evidence for a proximal myopathy not associated with fibrillation potentials.
Patient had blood drawn in February 2003. The results were unremarkable, with normal CBC, normal Chem 7, normal liver function test, thyroid function test, a CK 72, a CK MB of 184, a Folate of 118.5, B12 of 569, and a negative RPR.
Neuropathological examinations were performed with a focus upon FTD-related pathology (Mirra, 1991
; Lowe, 1998
; Trojanowski, 2001
; Munoz, 2003
). At autopsy, the brain weighed 1360 grams. Gross inspection revealed asymmetric cerebral cortical atrophy of the frontal lobes – most profoundly atrophic on the ventral aspects of the right side. Additionally, the temporal lobes showed atrophy – more so, anteriorly and superiorly. Hydrocephalus ex vacuo was noted especially at the lateral ventricles. A small 2mm vascular lesion in the basis pontis was observed.
Traditional histopathology staining with hematoxylin and eosin, modified Bielschowsky silver impregnation, and immunostaining with antibodies to β-amyloid revealed multiple foci of neuronal degeneration and loss. Within the frontal lobe, sparse primitive and diffuse neuritic plaques were found. Neurofibrillary tangles were not found in abundance (). The cingulate gyrus revealed conspicuous ballooned achromatic neurons and granulovacuolar degeneration (). Hippocampal histopathology revealed changes in both the pyramidal layer as well as the dentate gyrus. In the pyramidal layer, silver-impregnated inclusions, Pick’s bodies, were evident. As well, tau immunoreactive inclusions were identified. The dentate gyrus showed numerous Pick body inclusion and neuritic plaques (). Both the subiculum and hippocampus revealed immunoreactive astrocytes and “astrocytic plaques”. In addition, mild focal spongiosis was identified in both the frontal and temporal lobes.
Multiple foci of neuronal degeneration are shown in H & E staining above (shown by blue arrows). Neuritic plaques in the frontal lobe shown below (middle) with rare NF tangles (right).
Cingulate gyrus. Balloned neurons with granulovacuolar degeneration.
Hippocampus. Pyramidal layer reveals Pick Body inclusions. Dentate Gyrus demonstrates neuritic plaques.
In summary, neuropathological investigations identified cerebral cortical atrophy in an asymmetric pattern, most convincingly in the frontal and temporal lobes. Numerous neurons elaborated tau protein, especially within the hippocampus and temporal lobe. Additionally, scattered tau positive astrocytes were found cerebral cortex and subcortical white matter. These patterns are most consistent with a diagnosis of Pick’s disease.
In light of the patient’s proximal muscle weakness, histopathology was performed on his biceps and quadriceps muscles. These investigations revealed rare non-specific myopathic changes. A single muscle fiber showed myophagocytosis, but no inflammatory infiltrates are seen. No evidence of an inflammatory or necrotizing myopathy was present.
Finally, dissection of the anterolateral chest wall revealed the previous diagnosed osteochondroma. Histopathology identified the mass as a grade II chondrosarcoma.
As shown in the family tree (), the patient was a member of family greatly affected by multiple osteochondromas. The possibility of genetic testing for hereditary multiple exostosis, also called multiple osteochondromatosis, was pursued. Individuals with HME often develop benign cartilage-capped tumor (exostoses) at the ends of the long bones or the surface of flat bones (Zak, 2002
). HME usually presents early in life with 80% of patients diagnosed before the age of 10. Bony deformity, bowing of the long bones, limited range of motion, and premature osteoartrosis may be associated with HME. A commonly benign condition, its prevalence is estimated at 1 in 50,000. A rare but severe risk in patients with multiple exostoses is the development of malignant chondrosarcoma, which occurs in 1-2% of patients.
There is genetic heterogeneity in HME, and at least two loci are known to be associated with this condition, called Ext1, which maps to 8q24.1, and Ext2, which maps to 11p12-p11. HME is an autosomal dominant trait regardless of the gene involved. Mutations are found in approximately 80% of individuals, with 70% showing mutations in Ext1.
The patient as well as a sister were both tested and were found to be heterozygous for a deletion of four nucleotides in exon 2 of the EXT2 gene (c416_19delACAG). This mutation causes a frameshift and premature protein truncation 129 codons downstream. This mutation has not been reported previously in HME. Although the genetic correlation exists between mutations in EXT1 and EXT2 and HME, the mechanism by which alterations in heparan sulfate synthesis leads to ectopic bone growth is unknown.